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Sample records for catalepsy

  1. Catalepsy tests: what do they tell us?

    Science.gov (United States)

    Weitzenhoffer, A M

    1996-10-01

    In a survey of 200 clinicians regarding their use of catalepsy tests, three fourths of the respondents indicated that they used these tests. In light of this response, and considering both the scientific importance of being able to identify the presence of hypnosis and the fact that catalepsy may account for up to eight of the other indications of hypnosis in use, it is relevant to inquire into the reliability and validity of catalepsy tests. It was found that of the three tests of catalepsy currently in use, only one has the potential for being a test of hypnosis proper and can also justifiably be said to be "of catalepsy." This one test, however, has many serious weaknesses that need to be eliminated if it is to be truly useful.

  2. Dopaminergic mechanisms underlying catalepsy, fear and anxiety: do they interact?

    Science.gov (United States)

    Colombo, Ana Caroline; de Oliveira, Amanda Ribeiro; Reimer, Adriano Edgar; Brandão, Marcus Lira

    2013-11-15

    Haloperidol is a dopamine D2 receptor antagonist that induces catalepsy when systemically administered to rodents. The haloperidol-induced catalepsy is a state of akinesia and rigidity very similar to that seen in Parkinson's disease. There exists great interest in knowing whether or not some degree of emotionality underlies catalepsy. If so, what kind of emotional distress would permeate such motor disturbance? This study is an attempt to shed some light on this issue through an analysis of ultrasound vocalizations (USVs) of 22 kHz, open-field test, and contextual conditioned fear in rats with some degree of catalepsy induced by haloperidol. Systemic administration of haloperidol caused catalepsy and decreased exploratory activity in the open-field. There was no difference in the emission of USVs between groups during the catalepsy or the exploratory behavior in the open-field test. In the contextual conditioned fear, when administered before training session, haloperidol did not change the emission of USVs or the freezing response. When administered before testing session, haloperidol enhanced the freezing response and decreased the emission of USVs on the test day. These findings suggest that the involvement of dopaminergic mechanisms in threatening situations depends on the nature of the aversive stimulus. Activation of D2 receptors occurs in the setting up of adaptive responses to conditioned fear stimuli so that these mechanisms seem to be important for the emission of 22 kHz USVs during the testing phase of the contextual conditioned fear, but not during the training session or the open-field test (unconditioned fear stimuli). Catalepsy, on the other hand, is the result of the blockage of D2 receptors in neural circuits associated to motor behavior that appears to be dissociated from those directly linked to dopamine-mediated neural mechanisms associated to fear.

  3. Effects of antidepressants and antihistaminics on catalepsy induced by intracerebroventricular administration of histamine in mice.

    Science.gov (United States)

    Onodera, K

    1991-01-01

    The intracerebroventricular (icv) administration of histamine but not N-telemethylhistamine and 1-methyl-4-imidazole acetic acid induced catalepsy in mice. Histamine H1-receptor blockers such as cyproheptadine, mepyramine and diphenhydramine reduced histamine-induced catalepsy. However, astemizole which is known to be without central effects, did not reduce histamine-induced catalepsy. The icv pretreatment with histamine H2-receptor blockers, such as metiamide and cimetidine, also had no effect. Moreover, various antidepressants, both imipramine- and atypical-type drugs antagonized histamine-induced catalepsy to various degrees in this experiment. Thus, the induction of catalepsy by icv administration of histamine was mediated through histamine H1-receptors, and suggested that antidepressants reduced histamine-induced catalepsy via this mechanism. Histamine-induced catalepsy is a possible new animal model of depression which can also be used for evaluation of atypical antidepressants.

  4. Post-trial dopaminergic modulation of conditioned catalepsy: A single apomorphine induced increase/decrease in dopaminergic activation immediately following a conditioned catalepsy response can reverse/enhance a haloperidol conditioned and sensitized catalepsy response.

    Science.gov (United States)

    Oliveira, Lucas Rangel; Dias, Flávia Regina Cruz; Santos, Breno Garone; Silva, Jade Leal Loureiro; Carey, Robert J; Carrera, Marinete Pinheiro

    2016-09-15

    Haloperidol can induce catalepsy and this drug effect can be conditioned as well as sensitized to contextual cues. We used a paired/unpaired Pavlovian conditioning protocol to establish haloperidol catalepsy conditioned and sensitized responses. Groups of rats were given 10 daily catalepsy tests following administration of vehicle (n=24) or haloperidol (1.0mg/kg) either paired (n=18) or unpaired (n=18) to testing. Subsequently, testing for conditioning was conducted and conditioning and sensitization of catalepsy were observed selectively in the paired group. Immediately following a second test for catalepsy conditioning, the groups were subdivided into 4 vehicle groups, 3 unpaired haloperidol groups and 3 paired haloperidol groups and were given one of three post-trial treatments (vehicle, 0.05mg/kg or 2.0mg/kg apomorphine). One day later the conditioned catalepsy test 3 was carried out and on the next day, a haloperidol challenge test was performed. The post-trial apomorphine treatments had major effects on the paired groups upon both conditioning and the haloperidol challenge test. The low dose apomorphine post-trial treatment enhanced both the conditioned and the haloperidol sensitized catalepsy responses. The high dose apomorphine post-trial treatment eliminated conditioned catalepsy and eliminated the initial acute catalepsy response to haloperidol that was induced in the vehicle control groups. These results demonstrate the sensitivity of conditioned drug cues to modification by increases/decreases in activity of the dopamine system in the immediate post-trial interval after a conditioning trial. This demonstration that post-trial dopaminergic drug treatments can modify conditioned drug behavior has broad implications for conditioned drug effects.

  5. Histamine Potentiates Cyclosomatostatin-Induced Catalepsy in Old Rats

    Directory of Open Access Journals (Sweden)

    Ionov

    2015-05-01

    Full Text Available Background The decreased level of somatostatin and increased level of histamine are detected in the Parkinsonian brain. In old Wistar rats, the brain somatostatin deficiency can initiate catalepsy that suggests the pathogenic significance of this abnormality in Parkinson’s disease (PD. The ability of histamine to affect the somatostatin deficiency action is not studied. Objectives The current study aimed to examine if histamine alters the cataleptogenic activity of the brain somatostatin deficiency in Wistar rats. Materials and Methods The animals used in the study were 100 - 110 and 736 - 767 days old. Catalepsy was evaluated by the bar test. The inhibition of the brain somatostatin activity was simulated by I.C.V. administration of cyclosomatostatin (cycloSOM, a somatostatin receptor antagonist. Results CycloSOM (0.2, 1.0, and 5.0 µg and histamine (1.0 and 10.0 µg alone were ineffective in both young and old animals. In combination, however, cycloSOM and histamine initiated cataleptic response in old rats. Effect of the combination was inhibited by H1 and H2 but not H3 antagonists. Conclusions CycloSOM and histamine synergistically exert catalepsy in old rats. In light of these data, the combination of the decreased brain level of somatostatin and increased brain level of histamine may be of pathogenic relevance for extrapyramidal signs in PD.

  6. Effect of Tribulus terrestris on haloperidol-induced catalepsy in mice

    OpenAIRE

    2014-01-01

    Haloperidol, an antipsychotic drug, leads to the development of a behavioural state called catalepsy, in which the animal is not able to correct an externally imposed posture. In the present study we have attempted to evaluate the anticataleptic effect of Tribulus terrestris on haloperidol-induced catalepsy in albino mice. Mice were allocated to four groups, each group containing six animals. Both, the test drug, Tribulus terrestris and the standard drug trihexyphenidyl were uniformly suspend...

  7. Pharmacological characteristics of catalepsy induced by intracerebroventricular administration of histamine in mice: the importance of muscarinic step in central cholinergic neurons.

    Science.gov (United States)

    Onodera, K; Shinoda, H

    1991-05-01

    Histamine-induced catalepsy was antagonized potently by scopolamine, an antimuscarinic drug, and partially blocked by sparteine. Neither methylatropine nor antinicotinic drugs could reverse histamine-induced catalepsy. These results indicate the greater importance of muscarinic receptors rather than their nicotinic counterparts in histamine-induced catalepsy. Various antiparkinson drugs, i.e. biperiden and trihexyphenidyl, which have antimuscarinic activity or dopamine agonists, i.e. L-dopa, amantadine and bromocriptine, could antagonize the histamine-induced catalepsy to various degrees. Thus, catalepsy induced by icv histamine can be evoked not only by an activation of the histamine receptor, but also indirectly due to cholinergic and dopaminergic imbalance.

  8. A novel automated rat catalepsy bar test system based on a RISC microcontroller.

    Science.gov (United States)

    Alvarez-Cervera, Fernando J; Villanueva-Toledo, Jairo; Moo-Puc, Rosa E; Heredia-López, Francisco J; Alvarez-Cervera, Margarita; Pineda, Juan C; Góngora-Alfaro, José L

    2005-07-15

    Catalepsy tests performed in rodents treated with drugs that interfere with dopaminergic transmission have been widely used for the screening of drugs with therapeutic potential in the treatment of Parkinson's disease. The basic method for measuring catalepsy intensity is the "standard" bar test. We present here an easy to use microcontroller-based automatic system for recording bar test experiments. The design is simple, compact, and has a low cost. Recording intervals and total experimental time can be programmed within a wide range of values. The resulting catalepsy times are stored, and up to five simultaneous experiments can be recorded. A standard personal computer interface is included. The automated system also permits the elimination of human error associated with factors such as fatigue, distraction, and data transcription, occurring during manual recording. Furthermore, a uniform criterion for timing the cataleptic condition can be achieved. Correlation values between the results obtained with the automated system and those reported by two independent observers ranged between 0.88 and 0.99 (P<0.0001; three treatments, nine animals, 144 catalepsy time measurements).

  9. Antipsychotic-induced catalepsy is attenuated in mice lacking the M4 muscarinic acetylcholine receptor

    DEFF Research Database (Denmark)

    Fink-Jensen, Anders; Schmidt, Lene S; Dencker, Ditte

    2011-01-01

    of the striatum, suggesting a role for muscarinic M4 receptors in the motor side effects of antipsychotics, and in the alleviation of these side effects by anticholinergics. Here we investigated the potential role of the muscarinic M4 receptor in catalepsy induced by antipsychotics (haloperidol and risperidone...

  10. Effect of Tribulus terrestris on haloperidol-induced catalepsy in mice

    Directory of Open Access Journals (Sweden)

    B S Nishchal

    2014-01-01

    Full Text Available Haloperidol, an antipsychotic drug, leads to the development of a behavioural state called catalepsy, in which the animal is not able to correct an externally imposed posture. In the present study we have attempted to evaluate the anticataleptic effect of Tribulus terrestris on haloperidol-induced catalepsy in albino mice. Mice were allocated to four groups, each group containing six animals. Both, the test drug, Tribulus terrestris and the standard drug trihexyphenidyl were uniformly suspended in 1% gum acacia solution. Catalepsy was induced in mice with haloperidol (1.0 mg/kg, intraperitoneally. The first group received the vehicle (10 ml/kg, orally, the second group received trihexyphenidyl (10 mg/kg, orally and the remaining two groups received Tribulus terrestris (100, 200 mg/kg, orally. The animals were assessed after single and repeated dose administration for ten days, 30 min prior to haloperidol, using standard bar test. The result of the present study demonstrates Tribulus terrestris has a protective effect against haloperidol-induced catalepsy, which is comparable to the standard drug used for the same purpose. Our study indicates Tribulus terrestris can be used to prevent haloperidol-induced extrapyramidal side effects.

  11. Effect of Tribulus terrestris on Haloperidol-induced Catalepsy in Mice.

    Science.gov (United States)

    Nishchal, B S; Rai, S; Prabhu, M N; Ullal, Sheetal D; Rajeswari, S; Gopalakrishna, H N

    2014-01-01

    Haloperidol, an antipsychotic drug, leads to the development of a behavioural state called catalepsy, in which the animal is not able to correct an externally imposed posture. In the present study we have attempted to evaluate the anticataleptic effect of Tribulus terrestris on haloperidol-induced catalepsy in albino mice. Mice were allocated to four groups, each group containing six animals. Both, the test drug, Tribulus terrestris and the standard drug trihexyphenidyl were uniformly suspended in 1% gum acacia solution. Catalepsy was induced in mice with haloperidol (1.0 mg/kg, intraperitoneally). The first group received the vehicle (10 ml/kg, orally), the second group received trihexyphenidyl (10 mg/kg, orally) and the remaining two groups received Tribulus terrestris (100, 200 mg/kg, orally). The animals were assessed after single and repeated dose administration for ten days, 30 min prior to haloperidol, using standard bar test. The result of the present study demonstrates Tribulus terrestris has a protective effect against haloperidol-induced catalepsy, which is comparable to the standard drug used for the same purpose. Our study indicates Tribulus terrestris can be used to prevent haloperidol-induced extrapyramidal side effects.

  12. Reduced expression of haloperidol conditioned catalepsy in rats by the dopamine D3 receptor antagonists nafadotride and NGB 2904.

    Science.gov (United States)

    Banasikowski, Tomek J; Beninger, Richard J

    2012-10-01

    Haloperidol, a dopamine (DA) D2 receptor-preferring antagonist, produces catalepsy whereby animals maintain awkward posture for a period of time. Sub-threshold doses of haloperidol fail to produce catalepsy initially, however, when the drug is given repeatedly in the same test environment, gradual day-to-day increases in catalepsy are observed. More importantly, if sensitized rats are injected with saline instead of haloperidol they continue to be cataleptic in the test environment suggesting that environment-drug associations may play a role. DA D3 receptors have been implicated in a number of conditioned behaviors. We were interested if DA D3 receptors contribute to catalepsy sensitization and conditioning in rats. We tested this hypothesis using the DA D3 receptor-selective antagonist NGB 2904 (0.5, 1.8 mg/kg) and the DA D3 receptor-preferring antagonist nafadotride (0.1, 0.5 mg/kg). For 10 consecutive conditioning days rats were treated with one of the D3 receptor antagonists alone or in combination with haloperidol (0.25 mg/kg) and tested for catalepsy, quantified by the time a rat remained with its forepaws on a horizontal bar. On test day (day 11), rats were injected with saline or the D3 receptor antagonist and tested for conditioned catalepsy in the previously drug-paired environment. Rats treated with NGB 2904 or nafadotride alone did not develop catalepsy. Rats treated with haloperidol or haloperidol plus NGB 2904 or nafadotride developed catalepsy sensitization with repeated conditioning. When injected with saline they continued to exhibit catalepsy in the test environment--now conditioned. On the other hand, NGB 2904 (1.8 mg/kg) or nafadotride (0.5 mg/kg) given on the test day (after sensitization to haloperidol) significantly attenuated the expression of conditioned catalepsy. Our data suggest that the D3 receptor antagonist NGB 2904 (1.8 mg/kg) and nafadotride (0.5 mg/kg) significantly attenuate conditioned catalepsy in rats when given in test but

  13. Effects of Cannabis sativa extract on haloperidol-induced catalepsy and oxidative stress in the mice

    OpenAIRE

    Abdel-Salam, Omar M.E.; El-Din M. Gaafar, Alaa; El Sayed El-Shamarka, Marawa; Salem, Neveen A.

    2012-01-01

    Haloperidol is a classic antipsychotic drug known for its propensity to cause extrapyramidal symptoms due to blockade of dopamine D2 receptors in the striatum. Interest in medicinal uses of cannabis is growing. Cannabis sativa has been suggested as a possible adjunctive in treatment of Parkinson's disease. The present study aimed to investigate the effect of repeated administration of an extract of Cannabis sativa on catalepsy and brain oxidative stress induced by haloperidol administration i...

  14. Epilepsy and catalepsy in Anglo-American literature between romanticism and realism: Tennyson, Poe, Eliot and Collins.

    Science.gov (United States)

    Wolf, P

    2000-12-01

    Epilepsy and catalepsy were not clearly separated in the minds of people in the early 19th century, and catalepsy may have been used as a diagnostic euphemism for epilepsy. Tennyson, in "The Princess" describes, under the diagnosis of catalepsy, probable temporal lobe epileptic dreamy states with derealization which serve as a metaphor of sexual and moral ambivalence, the poem's central theme. It seems that Tennyson knew such seizures from his own father who had been given a diagnosis of catalepsy. Poe gave his Berenice in the novella of the same title a diagnosis of epilepsy as a reason for a premature burial. However, there was a good deal of unlikelyhood in this, and when he came to this theme in "The Fall of the House of Usher" and in "The Premature Burial" he chose instead a diagnosis of catalepsy which fitted better with the plot. The fits of the title character in George Eliot's Silas Marner, diagnosed as catalepsy, would today rather be seen as epileptic twilight states. It would seem that this author drew from contemporary dictionary descriptions which described conditions similar to Marner's fits under the heading of catalepsy. In Eliot's "legend with a realistic treatment", the twilight states are a central factor in the plot and explain Marner's reclusion and passivity. In Poor Miss Finch by English realist Wilkie Collins, the post-traumatic seizures of Oscar, one of the main characters, their cause, their treatment with silver nitrate, and the subsequent discoloration of his skin are central supporting elements of a perfectly constructed plot. Collins gives an exact description of a right versive seizure with secondary generalisation, and how to deal with it. In none of these works seizures are seen in a negative light. They rather evoke reactions of sympathy and support.

  15. Aspirin-triggered lipoxin induces CB1-dependent catalepsy in mice.

    Science.gov (United States)

    Pamplona, Fabrício A; Menezes-de-Lima, Octávio; Takahashi, Reinaldo N

    2010-02-05

    Evidence are that inhibition of cyclooxygenase 2 (COX-2) enhances endocannabinoid signaling, indicating a crosstalk between these two eicosanoid pathways. Aspirin, a non-selective COX inhibitor, acetylates COX-2 with generation of a lipoxygenase (LOX) substrate, whose end product is the 15-epi-lipoxin A(4) (15-epi-LXA(4)), an aspirin-triggered lipoxin. Our objective was to investigate whether 15-epi-LXA(4) would potentiate in vivo effects of the endocannabinoid anandamide (AEA). Catalepsy was selected as a behavioral parameter and tested 5 min after AEA injection in all experiments. AEA induced dose-dependent (200 pmol/2 microl, i.c.v.) catalepsy. A sub-dose of AEA (10 pmol/2 microl, i.c.v.) was potentiated by aspirin (300 mg/kg, p.o.) via a 5-LOX-dependent step. The cataleptic effect induced by the interaction between sub-doses of 15-epi-LXA(4) (0.01 pmol/2 microl, i.c.v.) and AEA (10 pmol/2 microl, i.c.v.) was prevented by the cannabinoid CB(1) receptors antagonist SR141716A (1mg/kg, i.p.), but not by the antagonist of lipoxin ALX receptors Boc-2 (10 microg/kg, i.p.). While previous studies have shown that COX inhibition itself may enhance endocannabinoid effects, here we add another piece of evidence revealing that a LOX-derivative produced in consequence of COX-2 acetylation participates in this process.

  16. Cannabidiol attenuates catalepsy induced by distinct pharmacological mechanisms via 5-HT1A receptor activation in mice.

    Science.gov (United States)

    Gomes, Felipe V; Del Bel, Elaine A; Guimarães, Francisco S

    2013-10-01

    Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa plant that produces antipsychotic effects in rodents and humans. It also reverses L-dopa-induced psychotic symptoms and improves motor function in Parkinson's patients. This latter effect raised the possibility that CBD could have beneficial effects on motor related striatal disorders. To investigate this possibility we evaluated if CBD would prevent catalepsy induced by drugs with distinct pharmacological mechanisms. The catalepsy test is largely used to investigate impairments of motor function caused by interference on striatal function. Male Swiss mice received acute pretreatment with CBD (5, 15, 30 or 60mg/kg, ip) 30min prior to the D2 receptor antagonist haloperidol (0.6mg/kg), the non-selective nitric oxide synthase (NOS) inhibitor L-nitro-N-arginine (L-NOARG, 80mg/kg) or the CB1 receptor agonist WIN55,212-2 (5mg/kg). The mice were tested 1, 2 or 4h after haloperidol, L-NOARG or WIN55,212-2 injection. These drugs significantly increased catalepsy time and this effect was attenuated dose-dependently by CBD. CBD, by itself, did not induce catalepsy. In a second set of experiments the mechanism of CBD effects was investigated. Thirty minutes before CBD (30mg/kg) the animals received the 5-HT1A receptor antagonist WAY100635 (0.1mg/kg). The anticataleptic effect of CBD was prevented by WAY100635. These findings indicate that CBD can attenuate catalepsy caused by different mechanisms (D2 blockade, NOS inhibition and CB1 agonism) via 5-HT1A receptor activation, suggesting that it could be useful in the treatment of striatal disorders.

  17. [Comparison of behavioral effects of fluoxetine, imipramine and new psychotropic drug TC-2153 on mice with hereditary predisposition to catalepsy].

    Science.gov (United States)

    Kulikova, E A; Tikhonova, M A; Volcho, K P; Khomenko, T M; Salakhutdinov, N F; Kulikov, A V; Popova, N K

    2015-01-01

    Behavioral effects of classic antidepressants, fluoxetine and imipramine, and new psychotropic benzopentathiepin TC-2153 (20 mg/kg, per os) were studied on mice differing in the predisposition to catalepsy-noncataleptic AKR strain and cataleptic strains CBA and AKR.CBA-D13Mit76 (D13). Mice of D13 strain was created by transferring the CBA-allele of major locus of catalepsy to AKR genome. In the forced swim test (FST) fluoxetine showed antidepressant effect on mice of all three strains, imipramine was effective only in D13 mice, while TC-2153 produced antidepressant effect on AKR and D13 mice. Unlike to imipramine and fluoxetine, TC-2153 did not produce negative side effects in the open field and elevated plus-maze tests. Thus, TC-2153 produces antidepressant effects similar to imipramine and fluoxetine, without any visible negative side effect on locomotory activity and anxiety. The D13 mice in the FST showed high sensitivity to the studied drugs in comparison to the parent strains and can be used as new genetic model for investigation of the mechanism of antidepressant effects.

  18. Pharmacokinetic-pharmacodynamic modeling of the relationship between D2 receptor occupancy and catalepsy in rats : Predicting extrapyramidal side effects in humans

    NARCIS (Netherlands)

    Johnson, Martin; Kozielska, Magdalena; Pilla Reddy, Venkatesh; Vermeulen, An; Barton, Hugh A.; Grimwood, Sarah; de Greef, Rik; Groothuis, Genoveva; Danhof, Meindert; Proost, Johannes

    2012-01-01

    Objectives: Dopamine D2 receptor occupancy (D2RO) is the major determinant of efficacy and safety in schizophrenia drug therapy (1,2). Excessive D2RO (>80 %) is known to cause catalepsy (CAT) in rats and extrapyramidal side effects (EPS) in human(3). The relationship between CAT scores in rats and E

  19. Learning and extinction of a passive avoidance response in mice with high levels of predisposition to catalepsy.

    Science.gov (United States)

    Dubrovina, N I; Zinov'ev, D R; Zinov'eva, D V; Kulikov, A V

    2009-06-01

    This report presents results obtained from comparative analysis of learning and the dynamics of extinction of a conditioned passive avoidance response in ASC mice, which were bred for a high level of predisposition to catalepsy, and in CBA and AKR mice. The following findings were obtained: 1) impairments to the extinction of the memory of fear represent an important symptom of depression in ASC mice; 2) extinction is delayed in CBA mice; and 3) new inhibitory learning occurs quickly in AKR mice. Prolonged retention of the fear memory in ASC mice appears to be related to increased anxiety on prolonged testing without a punishment. The deficit of inhibition of the fear reaction in ASC mice allows this strain to be regarded as a genetic model of depression.

  20. [Effect of sulpiride on immobility reflex and pinch-induced catalepsy in CBA/Lac male mice with various social status].

    Science.gov (United States)

    Lipina, T V; Vishnivetskaia, G B

    2009-01-01

    This study was aimed to determine the effect of D2/D3 receptor antagonist sulpiride on the expression of immobility reflex ("pinch-test") and pinch-induced catalepsy ("bar-test") of CBA/Lac male mice depending on their social status ("aggressors" with repeated experience of victories or a "losers" with repeated experience of social defeats). Sulpiride (20 mg/kg, i.p.) was acutely administered to "aggressors" and "losers" after 10 and 20 daily social contacts (victories or social defeats) and to a control group of male mice. Repeated experience of social victories and defeats altered the immobility duration in both tests and modified the expression of the sulpiride effect. In the pinch-tets, the duration of immobility was longer in "loosers" than in "aggressors". In the bar-test, the pinch-induced catalepsy was more expressed in "losers" and "aggressors" as compared to control. Sulpiride was more effective in increasing immobility of"aggressors" and had a weaker effect on the control and "losers". Therefore, the effect of sulpiride is affected by the social status of the animals.

  1. Comparative study of equimolar doses of gamma-hydroxybutyrate (GHB), 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL) on catalepsy after acute and chronic administration.

    Science.gov (United States)

    Towiwat, Pasarapa; Phattanarudee, Siripan; Maher, Timothy J

    2013-01-01

    Gamma-hydroxybutyrate (GHB), and its precursors 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL) are known drugs of abuse. The ability of acute and chronic administration of equimolar doses of GHB (200mg/kg), 1,4-BD (174mg/kg) and GBL (166mg/kg) to produce catalepsy in male Swiss Webster mice was examined. GHB, 1,4-BD, GBL produced catalepsy when injected acutely. Drug treatment was then continued for 14days. Tolerance development was determined on days 6, 14, and challenged with a higher dose on day 15 in those chronically pretreated mice, and compared with naïve mice. Chronic GHB produced tolerance to catalepsy, as evidenced from area under the curve (AUC) of catalepsy versus time (min-sec) on days 6 (678±254), 14 (272±247), which were less than those on day 1 (1923±269). However, less tolerance was seen from GBL or 1,4-BD, as AUCs on days 6 and 14 were not significantly lower than that of day 1. In conclusion, although equimolar doses were used, expecting similar levels of GHB in the body, 1,4-BD and GBL shared only some of the in vivo effects of GHB. The rate of metabolic conversion of 1,4-BD and GBL into GHB might be responsible for the differences in the tolerance development to these drugs.

  2. Characteristics of high-voltage electroencephalogram spindles and facial muscular activities in haioperidol-induced catalepsy rats%氟哌啶醇致僵直大鼠皮质高电压纺锤波节律及面部肌电特征

    Institute of Scientific and Technical Information of China (English)

    杨晨; 陈磊; 葛顺楠; 付建; 朱俊玲; 高国栋

    2012-01-01

    目的 研究氟哌啶醇对成年大鼠在自由活动状态下大脑皮质高电压纺锤波( high-voltage spindles,HVSs)及相应面部肌电活动的影响.方法 通过在体多通道电生理记录技术结合视频录像,对可自由活动的大鼠进行皮质脑电和面部肌电长程记录,观察氟哌啶醇致僵直大鼠皮质HVSs节律数量及相应面部活动及肌电的变化.结果 在清醒静止状态下,正常大鼠自发出现HVSs节律,面部可见触须震颤,经腹腔注射氟哌啶醇1.0mg/kg和3.0 mg/kg后,大鼠呈现僵直状态,HVSs节律数量增加,面部抽搐活动增多,波及范围扩大,强度增加,肌电显示节律性活动增多、持续时间延长.结论 氟哌啶醇作为多巴胺D2受体拮抗剂可增强HVSs节律及面部抽搐,提示多巴胺D2受体参与HVSs节律的调节.%Objective To study the effects of haloperidol on neocortical high-voltage spindles (HVSs) and accompanied facial muscular activities in freely moving adult rats. Methods Continuous video, neocortical electroencephalogram (EEG) and facial electromyography (EMG) were recorded simultaneously for more than six hours in freely moving rats. The number of HVSs and the facial muscular activities were analyzed after administration of saline or haloperidol. Results Spontaneous HVSs and whisker twitching were observed in normal rats during behavioral waking-immobility. In the haloperidol-induced catalepsy rats (intraperitoneal injection of 1.0 mg/kg and 3.0 mg/kg haloperidol, respectively), the number of HVSs and companied facial rhythmic muscular activities increased; tremor intensity was enhanced in eyes, ears and even in the dorsal of neck without gross body movement, the duration of rhythmic muscular activities was prolonged. Conclusions Haloperidol, the dopamine D2 receptors antagonist, could enhance HVSs and facial twitching, indicating that dopamine D2 receptors maybe contribute to the regulation of the HVSs, and the abnormal HVSs may be the

  3. ATTENUATION OF HALOPERIDOL-INDUCED CATALEPSY BY NORADRENALINE AND L-THREO-DOPS

    NARCIS (Netherlands)

    VERHAGENKAMERBEEK, WDJ; HAZEMEIJER, [No Value; KORF, J; LAKKE, JPWF

    1993-01-01

    In addition to impaired dopaminergic neurotransmission a dysfunctional noradrenergic system has been demonstrated in Parkinson's disease. L-threo-3,4-dihydroxyphenylserine (DOPS), a synthetic precursor of noradrenaline (NA), appears to be effective in the treatment of some akinetic symptoms in parki

  4. 苍白球注射5-HT对氟哌啶醇所致大鼠僵直症状影响%EFFECTS OF 5-HT ON GLOBUS PALLIDUS OF RATS WITH HALOPERIDOL-INDUCED CATALEPSY

    Institute of Scientific and Technical Information of China (English)

    魏磊; 陈蕾

    2009-01-01

    目的 探讨苍白球注射5-羟色胺(5-HT)对氟哌啶醇导致的大鼠僵直症状的调节作用.方法 大鼠单侧苍白球埋置套管,恢复3 d后腹腔注射氟哌啶醇(1 mg/kg),苍白球内微量注射不同浓度的5-HT,以大鼠张力障碍性体态偏转角度评分作为指标,观察5-HT对氟哌啶醇导致的僵直症状的影响.结果 单侧苍白球微量注射5-HT可引起模型大鼠头部对侧偏转,5-HT浓度在10 nmol/L~100 μmol/L范围内,大鼠体态偏转评分呈现以10 μmol/L为最高分浓度的钟形量效关系.结论 5-HT可能通过影响苍白球神经元兴奋性来调节氟哌啶醇所致的大鼠僵直症状.

  5. EFFECTS OF VERAPAMIL ON DOPAMINE DEPENDENT BEHAVIOURS IN RATS.

    Science.gov (United States)

    Malekar, A R; Balsara, J J; Gaonkar, R K

    1999-01-01

    Abstract : Verapamil at 5, 10 and 20 mg/kg ip did not inhibit the conditioned avoidance response, neither induced catalepsy nor antagonised apomorphine stereotypy in rats indicating that these doses do not block the postsynaptic striatal D 2 and D 1 dopamine (DA) receptors. However, pretreatment with 10 and 20 mg/kg ip verapamil potentiated methamphetamine stereotypy and antagonised catalepsy induced by small doses (0.05 and 0.1 mg/kg ip) of apomorphine. Antagonism of small dose apomorphine-induced catalepsy suggests that at these doses verapamil blocks the presynaptic D2 DA autoreceptors. Further, pretreatment with 10 mg/kg verapamil antagonised, while pretreatment with 20 mg/kg potentiated haloperidol catalepsy. Potentiation of methamphetamine stereotypy by 10 and 20 mg/kg verapamil is explained on the basis of blockade of presynaptic D2 DA autoreceptors by these doses of verapamil and its reported DA neuronal uptake blocking activity. Antagonism of haloperidol catalepsy by 10 mg/kg verapamil is also explained on the basis of presynaptic D2 DA autoreceptor induced blockade by 10 mg/kg verapamil whereas potentiation of haloperidol catalepsy by 20 mg/kg verapamil is explained on the basis of its calcium channel blocking activity.

  6. Effects of dextromethorphan on dopamine dependent behaviours in rats.

    Science.gov (United States)

    Gaikwad, R V; Gaonkar, R K; Jadhav, S A; Thorat, V M; Jadhav, J H; Balsara, J J

    2007-08-01

    Dextromethorphan, a noncompetitive blocker of N-methyl-D- aspartate (NMDA) type of glutamate receptor, at 7.5-75 mg/kg, ip did not induce oral stereotypies or catalepsy and did not antagonize apomorphine stereotypy in rats. These results indicate that dextromethorphan at 7.5-75 mg/kg does not stimulate or block postsynaptic striatal D2 and D1 dopamine (DA) receptors. Pretreatment with 15 and 30 mg/kg dextromethorphan potentiated dexamphetamine stereotypy and antagonised haloperidol catalepsy. Pretreatment with 45, 60 and 75 mg/kg dextromethorphan, which release 5-hydroxytryptamine (5-HT), however, antagonised dexamphetamine stereotypy and potentiated haloperidol catalepsy. Apomorphine stereotypy was not potentiated or antagonised by pretreatment with 7.5-75 mg/kg dextromethorphan. This respectively indicates that at 7.5-75 mg/kg dextromethorphan does not exert facilitatory or inhibitory effect at or beyond the postsynaptic striatal D2 and D1 DA receptors. The results are explained on the basis of dextromethorphan (15-75 mg/kg)-induced blockade of NMDA receptors in striatum and substantia nigra pars compacta. Dextromethorphan at 15 and 30 mg/kg, by blocking NMDA receptors, activates nigrostriatal dopaminergic neurons and thereby potentiates dexampetamine stereotypy and antagonizes haloperidol catalepsy. Dextromethorphan at 45, 60 and 75 mg/kg, by blocking NMDA receptors, releases 5-HT and through the released 5-HT exerts an inhibitory influence on the nigrostriatal dopaminergic neurons with resultant antagonism of dexampetamine stereotypy and potentiation of haloperidol catalepsy.

  7. Effects of dexfenfluramine on dopamine dependent behaviours in rats.

    Science.gov (United States)

    Thorat, V M; Gaonkar, R K; Bhosale, K B; Balsara, J J

    2005-01-01

    5-hydroxytryptamine (5-HT) inhibits the synthesis and release of dopamine (DA) from rat nigrostriatal DAergic neurons. Dexfenfluramine releases 5-HT from brain 5-HTergic neurons. The present study was undertaken to determine whether dexfenfluramine, through the released 5-HT, modulates the intensity of the behaviours dependent on the functional status of the nigrostriatal DAergic system. The effect of pretreatment with dexfenfluramine on dexamphetamine and apomorphine stereotypies of the oral movement variety and on catalepsy induced by haloperidol and small doses (0.05 and 0.1 mg/kg ip) of apomorphine was studied in rats. We also investigated whether dexfenfluramine induces catalepsy in rats. Dexfenfluramine at 2.5, 5 and 10 mg/kg ip did not induce catalepsy and did not antagonise apomorphine stereotypy. However, 1 h pretreatment with 5-HT releasing doses of dexfenfluramine ie 5 and 10 mg/kg ip, antagonized dexamphetamine stereotypy and potentiated catalepsy induced by haloperidol and small doses of apomorphine. Our results, that dexfenfluramine at 2.5, 5 and 10 mg/kg ip neither induced catalepsy nor antagonised apomorphine stereotypy, indicate that dexfenfluramine at these doses does not block the postsynaptic striatal D2 and D1 DA receptors. They also indicate that the 5-HT released by 5 and 10 mg/kg dexfenfluramine does not exert an inhibitory effect at or beyond the postsynaptic striatal D2 and D1 DA receptor sites. However, 5 and 10 mg/kg doses of dexfenfluramine, through the released 5-HT, inhibit the synthesis and release of DA from the nigrostriatal DAergic neurons and thus antagonise dexamphetamine stereotypy and potentiate catalepsy induced by haloperidol and small doses of apomorphine.

  8. Righting elicited by novel or familiar auditory or vestibular stimulation in the haloperidol-treated rat: rat posturography as a model to study anticipatory motor control.

    Science.gov (United States)

    Clark, Callie A M; Sacrey, Lori-Ann R; Whishaw, Ian Q

    2009-09-15

    External cues, including familiar music, can release Parkinson's disease patients from catalepsy but the neural basis of the effect is not well understood. In the present study, posturography, the study of posture and its allied reflexes, was used to develop an animal model that could be used to investigate the underlying neural mechanisms of this sound-induced behavioral activation. In the rat, akinetic catalepsy induced by a dopamine D2 receptor antagonist (haloperidol 5mg/kg) can model human catalepsy. Using this model, two experiments examined whether novel versus familiar sound stimuli could interrupt haloperidol-induced catalepsy in the rat. Rats were placed on a variably inclined grid and novel or familiar auditory cues (single key jingle or multiple key jingles) were presented. The dependent variable was movement by the rats to regain equilibrium as assessed with a movement notation score. The sound cues enhanced movements used to regain postural stability and familiar sound stimuli were more effective than unfamiliar sound stimuli. The results are discussed in relation to the idea that nonlemniscal and lemniscal auditory pathways differentially contribute to behavioral activation versus tonotopic processing of sound.

  9. Dose-dependent response of central dopaminergic systems to buspirone in mice.

    Science.gov (United States)

    Jadhav, S A; Gaikwad, R V; Gaonkar, R K; Thorat, V M; Gursale, S C; Balsara, J J

    2008-10-01

    Buspirone, a partial agonist of 5-hydroxytryptaminelA autoreceptors, preferentially blocks the presynaptic rather than the postsynaptic D2 dopamine (DA) receptors. Behavioural effects of a wide dose range of buspirone were therefore studied in mice. Buspirone at 0.625 to 5 mg/kg ip induced stereotyped cage climbing behaviour which was antagonized by pretreatment with haloperidol, alpha-methyl-p-tyrosine and small doses of apomorphine. Buspirone at 10, 20 and 40 mg/kg ip induced catalepsy and antagonized oral stereotypies induced by high doses of apomorphine and methamphetamine and apomorphine-induced cage climbing behaviour. The findings indicate that buspirone at 0.625 to 5 mg/kg selectively blocks the presynaptic mesolimbic D2 DA autoreceptors and releases DA which stimulates the postsynaptic mesolimbic D2 and D1 DA receptors and induces cage climbing behaviour. Buspirone, at 10, 20 and 40 mg/kg blocks the postsynaptic striatal and mesolimbic D2 and D1 DA receptors. Pretreatment with 1-tryptophan, dexfenfluramine and fluoxetine antagonized buspirone induced cage climbing behaviour and potentiated buspirone induced catalepsy. Pretreatment with trazodone, mianserin and p-chlorophenylalanine potentiated buspirone induced cage climbing behaviour and antagonized buspirone induced catalepsy. The results indicate that drugs which influence the activity of central serotonergic systems modulate the intensity of buspirone induced cage climbing behaviour and catalepsy.

  10. Central effects of angiotensin II, its fragment and analogues.

    Science.gov (United States)

    Georgiev, V P; Klousha, V E; Petkov, V D; Markovska, V L; Svirskis, S V; Mountsinietse, R K; Anouans, Z E

    1984-01-01

    The effects of the octapeptide angiotensin II (AT II), its fragment Ile8 AT3-8 and the analogues Sar1 Ala8 AT II, Ala8 AT II and Ile8 AT II were studied with respect to: the level of biogenic amines (DA, 5-HT and their metabolites HVA and 5-HIAA) in the forebrain; the behaviour of the animals--haloperidol catalepsy, apomorphine stereotypy, unconditioned jumping reaction (UJR), convulsive threshold. Good correlation was found between the biochemical and behavioural effects. The fragment of AT II where phenylalanine is substituted at the C-terminal by Ile reduces the haloperidol-increased content of HVA, potentiates apomorphine stereotypy and reduces catalepsy, whereas the AT II analogues (where the C-terminal phenylalanine is substituted by Ala, and the N-terminal--by Sar) potentiate the effect of haloperidol increasing the HVA content, reduce apomorphine stereotypy and potentiate catalepsy; saralasine independently applied induces brief catalepsy; AT II, its fragment and analogues inhibit UJR, in combination with amphetamine and PTZ this effect becomes deeper; the duration of hexobarbital sleep is increased. The peptides investigated increase the convulsive threshold. The results show that the hexapeptide fragment has preserved the effects of AT II, whereas in the analogues (with changed C- and N-terminals) they are changed. The results obtained may be explained with the modulating influence of AT II-receptors on the DA-ergic receptors in the brain structures with which AT II and its fragment and analogues enter in contact.

  11. Effects of buspirone on dopamine dependent behaviours in rats.

    Science.gov (United States)

    Dhavalshankh, A G; Jadhav, S A; Gaikwad, R V; Gaonkar, R K; Thorat, V M; Balsara, J J

    2007-01-01

    Buspirone, a partial agonist of 5-hydroxytryptamine autoreceptors, selectively blocks presynaptic nigrostriatal D2 dopamine (DA) autoreceptors. At doses which antagonised action of apomorphine in biochemical presynaptic nigrostriatal D2 DA autoreceptor test systems buspirone neither induced catalepsy nor antagonised apomorphine-induced turning behaviour in rats indicating that at these doses buspirone does not block postsynaptic striatal D2 and D1 DA receptors. This study determines whether at high doses buspirone blocks postsynaptic striatal D2 and D1 DA receptors and provides behavioural evidence for selective blockade of presynaptic nigrostriatal D2 DA autoreceptors by smaller doses of buspirone. We investigated in rats whether buspirone induces catalepsy and effect of its pretreatment on DA agonist induced oral stereotypies and on cataleptic effect of haloperidol and small doses (0.05, 0.1 mg/kg, ip) of apomorphine. Buspirone at 1.25, 2.5, 5 mg/kg, ip neither induced catalepsy nor antagonised apomorphine stereotypy but did potentiate dexamphetamine stereotypy and antagonised cataleptic effect of haloperidol and small doses of apomorphine. Buspirone at 10, 20, 40 mg/kg, ip induced catalepsy and antagonised apomorphine and dexamphetamine stereotypies. Our results indicate that buspirone at 1.25, 2.5, 5 mg/kg blocks only presynaptic nigrostriatal D2 DA autoreceptors while at 10, 20, 40 mg/kg, it blocks postsynaptic striatal D2 and D1 DA receptors. Furthermore, buspirone at 1.25, 2.5, 5 mg/kg by selectively blocking presynaptic nigrostriatal D2 DA autoreceptors, increases synthesis of DA and makes more DA available for release by dexamphetamine and during haloperidol-induced compensatory 'feedback' increase of nigrostriatal DAergic neuronal activity and thus potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy.

  12. Evaluations of antidepressant activity of Anacyclus pyrethrum root extract

    Directory of Open Access Journals (Sweden)

    Badhe S

    2010-01-01

    Full Text Available The present study was designed to screen antidepressant activity of Anacyclus pyrethrum (AP root extract. An experiment was designed by different method such as Locomotor activity, Haloperidol-induced catalepsy, Forced swim test (FST, Tail suspension test (TST, Clonidine-induced hypothermia and Reserpine-induced hypothermia on Swiss male albino mice. Standard root extract of Anacyclus pyrethrum (AP root extract showed an increase in ambulatory behaviour indicating a stimulant effect of the photoactometer. AP root extract produces a significant antidepressant effect in both FST and TST as they reduced the immobility. AP root extract was found to be effective in reversing hypothermia produced by clonidine and reserpine. In our study, we found that AP root extract inhibited haloperidol-induced catalepsy. These study suggest that AP root extract might produce antidepressant effect by interaction with adrenergic and dopamine receptor thereby increasing the level of noradrenaline and dopamine in brains of mice.

  13. Antagonism of haloperidol-induced swim impairment in L-dopa and caffeine treated mice: a pre-clinical model to study Parkinson's disease.

    Science.gov (United States)

    Luthra, Pratibha Mehta; Barodia, Sandeep Kumar; Raghubir, Ram

    2009-04-15

    Parkinson's disease (PD) exhibits symptoms of motor dysfunction such as tremor, akinesia and rigidity. Agents that selectively disrupt or destroy catecholaminergic systems, such as reserpine, methamphetamine, 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, have been used to develop PD models and to study the animal behavior like catalepsy, akinesia, swim-test, etc. The major apprehension while working with these chemicals is their irreversible neuro-toxic effect. Haloperidol is a classical antipsychotic drug, which produces extra-pyrimidal Parkinson's symptoms (EPS). Measuring catalepsy and akinesia in the treated mice monitored the haloperidol-induced EPS. Alternatively, swimming disability was tested as a new parameter to monitor haloperidol-induced EPS. The results showed that the restoration of swimming disability in haloperidol-induced L-dopa and caffeine pre-treated mice could be used as pre-clinical model to study PD.

  14. Cataleptic postures in thalamic hemorrhage: case report

    Directory of Open Access Journals (Sweden)

    Saposnik Gustavo

    2001-01-01

    Full Text Available We report a case of catalepsy associated with thalamic hemorrhage. A 72 year-old hypertensive woman had acute onset of right-sided weakness and speech disturbances. She was on anticoagulants because of aortic valve replacement. When postures were imposed, the patient maintained the left upper limb raised for several minutes, even in uncomfortable or bizarre positions. A CT scan of the head revealed a left thalamic hemorrhage. Cataleptic postures have been reported in few cases with acute stroke.

  15. Katatoni er ofte overset i børne- og ungdomspsykiatrien

    DEFF Research Database (Denmark)

    Ballin, Nicola Hvidt; Pagsberg, Anne Katrine

    2016-01-01

    Catatonia is a common but often overlooked motor syndrome in child and adolescent psychiatry. It is characterized by a variety of symptoms, most often excitement, immobility, stupor, catalepsy, grimacing, echolalia, echopraxia, stereotypies, mannerisms, logorrhoea, verbigeration, negativism......, staring and withdrawal. This case report illustrates how a 17-year-old man was diagnosed with catatonia after one year of repeating psychiatric care. The catatonic symptoms decreased significantly after a short period of lorazepam administration....

  16. Effects of H1–receptor antagonists in antidepressant tests in rats

    OpenAIRE

    Chitra C. Khanwelkar

    2008-01-01

    : Considering the vast data suggesting the role of brain histamine(HA) in behaviour,emotions,anxiety and depression;four H1-receptor antagonists; promethazine, diphenhydramine, cyclizine and pheniramine were subjected to antidepressant tests in rats. All H1 – antagonists behaved like antidepressants in animal tests. They antagonized reserpine induced catalepsy, potentiated methamphetamine induced stereotypy and reduced the period of immobility in Porsolt’s behavioural despair test. It is sug...

  17. Anxiolytic Effects of Royal Sun Medicinal Mushroom, Agaricus brasiliensis (Higher Basidiomycetes) on Ischemia-Induced Anxiety in Rats.

    Science.gov (United States)

    Zhang, Chunjing; Gao, Xiulan; Sun, Yan; Sun, Xiaojie; Wu, Yanmin; Liu, Ying; Yu, Haitao; Cui, Guangcheng

    2015-01-01

    We investigated the anxiolytic effects Agaricus brasiliensis extract (AbSE) on ischemia-induced anxiety using the plus-maze test and the social interaction test. The animals were treated orally with AbSE (4, 8, and 10 mg/kg/d, respectively) for 30 d, followed by middle cerebral artery occlusion-induced cerebral ischemia. Levels of noradrenaline, dopamine, and serotonin in the cerebral cortex of rats, as well as oxidative stress and plasma corticosterone levels were analyzed, respectively. The rota-rod test was carried out to exclude any false positive results in experimental procedures related to anxiety disorders, and the catalepsy test was carried out to investigate whether AbSE induces catalepsy. Our results demonstrate that oral administration of AbSE presented anxiolytic-like effects in the elevated plus-maze test and the social interaction test. Furthermore, AbSE did not induce extrapyramidal symptoms in the catalepsy test. The mechanism underlying the anxiolytic effect of AbSE might be increased brain monoamine levels and plasma corticosterone levels and decreased oxidative stress in cerebral ischemia/reperfusion rats.

  18. Preliminary screening of five ethnomedicinal plants of Guatemala.

    Science.gov (United States)

    Morales, C; Gomez-Serranillos, M P; Iglesias, I; Villar, A M; Cáceres, A

    2001-01-01

    We performed the Irwin test on some different extracts of the aerial parts of Tridax procumbens L., of the leaves of Neurolaena lobata (L.) R. Br., of the bark and leaves of Byrsonima crassifolia (L.) Kunth. and Gliricidia sepium Jacq. Walp. and of the root and leaves of Petiveria alliacea L. At a dosage of 1.25 g extract/100 g dried plant, the aqueous extracts of bark and leaves of Byrsonima crassifolia (L.) Kunth. and G. sepium Jacq. Walp. showed higher activity: decrease in motor activity, back tonus, reversible parpebral ptosis. catalepsy and strong hypothermia.

  19. Synthesis, Computational Studies and Preliminary Pharmacological Evaluation of New Arylpiperazines

    Directory of Open Access Journals (Sweden)

    Sushil Kumar

    2011-01-01

    Full Text Available A series of novel arylpiperazines were synthesized and the target compounds evaluated for atypical antipsychotic activity in apomorphine induced climbing behavior (D2 antagonism, 5-HTP induced head twitches (5-HT2A antagonism and catalepsy studies in albino mice. The physicochemical similarity of the target compounds with respect to standard drugs clozapine, ketanserine and risperidone was assessed by calculating from a set of physiochemical properties using software programs. The test compounds (3a-j demonstrated good similarity values with respect to the standard drugs. Among them, compound 3d has emerged as an important lead compound showing potential atypical antipsychotic like profile.

  20. [Joseph Babinski's contribution to neurological symptomatology].

    Science.gov (United States)

    Furukawa, Tetsuo

    2014-11-01

    Joseph Babinski (1857-1932) was an excellent clinician. André Breton, a French poet, described Babinski's way of clinical examination in his Manifeste du surréalisme (1924), which vividly revealed Babinski's meticulous character. Babinski is well known by his eponymous Babinski reflex. Although some predecessors had described this phenomenon briefly, its meaning was interpreted by Babinski. His contribution to neurological symptomatology was not restricted to his plantar skin reflex, but also to other wide area. In this article, symptoms described by Babinski, i.e. plantar skin reflex, cerebellar symptoms including cerebellar asynergy, adiadochokinesis, dysmetria, cerebellar catalepsy, and rising sign, platysma sign, anosognosia are explained and are critically discussed.

  1. Dopamine-dependent behavior in adult rats after perinatal exposure to purity-controlled polychlorinated biphenyl congeners (PCB52 and PCB180).

    Science.gov (United States)

    Lilienthal, Hellmuth; Heikkinen, Päivi; Andersson, Patrik L; van der Ven, Leo T M; Viluksela, Matti

    2014-01-03

    Since knowledge about toxic effects of non-dioxinlike (NDL) PCBs is fragmentary, regulatory panels have concluded that risk assessment of these congeners is hampered or impossible. As the dopaminergic system is one of the main targets in PCB-related neurotoxic effects after developmental exposure, we selected catalepsy induced by the dopamine receptor blocker haloperidol to characterize effects of the NDL congeners PCB52 and PCB180 in adult offspring from exposed rat dams. Rat dams were treated with PCB congeners by gavage using six dose levels (total doses: PCB52 - 0, 30, 100, 300, 1000 or 3000 mg/kg body wt.; PCB180 - 0, 10, 30, 100, 300, or 1000 mg/kg body wt.) to allow benchmark dose analysis of the results. Testing of adult offspring (starting at 180 days of age) for catalepsy induced by injection with haloperidol revealed slightly prolonged latencies to movement onset in female offspring exposed to PCB52. Exposure to PCB180 resulted in more pronounced effects, with generally reduced latencies in male offspring. These results indicate reduced dopaminergic activity after PCB52 exposure, whereas the outcome for PCB180 may be related to increased extracellular dopamine as reported in the literature.Benchmark dose analyses revealed that both PCB congeners exerted effects mainly at moderate exposure levels. Together, these results underline the importance of effects on the dopaminergic system as indicated by studies in human females after occupational PCB exposure.

  2. Magnesium Supplementation Prevents and Reverses Experimentally Induced Movement Disturbances in Rats: Biochemical and Behavioral Parameters.

    Science.gov (United States)

    Kronbauer, Maikel; Segat, Hecson J; De David Antoniazzi, Caren Tatiane; Roversi, Karine; Roversi, Katiane; Pase, Camila S; Barcelos, Raquel C S; Burger, Marilise E

    2015-08-01

    Reserpine administration results in a predictable animal model of orofacial dyskinesia (OD) that has been largely used to access movement disturbances related to extrapyramidal oxidative damage. Here, OD was acutely induced by reserpine (two doses of 0.7 mg/kg subcutaneous (s.c.)), every other day for 3 days), which was administered after (experiment 1) and before (experiment 2) magnesium (Mg) supplementation (40 mg/kg/mL, peroral (p.o.)). In experiment 1, Mg was administered for 28 days before reserpine treatment, while in experiment 2, it was initiated 24 h after the last reserpine administration and was maintained for 10 consecutive days. Experiment 1 (prevention) showed that Mg supplementation was able to prevent reserpine-induced OD and catalepsy development. Mg was also able to prevent reactive species (RS) generation, thus preventing increase of protein carbonyl (PC) levels in both cortex and substantia nigra, but not in striatum. Experiment 2 (reversion) showed that Mg was able to decrease OD and catalepsy at all times assessed. In addition, Mg was able to decrease RS generation, with lower levels of PC in both cortex and striatum, but not in substantia nigra. These outcomes indicate that Mg is an important metal that should be present in the diet, since its intake is able to prevent and minimize the development of movement disorders closely related to oxidative damage in the extrapyramidal brain areas, such as OD.

  3. Studies on sensitivity of zebrafish as a model organism for Parkinson′s disease: Comparison with rat model

    Directory of Open Access Journals (Sweden)

    Dinesh T Makhija

    2014-01-01

    Full Text Available Objective: To determine the utility of zebra fish as an animal model for Parkinson′s disease (PD in comparison with rat model. Materials and Methods: MTT assay was performed on rat and zebrafish brain synaptosomal fractions using rotenone as a neurotoxic agent. Quercetin and resveratrol were used as standards to compare anti-apoptotic activity in both organisms. Catalepsy was induced in zebrafish by exposing them to haloperidol (9 μM solution. Drug-treated groups were exposed to bromocriptine and pramipexole, 30 min prior to haloperidol exposure at the dose of 2, 5, and 10 μg/mL. Swimming speed, time spent in the bottom of the tank, and complete cataleptic time were evaluated to assess behavioral changes. In rats, catalepsy was induced using haloperidol (1.25 mg/kg i.p.. Drug-treated groups received bromocriptine (2.5 mg/kg. and pramipexole (1 mg/kg orally. Bar test, block test, and locomotor activity were carried out to assess behavioral changes. Results: Resveratrol and quercetin showed comparable inhibition of apoptosis in rats and zebrafish. In anti-cataleptic study, bromocriptine and pramipexole-treated groups showed significant difference (P < 0.05 in behavioral parameters as compared to haloperidol control group in both the experimental organisms. Results obtained from fish model were in correlation with rat model. Conclusion: Findings of the present study revealed that zebrafish model is highly sensitive and can be used for basic screening of drugs against PD.

  4. Atypical neuroleptic properties of l-stepholidine -Electrophysiological and behavioral studies

    Institute of Scientific and Technical Information of China (English)

    张雪翔; 孙宝存; 金国章

    1997-01-01

    Intravenous administration of l-stepholidine (SPD), a dopamine (DA) receptor antagonist, in-creased the firing rate of DA neurons located in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) in both anaesthetized and paralyzed rats. However, with the increase of dose, SPD selectively inhibited the fir-ing activity of DA neurons in the VTA but not in the SNC. The inhibition was reversed by the DA agonist apomor-phine (APO), suggesting that it may be via the mechanism of depolarization inactivation (DI). In rats, chronic admin-istration of SPD for 21 d dose-dependently decreased the number of spontaneously active DA neurons in the VTA, of which effect was reversed by APO (i. v. ). In contrast, the same treatment failed to affect the population of DA neu-rons in the SNC. Similarly, the acute treatment of SPD also decreased the number of spontaneously firing DA neurons in the VTA, but not in the SNC. SPD per se only induced very weak catalepsy. Its catalepsy which was not in pro-port

  5. Cannabidiol prevents motor and cognitive impairments induced by reserpine in rats

    Directory of Open Access Journals (Sweden)

    Fernanda Fiel Peres

    2016-09-01

    Full Text Available Cannabidiol (CBD is a non-psychotomimetic compound from Cannabis sativa that presents antipsychotic, anxiolytic, anti-inflammatory and neuroprotective effects. In Parkinson’s disease patients, CBD is able to attenuate the psychotic symptoms induced by L-DOPA and to improve quality of life. Repeated administration of reserpine in rodents induces motor impairments that are accompanied by cognitive deficits, and has been applied to model both tardive dyskinesia and Parkinson’s disease. The present study investigated whether CBD administration would attenuate reserpine-induced motor and cognitive impairments in rats. Male Wistar rats received four injections of CBD (0.5 or 5 mg/kg or vehicle (days 2-5. On days 3 and 5, animals received also one injection of 1 mg/kg reserpine or vehicle. Locomotor activity, vacuous chewing movements and catalepsy were assessed from day 1 to day 7. On days 8 and 9, we evaluated animals’ performance on the plus-maze discriminative avoidance task, for learning/memory assessment. CBD (0.5 and 5 mg/kg attenuated the increase in catalepsy behavior and in oral movements – but not the decrease in locomotion – induced by reserpine. CBD (0.5 mg/kg also ameliorated the reserpine-induced memory deficit in the discriminative avoidance task. Our data show that CBD is able to attenuate motor and cognitive impairments induced by reserpine, suggesting the use of this compound in the pharmacotherapy of Parkinson’s disease and tardive dyskinesia.

  6. Cannabidiol Prevents Motor and Cognitive Impairments Induced by Reserpine in Rats

    Science.gov (United States)

    Peres, Fernanda F.; Levin, Raquel; Suiama, Mayra A.; Diana, Mariana C.; Gouvêa, Douglas A.; Almeida, Valéria; Santos, Camila M.; Lungato, Lisandro; Zuardi, Antônio W.; Hallak, Jaime E. C.; Crippa, José A.; Vânia, D’Almeida; Silva, Regina H.; Abílio, Vanessa C.

    2016-01-01

    Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that presents antipsychotic, anxiolytic, anti-inflammatory, and neuroprotective effects. In Parkinson’s disease patients, CBD is able to attenuate the psychotic symptoms induced by L-DOPA and to improve quality of life. Repeated administration of reserpine in rodents induces motor impairments that are accompanied by cognitive deficits, and has been applied to model both tardive dyskinesia and Parkinson’s disease. The present study investigated whether CBD administration would attenuate reserpine-induced motor and cognitive impairments in rats. Male Wistar rats received four injections of CBD (0.5 or 5 mg/kg) or vehicle (days 2–5). On days 3 and 5, animals received also one injection of 1 mg/kg reserpine or vehicle. Locomotor activity, vacuous chewing movements, and catalepsy were assessed from day 1 to day 7. On days 8 and 9, we evaluated animals’ performance on the plus-maze discriminative avoidance task, for learning/memory assessment. CBD (0.5 and 5 mg/kg) attenuated the increase in catalepsy behavior and in oral movements – but not the decrease in locomotion – induced by reserpine. CBD (0.5 mg/kg) also ameliorated the reserpine-induced memory deficit in the discriminative avoidance task. Our data show that CBD is able to attenuate motor and cognitive impairments induced by reserpine, suggesting the use of this compound in the pharmacotherapy of Parkinson’s disease and tardive dyskinesia. PMID:27733830

  7. Evaluation of the antipsychotic potential of aqueous fraction of Securinega virosa root bark extract in mice.

    Science.gov (United States)

    Magaji, M G; Mohammed, M; Magaji, R A; Musa, A M; Abdu-Aguye, I; Hussaini, I M

    2014-03-01

    Securinega virosa (Roxb ex. Willd) Baill. is a plant which is commonly used in African traditional medicine in management of mental illness. Previous study showed that the crude methanolic root bark extract of the plant possesses antipsychotic activity. In this study, the antipsychotic potential of the residual aqueous fraction of the plant was evaluated using two experimental models, apomorphine induced stereotypic climbing behaviour and swim induced grooming, all in mice. The effect of the fraction on haloperidol-induced catalepsy was also evaluated. The fraction significantly reduced the mean climbing score at the highest dose tested (500 mg/kg). In the swim-induced grooming test, the fraction significantly and dose-dependently (125-500 mg/kg) decreased the mean number and mean duration of swim-induced grooming activity in mice. Similarly, the standard haloperidol (1 mg/kg) significantly (p < 0.001) decreased the mean grooming episodes and duration. However, the fraction did not significantly potentiate haloperidol-induced catalepsy. These results suggest that the residual aqueous fraction of methanol root bark extract of Securinega virosa contains biological active principle with antipsychotic potential.

  8. Mast Cell Stabilizing,Antianaphylactic and Antihistaminic Activity of Coccinia grandis Fruits in Asthma

    Institute of Scientific and Technical Information of China (English)

    Dnyaneshwar J Taur; Ravindra Y Patil

    2011-01-01

    Coccinia grandis Linn(Curcubitaceae)is a climber herb cultivated throughout India.In traditional medicine fruits have been used to treat leprosy,fever,asthma,bronchitis and jaundice.In present study,ethanol extract of C.grandis fruit(ECGF)at 100,125 and 150 mg·kg-1,i.p.,was evaluated for mast cell stabilizing,antianaphylactic and antihistaminic activity using egg albumin induced mast cell degranulation in mice;passive cutaneous anaphylaxis in rats and clonidine induced catalepsy in mice respectively.ECGF at(100-150 mg·kg-1,i.p.)significantly protected egg albumin induced degranulations of mast cells and caused reduction of blue dye leakage in passive cutaneous anaphylaxis in dose dependently.The treatment ECGF also inhibited clonidine induced catalepsy in dose dependent manner.Phytochemical studies observed presence of saponin,steroids,alkaloids,flavonoids and glycosides.In conclusion ECGF possesses mast cell stabilizing;anti anaphylactic and antihistaminic potential which might be used in treatment of asthma.

  9. Nootropic activity of tuber extract of Pueraria tuberosa (Roxb).

    Science.gov (United States)

    Rao, N Venkata; Pujar, Basavaraj; Nimbal, S K; Shantakumar, S M; Satyanarayana, S

    2008-08-01

    Nootropic effect of alcoholic (ALE; 50, 75, 100 mg/kg) and aqueous (AQE; 100, 200, 400 mg/kg) extracts of P. tuberosa was evaluated by using Elevated Plus Maze (EPM), scopolamine-induced amnesia (SIA), diazepam-induced amnesia (DIA), clonidine-induced (NA-mediated) hypothermia (CIH), lithium-induced (5-HT mediated) head twitches (LIH) and haloperidol-induced (DA- mediated) catalepsy (HIC) models. Piracetam was used as the standard drug. A significant increase in inflexion ratio (IR) was recorded in EPM, SIA and DIA models. A significant reversal effect was observed on rectal temperature in CIH model, reduction of head twitches in LIH models. However no significant reduction in catalepsy scores in HIC models were observed with test extracts and standard piracetam. The results indicate that nootropic activity observed with ALE and AQE of tuber extracts of P. tuberosa could be through improved learning and memory either by augmenting the noradrenaline (NA) transmission or by interfering with 5-hydroxytryptamine (5-HT) release. Further, the extracts neither facilitated nor blocked release of the dopamine (DA). Thus ALE and AQE elicited significant nootropic effect in mice and rats by interacting with cholinergic, GABAnergic, adrenergic and serotonergic systems. Phytoconstituents like flavonoids have been reported for their nootropic effect and these are present in both ALE and AQE extracts of tubers of P. tuberosa (Roxb) and these active principles may be responsible for nootropic activity.

  10. Renal Failure in Dementia with Lewy Bodies Presenting as Catatonia

    Directory of Open Access Journals (Sweden)

    Robert Fekete

    2013-01-01

    Full Text Available Catatonia, originally described by Karl Kahlbaum in 1874, may be regarded as a set of clinical features found in a subtype of schizophrenia, but the syndrome may also stem from organic causes including vascular parkinsonism, brain masses, globus pallidus lesions, metabolic derangements, and pharmacologic agents, especially first generation antipsychotics. Catatonia may include paratonia, waxy flexibility (cerea flexibilitas, stupor, mutism, echolalia, and catalepsy (abnormal posturing. A case of catatonia as a result of acute renal failure in a patient with dementia with Lewy bodies is described. This patient recovered after intravenous fluid administration and reinstitution of the atypical dopamine receptor blocking agent quetiapine, but benzodiazepines and amantadine are additional possible treatments. Recognition of organic causes of catatonia leads to timely treatment and resolution of the syndrome.

  11. Electroconvulsive therapy for catatonia in juvenile neuropsychiatric lupus.

    Science.gov (United States)

    Leon, T; Aguirre, A; Pesce, C; Sanhueza, P; Toro, P

    2014-09-01

    Neuropsychiatric manifestations are serious and frequent complications of systemic lupus erythematous (SLE). Catatonia is a neuropsychiatric disorder characterized by motor disturbance (including waxy flexibility and catalepsy), stupor, excitement, negativism, mutism, echopraxia and echolalia. Catatonia associated with SLE has been only rarely reported, especially in children. Here we present a case of a 14-year-old patient encountered in consultation-liaison psychiatry who presented catatonia associated with SLE. Her catatonia was refractory to treatment with pulse methylprednisolone, intravenous cyclophosphamide and rituximab. The patient responded to a combined therapy of electroconvulsive therapy and benzodiazepines. The present case suggests that although rarely reported, catatonia seen in the background of SLE should be promptly identified and treated to reduce the morbidity.

  12. Movement disorders in catatonia.

    Science.gov (United States)

    Wijemanne, Subhashie; Jankovic, Joseph

    2015-08-01

    Catatonia is a complex neuropsychiatric syndrome characterised by a broad range of motor, speech and behavioural abnormalities. 'Waxy flexibility', 'posturing' and 'catalepsy' are among the well-recognised motor abnormalities seen in catatonia. However, there are many other motor abnormalities associated with catatonia. Recognition of the full spectrum of the phenomenology is critical for an accurate diagnosis. Although controlled trials are lacking benzodiazepines are considered first-line therapy and N-Methyl-d-aspartate receptor antagonists also appears to be effective. Electroconvulsive therapy is used in those patients who are resistant to medical therapy. An underlying cause of the catatonia should be identified and treated to ensure early and complete resolution of symptoms.

  13. Pharmacological evaluation of bee venom and melittin

    Directory of Open Access Journals (Sweden)

    Camila G. Dantas

    2014-01-01

    Full Text Available The objective of this study was to identify the pharmacological effects of bee venom and its major component, melittin, on the nervous system of mice. For the pharmacological analysis, mice were treated once with saline, 0.1 or 1.2 mg/kg of bee venom and 0.1 mg/kg of melittin, subcutaneously, 30 min before being submitted to behavioral tests: locomotor activity and grooming (open-field, catalepsy, anxiety (elevated plus-maze, depression (forced swimming test and apomorphine-induced stereotypy. Haloperidol, imipramine and diazepam were administered alone (positive control or as a pre-treatment (haloperidol.The bee venom reduced motor activity and promoted cataleptic effect, in a similar manner to haloperidol.These effects were decreased by the pretreatment with haloperidol. Both melittin and bee venom decreased the apomorphine-induced stereotypies. The data indicated the antipsychotic activity of bee venom and melittin in a murine model.

  14. Synthesis, computational studies and preliminary pharmacological evaluation of 2-[4-(aryl substituted piperazin-1-yl]-N-benzylacetamides as potential antipsychotics

    Directory of Open Access Journals (Sweden)

    Sushil Kumar

    2016-11-01

    Full Text Available A series of 2-[4-(aryl substituted piperazin-1-yl]-N-benzylacetamides were synthesized and the target compounds (3a–j were evaluated for atypical antipsychotic activity by studying apomorphine induced climbing behavior, 5-HTP induced head twitches behavior and catalepsy in mice. The physicochemical similarity of the target compounds with respect to standard drugs clozapine, ketanserin and risperidone was assessed by calculating from a set of physicochemical properties using software programs. The test compounds (3a–j demonstrated good similarity values with respect to the standard drugs. Among them, compound 3b has emerged as an important lead compound showing potential atypical antipsychotic-like profile.

  15. Synthesis and pharmacological evaluation of piperidine (piperazine)-substituted benzoxazole derivatives as multi-target antipsychotics.

    Science.gov (United States)

    Huang, Ling; Zhang, Wenjun; Zhang, Xiaohua; Yin, Lei; Chen, Bangyin; Song, Jinchun

    2015-11-15

    The present study describes the optimization of a series of novel benzoxazole-piperidine (piperazine) derivatives combining high dopamine D2 and serotonin 5-HT1A, 5-HT2A receptor affinities. Of these derivatives, the pharmacological features of compound 29 exhibited high affinities for the DA D2, 5-HT1A and 5-HT2A receptors, but low affinities for the 5-HT2C and histamine H1 receptors and human ether-a-go-go-related gene (hERG) channels. Furthermore, compound 29 reduced apomorphine-induced climbing and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head twitching without observable catalepsy, even at the highest dose tested. Thus, compound 29 is a promising candidate as a multi-target antipsychotic treatment.

  16. Design, synthesis, pharmacological evaluation and computational studies of 1-(biphenyl-4-yl)-2-[4-(substituted phenyl)-piperazin-1-yl]ethanones as potential antipsychotics.

    Science.gov (United States)

    Bhosale, Sharad H; Kanhed, Ashish M; Dash, Radha Charan; Suryawanshi, Mugdha R; Mahadik, K R

    2014-03-03

    This article describes the design of biphenyl moiety linked with aryl piperazine and syntheses of fourteen 1-(biphenyl-4-yl)-2-[4-(substituted phenyl)-piperazin-1-yl]ethanone derivatives along with their pharmacological evaluation for antipsychotic activity and computational studies including quantitative structure activity relationship (QSAR) and descriptor based similarity study. All compounds were found to exhibit considerable anti-dopaminergic and anti-serotonergic activity in behavioural models. Among all derivatives, compound 1-(biphenyl-4-yl)-2-[4-(2-methoxyphenyl)-piperazin-1-yl]ethanone (3c) and 1-(biphenyl-4-yl)-2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]ethanone (3k) showed impressive antipsychotic profile with lower potency for catalepsy induction. These results were found to be sturdily matching with docking study in designing of compounds with homology model of human dopamine D2 receptor. Also the QSAR study strongly supports the obtained results.

  17. SYNTHESIS, COMPUTATIONAL STUDY AND PRELIMINARY PHARMACOLOGICAL EVALUATION OF 2-[4-(2-CHLOROBENZYL/BENZOYL SUBSTITUTED PIPERAZIN-1-YL]-N-PHENYLACETAMIDE: POTENTIAL ANTIPSYCHOTICS

    Directory of Open Access Journals (Sweden)

    Tomar Amita

    2011-06-01

    Full Text Available Benzyl and benzoyl substituted acetamides have been synthesized and evaluated as potential antipsychotic agents. The target compounds (4a-b were prepared by reaction of substituted anilines with chloroacetylchloride which further treated with 2-chlorobenzyl or 2-chlorobenzoyl piperazine in presence of potassium carbonate and potassium iodide as catalyst in acetonitrile. The structures of the target compounds (4a-b were characterized on the basis of their M.P., TLC, IR and 1H-NMR data. Computational studies of target compounds (4a-b were carried out by using software programs. The target compounds showed good similarity with respect to standard drugs. The target compounds (4a-b showed inhibition of 5-HTP induced head twitches behavior and low induction of catalepsy in mice.

  18. Solcoseryl improves learning and memory in rats.

    Science.gov (United States)

    Winnicka, M M; Braszko, J J; Wisniewski, K

    1996-01-01

    Our previous experiments have shown that Solcoseryl (S), a protein-free extract of calves' blood stimulates locomotor activity and decreases haloperidol catalepsy in rats. In this study the influence of S on acquisition, consolidation, and recall of both, conditioned avoidance responses (CARs) and passive avoidance behaviour was tested. S at the intraperitoneal (i.p.) dose of 1.25 ml/kg significantly improved acquisition and at the dose of 1.0 ml/kg recall of CARs. In the passive avoidance situation the significant effect on acquisition and recall of information was observed after i.p. injection of 1.0 ml/kg of S, and on consolidation after 0.75 ml/kg. These data indicate that S may positively affect the CNS processes responsible for learning and memory.

  19. Bromocriptine loaded chitosan nanoparticles intended for direct nose to brain delivery: pharmacodynamic, pharmacokinetic and scintigraphy study in mice model.

    Science.gov (United States)

    Md, Shadab; Khan, Rashid A; Mustafa, Gulam; Chuttani, Krishna; Baboota, Sanjula; Sahni, Jasjeet K; Ali, Javed

    2013-02-14

    The primary aim of this study was to investigate the potential use of chitosan nanoparticles as a delivery system to enhance the brain targeting efficiency of bromocriptine (BRC) following intranasal (i.n.) administration. The BRC loaded chitosan nanoparticles (CS NPs) were prepared by ionic gelation of CS with tripolyphosphate anions. These NPs had a mean size (161.3 ± 4. 7 nm), zeta potential (+40.3 ± 2.7 mV), loading capacity (37.8% ± 1.8%) and entrapment efficiency (84.2% ± 3.5%). The oral administration of haloperidol (2mg/kg) to mice produced typical Parkinson (PD) symptoms. Catalepsy and akinesia outcomes in animals receiving BRC either in solution or within CS NPs showed a reversal in catalepsy and akinesia behavior when compared to haloperidol treated mice, this reversal being specially pronounced in mice receiving BRC loaded CS NPs. Biodistribution of BRC formulations in the brain and blood of mice following i.n. and intravenous (i.v.) administration was performed using optimized technetium labeled (99mTc-labeled) BRC formulations. The brain/blood ratio of 0.47 ± 0.04, 0.69 ± 0.031, and 0.05 ± 0.01 for BRC solution (i.n.), BRC loaded CS NPs (i.n.) and (i.v.) respectively, at 0.5h are suggestive of direct nose to brain transport bypassing the blood-brain barrier. Gamma scintigraphy imaging of mice brain following i.v. and i.n. administrations were performed to determine the localization of drug in brain. The drug targeting index and direct transport percentage for BRC loaded CS NPs following i.n. route were 6.3 ± 0.8 and 84.2% ± 1.9%. These encouraging results confirmed the development of a novel non-invasive nose to brain delivery system of BRC for the treatment of PD.

  20. Neuroprotective potential of Beta vulgaris L. in Parkinson′s disease

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    Vandana S Nade

    2015-01-01

    Full Text Available Objective: The objective was to investigate the neuroprotective role of Beta vulgaris in Parkinson′s disease (PD. Materials and Methods: PD was induced by administration of reserpine (5 mg/kg/day, i.p for 5 consecutive days, haloperidol (1 mg/kg, i.p., and tacrine (2.5 mg/kg, i.p. in experimental animals. The symptoms of PD such as tremors, akinesia, rigidity, catalepsy, and vacuous chewing movements (VCMs were evaluated. Foot shock-induced aggression (FSIA model was used to confirm anti-parkinsonian activity. The methanolic extract of Beta vulgaris (MEBV was administered at doses of 100, 200, and 300 mg/kg, p.o. The combination of L-dopa and carbidopa was used as a standard drug. Behavioral studies such as locomotor activity and grip strength were determined, and oxidative stress was evaluated in FSIA model in rat brain. Results: Pretreatment with MEBV (200 and 300 mg/kg significantly reduced the intensity of muscular rigidity, duration of catalepsy, akinesia, the number of tremors, VCMs, and increase fighting behavior. The locomotor activity and grip strength were significantly increased by MEBV. In FSIA, the biochemical analysis of brain revealed the increased level of lipid peroxidation (LPO and decreased levels of superoxide dismutase (SOD and catalase (CAT. MEBV significantly reduced LPO level and restored the defensive antioxidant enzymes SOD and CAT in rat brain. Conclusions: The results indicated the protective role of B. vulgaris against PD. The mechanism of protection may be due to augmentation of cellular antioxidants.

  1. Augmentation by escitalopram, but not citalopram or R-citalopram, of the effects of low-dose risperidone: behavioral, biochemical, and electrophysiological evidence.

    Science.gov (United States)

    Marcus, Monica M; Jardemark, Kent; Malmerfelt, Anna; Gertow, Jens; Konradsson-Geuken, Asa; Svensson, Torgny H

    2012-04-01

    Antidepressant drugs are frequently used to treat affective symptoms in schizophrenia. We have recently shown that escitalopram, but not citalopram or R-citalopram, increases firing rate and burst firing of midbrain dopamine neurons, potentiates cortical N-methyl-D-aspartate (NMDA) receptor-mediated transmission and enhances cognition, effects that might influence the outcome of concomitant antipsychotic medication. Here, we studied, in rats, the behavioral and neurobiological effects of adding escitalopram, citalopram, or R-citalopram to the second-generation antipsychotic drug risperidone. We examined antipsychotic efficacy using the conditioned avoidance response (CAR) test, extrapyramidal side effect (EPS) liability using a catalepsy test, dopamine outflow in the medial prefrontal cortex (mPFC) and nucleus accumbens using in vivo microdialysis in freely moving animals, and NMDA receptor-mediated transmission in the mPFC using intracellular electrophysiological recording in vitro. Only escitalopram (5 mg/kg), but not citalopram (10 mg/kg), or R-citalopram (10 mg/kg), dramatically enhanced the antipsychotic-like effect of a low dose of risperidone (0.25 mg/kg), without increasing catalepsy. Given alone, escitalopram, but not citalopram or R-citalopram, markedly enhanced both cortical dopamine output and NMDA receptor-mediated transmission. Addition of escitalopram and to some extent R-citalopram, but not citalopram, significantly enhanced both cortical dopamine output and cortical NMDA receptor-mediated transmission induced by a suboptimal dose/concentration of risperidone. These results suggest that adjunct treatment with escitalopram, but not citalopram, may enhance the effect of a subtherapeutic dose of risperidone on positive, negative, cognitive, and depressive symptoms in schizophrenia, yet without increased EPS liability.

  2. S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1] benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenyl-acetamide), a preferential dopamine D3 versus D2 receptor antagonist and potential antipsychotic agent: III. Actions in models of therapeutic activity and induction of side effects.

    Science.gov (United States)

    Millan, Mark J; Loiseau, Florence; Dekeyne, Anne; Gobert, Alain; Flik, Gunnar; Cremers, Thomas I; Rivet, Jean-Michel; Sicard, Dorothée; Billiras, Rodolphe; Brocco, Mauricette

    2008-03-01

    In contrast to clinically available antipsychotics, the novel benzopyranopyrrolidine derivative, S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenyl-acetamide), behaves as a preferential antagonist of D(3) versus D(2) receptors and does not interact with histamine H(1) and muscarinic receptors. In contrast to haloperidol, clozapine, olanzapine, and risperidone, S33138 (0.16-2.5 mg/kg s.c.) did not disrupt performance in passive-avoidance and five-choice serial reaction time procedures. Furthermore, upon either systemic administration (0.04-2.5 mg/kg s.c.) or introduction into the frontal cortex (0.04-0.63 mug/side), S33138 potently attenuated the perturbation of social recognition by scopolamine or a prolonged intersession delay. Over a comparable and low-dose range, S33138 (0.04-0.63 mg/kg s.c.) elevated dialysis levels of acetylcholine in the frontal cortex of freely moving rats. At higher doses (2.5-10.0 mg/kg s.c.), S33138 also increased frontocortical levels of histamine, whereas monoamines, glutamate, glycine, and GABA were unaffected. By analogy to the other antipsychotics, S33138 (0.63-10.0 mg/kg s.c.) inhibited conditioned avoidance responses in rats, apomorphine-induced climbing in mice, and hyperlocomotion elicited by amphetamine, cocaine, dizocilpine, ketamine, and phencyclidine in rats. S33138 (0.16-2.5 mg/kg s.c.) also blocked the reduction of prepulse inhibition elicited by apomorphine. In comparison with the above actions, only "high" doses of S33138 (10.0-40.0 mg/kg s.c.) elicited catalepsy. To summarize, reflecting preferential blockade of D(3) versus D(2) receptors, S33138 preserves and/or enhances cognitive function, increases frontocortical cholinergic transmission, and is active in models of antipsychotic properties at doses well below those inducing catalepsy. In comparison with clinically available agents, S33138 displays, thus, a distinctive and promising profile of potential

  3. CB1 Knockout Mice Unveil Sustained CB2-Mediated Antiallodynic Effects of the Mixed CB1/CB2 Agonist CP55,940 in a Mouse Model of Paclitaxel-Induced Neuropathic Pain.

    Science.gov (United States)

    Deng, Liting; Cornett, Benjamin L; Mackie, Ken; Hohmann, Andrea G

    2015-07-01

    Cannabinoids suppress neuropathic pain through activation of cannabinoid CB1 and/or CB2 receptors; however, unwanted CB1-mediated cannabimimetic effects limit clinical use. We asked whether CP55,940 [(-)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexanol], a potent cannabinoid that binds with similar affinity to CB1 and CB2 in vitro, produces functionally separable CB1- and CB2-mediated pharmacological effects in vivo. We evaluated antiallodynic effects, possible tolerance, and cannabimimetic effects (e.g., hypothermia, catalepsy, CB1-dependent withdrawal signs) after systemic CP55,940 treatment in a mouse model of toxic neuropathy produced by a chemotherapeutic agent, paclitaxel. The contribution of CB1 and CB2 receptors to in vivo actions of CP55,940 was evaluated using CB1 knockout (KO), CB2KO, and wild-type (WT) mice. Low-dose CP55,940 (0.3 mg/kg daily, i.p. ) suppressed paclitaxel-induced allodynia in WT and CB2KO mice, but not CB1KO mice. Low-dose CP55,940 also produced hypothermia and rimonabant-precipitated withdrawal in WT, but not CB1KO, mice. In WT mice, tolerance developed to CB1-mediated hypothermic effects of CP55,940 earlier than to antiallodynic effects. High-dose CP55,940 (10 mg/kg daily, i.p.) produced catalepsy in WT mice, which precluded determination of antiallodynic efficacy but produced sustained CB2-mediated suppression of paclitaxel-induced allodynia in CB1KO mice; these antiallodynic effects were blocked by the CB2 antagonist 6-iodopravadoline (AM630). High-dose CP55,940 did not produce hypothermia or rimonabant-precipitated withdrawal in CB1KO mice. Our results using the mixed CB1/CB2 agonist CP55,940 document that CB1 and CB2 receptor activations produce mechanistically distinct suppression of neuropathic pain. Our study highlights the therapeutic potential of targeting cannabinoid CB2 receptors to bypass unwanted central effects associated with CB1 receptor activation.

  4. Ameliorative effect of Sida cordifolia in rotenone induced oxidative stress model of Parkinson's disease.

    Science.gov (United States)

    Khurana, Navneet; Gajbhiye, Asmita

    2013-12-01

    Present study focused on the evaluation of aqueous extract of Sida cordifolia (AESC), and its different fractions; hexane (HFSC), chloroform (CFSC) and aqueous (AFSC), against rotenone induced biochemical, neurochemical, histopathological and behavioral alterations in a rat model of Parkinson's disease (PD). An estimation of the level of thiobarbituric acid reactive substances (TBARS), glutathione (GSH) and catalase (CAT) along with superoxide anion generation (SAG) in different brain regions (cortex, midbrain and cerebellum) was carried out to assess biochemical changes. Behavioral evaluation tests (catalepsy, rearing behavior and posture instability) and neurochemical estimations (norepinephrine, dopamine and serotonin level) along with histopathological evaluations of different brain regions were also performed. The varying doses (50, 100, 250mg/kg; p.o.) of different test treatments (AESC, HFSC, CFSC and AFSC) were co-administered along with rotenone (2mg/kg; s.c.), for a period of 35 days to rats of various groups and compared with rotenone per se (negative control) and l-deprenyl (positive control; 10mg/kg; p.o.) treated groups for the above mentioned parameters. The increase in catalepsy and posture instability along with decrease in rearing behavior observed due to rotenone treatment was significantly attenuated by co-treatment with varying doses of AESC and AFSC. Results of the histopathological studies of different brain regions of rats showed eosinophilic lesions in the mid brain region due to rotenone treatment. The eosinophilic lesions were significantly attenuated in co-treated groups of AESC-100mg/kg and AFSC-100mg/kg. Rotenone induced oxidative damage, revealed by increased level of TBARS, SAG and decreased level of GSH and CAT in mid brain region of rats, was attenuated by the co-treatment of AESC and AFSC. The rotenone induced decrease of dopamine level in the midbrain region of rats was also attenuated by co-treatment of AESC-100mg/kg and AFSC

  5. The Antinociceptive and Anti-Inflammatory Activities of Aspidosperma tomentosum (Apocynaceae

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    Anansa Bezerra de Aquino

    2013-01-01

    Full Text Available We investigated the antinociceptive and anti-inflammatory activities of the crude ethanolic extract (CEE, its fractions, and the flavonoid isorhamnetin from Aspidosperma tomentosum using models of nociception and inflammation in mice. In the writhing test, the CEE and its fractions (except for soluble phase, CHCl3 100% and EtAcO 100% at 100 mg/kg p.o. induced antinociceptive activity. Isorhamnetin (100 μmol/kg, p.o. was also active. In the hot plate test, only the treatment with the fractions Hex : CHCl3 50%, CHCl3 100%, and CHCl3 : MeOH 5% (100 mg/kg, p.o. increased the latency time, reversed by the opioid antagonist naloxone. Fractions that were active in the hot plate test did not show catalepsy condition. It was observed that CEE, all fractions, and isorhamnetin reduced the formalin effects in the neurogenic phase. In the inflammatory phase, only CEE, isorhamnetin, and CHCl3 100% and CHCl3 : MeOH 5% fractions were active. CEE and all fractions, except for CHCl3 : MeOH 10% fraction, isorhamnetin, and soluble fraction were able to produce an antioedematogenic activity in the ear capsaicin-induced edema test. In the thioglycolate-induced peritonitis, only EtAcO 100% fraction was not active. The results demonstrate that A. tomentosum has antinociceptive and anti-inflammatory activities in animal models.

  6. Synthesis and evaluation of fluorinated derivatives of fentanyl as candidates for opiate receptor studies using positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Dahren Hwang; Feliu, A.L.; Wolf, A.P.; MacGregor, R.R.; Fowler, J.S.; Arnett, C.D.

    1986-03-01

    Three fluorinated derivatives of fentanyl, fluorofentanyl (3), keto-fluorofentanyl (5), and fluorofentanol (6), were synthesized and their abilities to compete with /sup 3/diprenorphine for binding sites in guinea pig brain membranes were determined. The relative potencies were fentanyl > 3 approx.= 6 >> 5. On the basis of its apparent affinity for opiate receptors and its relative ease of synthesis, 6 was selected for further study. Fentanyl was slightly better than 6 in its ability to compete with (/sup 3/H)naltrexone for binding sites in rat brain membranes. Both fentayl and 6 exhibited a similar high ''sodium ratio'' (quotient of the IC/sub 50/'s against (/sup 3/H)naltrexone in the presence and absence of sodium chloride) generally characteristic of opiate agonists. The analgesic potencies of fentanyl and 6 were determined in rats by measuring suppression of locomotion and vocalization responses to footshock. 6 appeared slightly less potent than fentanyl, but produced a similar analgesia and catalepsy which was entirely blocked by pretreatment of rats with naloxone, an opiate antagonist. A rapid synthesis of (/sup 18/F)-6 was developed and the tissue distribution of (/sup 18/F)-6 in mice was determined 5, 60, and 120 minutes after intravenous injection. The use of this general route to /sup 18/F-labeled derivatives of fentanyl for studies of the opiate receptor using positron emission tomography is planned.

  7. (+)-WIN 55,212-2, a novel cannabinoid receptor agonist, exerts antidystonic effects in mutant dystonic hamsters.

    Science.gov (United States)

    Richter, A; Löscher, W

    1994-11-03

    The effects of the novel high affinity cannabinoid receptor agonist (+)-WIN 55,212-2 ((R)-4,5-dihydro-2-methyl-4(4-morphoinylmethyl)-1-(1-naphthalen ylcarbonyl)-6H-pyrrolo[3,2,1-ij]quinolin-6-one) on severity of dystonia were investigated in mutant Syrian hamsters with primary generalized dystonia. Following injections of (+)-WIN 55,212-2 (1.0-5.0 mg/kg i.p.) a dose-dependent reduction of the severity of dystonia was observed. At antidystonic doses (2.5 and 5.0 mg/kg i.p.) (+)-WIN 55,212-2 caused a reduction of spontaneous motor activity and catalepsy. 1 mg/kg of (+)-WIN 55,212-2 exhibited neither antidystonic effects nor any side effects. However, the coadministration of 1.0 mg/kg (+)-WIN 55,212-2 with an ineffective dose of diazepam (0.1 mg/kg i.p.) exerted antidystonic effects in the absence of severe side effects. Although psychotropic effects of cannabinoids, such as (+)-WIN 55,212-2, limit the therapeutical utility of cannabinoids, the present data indicate that cannabinoids exert antidystonic effects and that low doses of cannabinoids may increase antidystonic efficacy of benzodiazepines.

  8. Wax on, wax off: a rare case of catatonia.

    Science.gov (United States)

    Greenberg, Karen; D'Ambrosio, Michael; Liebman, Kenneth M; Veznedaroglu, Erol

    2014-10-01

    Catatonia was first described by a German psychiatrist, Karl Kahlbaum, in 1874. It is a behavioral syndrome marked by an inability to move normally, which can occur in the context of many underlying general medical and psychiatric disorders. A wide variety of neurologic, metabolic, drug-induced, and psychiatric causes of catatonia have been reported. We present a unique case of late onset catatonia in a 56-year-old man with no prior medical or psychiatric history initially presenting with stroke-like symptoms. The patient was awake and alert, with spontaneous eye opening, but completely nonverbal and not following any commands. Specifically, the patient demonstrated stupor, catalepsy, mutism, and negativism. After extensive emergency department testing, including negative computed tomography head, negative magnetic resonance imaging brain, negative electroencephalogram, and normal laboratory results, the patient was diagnosed with new-onset bipolar disorder with depressive features presenting as catatonia. Recognizing catatonia is important because it may be caused or exacerbated by treatment of the underlying disorder. Failure to institute treatment early in the course of catatonia is associated with a poor prognosis.

  9. The potent opioid agonist, (+)-cis-3-methylfentanyl binds pseudoirreversibly to the opioid receptor complex in vitro and in vivo: Evidence for a novel mechanism of action

    Energy Technology Data Exchange (ETDEWEB)

    Band, L.; Xu, Heng; Bykov, V.; Rothman, R.B.; Kim, Chongho; Newman, A.; Jacobson, A.E.; Rice, K.C. (NIDDK, Bethesda, MD (USA)); Greig, N. (NIA, Bethesda, MD (USA))

    1990-01-01

    The present study demonstrates that pretreatment of rat brain membranes with (+)-cis-3-methylfentanyl ((+)-cis-MF), followed by extensive washing of the membranes, produces a wash-resistant decreasing in the binding of ({sup 3}H)-(D-ala{sup 2}, D-leu{sup 5})enkephalin to the d binding site of the opioid receptor complex ({delta}{sub cx} binding site). Intravenous administration of (+)-cis-MF (50 {mu}g/kg) to rats produced a pronounced catalepsy and also produced a wash-resistant masking of {delta}{sub cx} and {mu} binding sites in membranes prepared 120 min post-injection. Administration of 1 mg/kg i.v. of the opioid antagonist, 6-desoxy-6{beta}-fluoronaltrexone (cycloFOXY), 100 min after the injection of (+)-cis-MF (20 min prior to the preparation of membranes) completely reversed the catatonia and restored masked {delta}{sub cx} binding sites to control levels. This was not observed with (+)-cycloFOXY. The implications of these and other findings for the mechanism of action of (+)-cis-MF and models of the opioid receptors are discussed.

  10. Preliminary evaluation of manassantin A, a potential neuroleptic agent from Saururus cernuus.

    Science.gov (United States)

    Rao, K V; Puri, V N; Diwan, P K; Alvarez, F M

    1987-09-01

    Manassantin A (MNS-A), a novel dineolignan isolated from Saururus cernuus was evaluated for its central depressant effects. Intraperitoneal (IP) administration of MNS-A to mice at nontoxic doses caused a decrease in spontaneous motor activity and inhibition of amphetamine-induced stereotypy, with an ED50 of 0.21 +/- 0.02 mg/kg for its antiamphetamine activity. Doses of MNS-A up to the LD50 did not produce catalepsy and ptosis as were observed with haloperidol used as a reference drug. The compound caused a dose-dependent hypothermia, while haloperidol was not very effective in this test. Potentiation of pentobarbital-sleeping time was observed to be of comparable degree with both drugs. In spite of the higher toxicity (acute LD50 5.4 +/- 0.2 mg/kg, IP) than that shown by haloperidol, the somewhat selective neuroleptic profile of MNS-A makes it an interesting candidate for more detailed studies.

  11. Further studies on the neuroleptic profile of manassantin A.

    Science.gov (United States)

    Rao, K V; Puri, V N; el-Sawaf, H A

    1990-04-25

    In an earlier preliminary study, manassantin A, a neolignoid from Saururus cernuus was found to show neuroleptic type activity in mice when given by the i.p. route. It blocked the stereotypy and hyperactivity caused by amphetamine at doses comparable to those of haloperidol, but unlike the latter, did not show catalepsy or ptosis at atoxic doses. In the present study, a more detailed comparison of manassantin A with haloperidol and in some cases with chlorpromazine and reserpine using a variety of neuroleptic parameters and by various routes of administration is described. Results of the present study clearly show that the drug is readily absorbed from various routes of administration and shows many of the patterns of neuroleptic activity. Manassantin A was comparable to haloperidol in many of the tests but unlike the latter, did not produce antiadrenergic or anticholinergic effects. Manassantin A was found to bind weakly to calf caudate membranes (IC50 3500 nM) while haloperidol (IC50 5 nM) and chlorpromazine (IC50 50 nM) inhibited [3H]haloperidol binding. Manassantin A also did not affect the dopamine-induced adenylate cyclase activity in rat caudate nuclei (IC50 greater than 10,000 nM) while haloperidol (IC50 700 nM) and chlorpromazine (IC50 350 nM) inhibited the enzyme synthesis. These biochemical and behavioral tests suggest that manassantin A exhibits a selective neuroleptic profile and may be considered to behave as an atypical agent.

  12. Antiparkinsonian effects of aqueous methanolic extract of Hyoscyamus niger seeds result from its monoamine oxidase inhibitory and hydroxyl radical scavenging potency.

    Science.gov (United States)

    Sengupta, T; Vinayagam, J; Nagashayana, N; Gowda, B; Jaisankar, P; Mohanakumar, K P

    2011-01-01

    Hyoscyamus species is one of the four plants used in Ayurveda for the treatment of Parkinson's disease (PD). Since Hyoscyamus niger was found to contain negligible levels of L-DOPA, we evaluated neuroprotective potential, if any, of characterized petroleum ether and aqueous methanol extracts of its seeds in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD in mice. Air dried authenticated H. niger seeds were sequentially extracted using petroleum ether and aqueous methanol and were characterized employing HPLC-electrochemistry and LCMS. Parkinsonian mice were treated daily twice with the extracts (125-500 mg/kg, p.o.) for two days and motor functions and striatal dopamine levels were assayed. Administration of the aqueous methanol extract (containing 0.03% w/w of L-DOPA), but not petroleum ether extract, significantly attenuated motor disabilities (akinesia, catalepsy and reduced swim score) and striatal dopamine loss in MPTP treated mice. Since the extract caused significant inhibition of monoamine oxidase activity and attenuated 1-methyl-4-phenyl pyridinium (MPP+)-induced hydroxyl radical (·OH) generation in isolated mitochondria, it is possible that the methanolic extract of Hyoscyamus niger seeds protects against parkinsonism in mice by means of its ability to inhibit increased ·OH generated in the mitochondria.

  13. Dorsal striatum D1-expressing neurons are involved with sensorimotor gating on prepulse inhibition test.

    Science.gov (United States)

    Rodrigues, Samanta; Salum, Cristiane; Ferreira, Tatiana L

    2017-01-01

    Prepulse inhibition (PPI) is a behavioral test in which the startle reflex response to a high-intensity stimulus (pulse) is inhibited by the prior presentation of a weak stimulus (prepulse). The classic neural circuitry that mediates startle response is localized in the brainstem; however, recent studies point to the contribution of structures involved in higher cognitive functions in regulating the sensorimotor gating, particularly forebrain regions innervated by dopaminergic nuclei. The aim of the present study was to verify the role of dorsal striatum (DS) and dopaminergic transmitting mediated by D1 and D2 receptors on PPI test in rats. DS inactivation induced by muscimol injection did not affect PPI (%PPI and startle response), although it impaired the locomotor activity and caused catalepsy. Infusion of D1-like antagonist SCH23390 impaired %PPI but did not disturb the startle response and locomotor activity evaluated immediately after PPI test. D2 antagonist microinjection (sulpiride) did not affect %PPI and startle response, but impaired motor activity. These results point to an important role of DS, probably mediated by direct basal ganglia pathway, on modulation of sensorimotor gating, in accordance with clinical studies showing PPI deficits in schizophrenia, Tourette syndrome, and compulsive disorders - pathologies related to basal ganglia dysfunctions.

  14. Nonhuman primates: translational models for predicting antipsychotic-induced movement disorders.

    Science.gov (United States)

    Porsolt, Roger D; Castagné, Vincent; Hayes, Eric; Virley, David

    2013-12-01

    Repeated haloperidol treatment administered to nonhuman primates (NHPs) over several months or even years leads to the gradual appearance of drug-induced dystonic reactions in the orofacial region (mouth opening, tongue protrusion or retraction, bar biting) and in the whole body (writhing of the limbs and trunk, bar grasping). The propensity of antipsychotics to induce dystonia in NHPs is not correlated with their propensity to induce catalepsy in rodents, suggesting that the two types of effects are dissociated and may represent distinct aspects of the extrapyramidal symptoms induced by antipsychotics. In view of the clear homology to clinically observed phenomena, antipsychotic-induced dystonias in antipsychotic-primed NHPs would appear to possess a high degree of translational validity. These NHP phenomena could therefore serve as a useful model for predicting the occurrence of similar abnormal movements with novel substances developed for the treatment of schizophrenia or other psychotic disorders. Moreover, the NHP dystonia model could possibly serve as a biomarker for substances that will eventually cause tardive dyskinesia in patients.

  15. Animal models for predicting the efficacy and side effects of antipsychotic drugs

    Directory of Open Access Journals (Sweden)

    Pedro H. Gobira

    2013-01-01

    Full Text Available The use of antipsychotic drugs represents an important approach for the treatment of schizophrenia. However, their efficacy is limited to certain symptoms of this disorder, and they induce serious side effects. As a result, there is a strong demand for the development of new drugs, which depends on reliable animal models for pharmacological characterization. The present review discusses the face, construct, and predictive validity of classical animal models for studying the efficacy and side effects of compounds for the treatment of schizophrenia. These models are based on the properties of antipsychotics to impair the conditioned avoidance response and reverse certain behavioral changes induced by psychotomimetic drugs, such as stereotypies, hyperlocomotion, and deficit in prepulse inhibition of the startle response. Other tests, which are not specific to schizophrenia, may predict drug effects on negative and cognitive symptoms, such as deficits in social interaction and memory impairment. Regarding motor side effects, the catalepsy test predicts the liability of a drug to induce Parkinson-like syndrome, whereas vacuous chewing movements predict the liability to induce dyskinesia after chronic treatment. Despite certain limitations, these models may contribute to the development of more safe and efficacious antipsychotic drugs.

  16. Haloperidol-loaded polysorbate-coated polymeric nanocapsules increase its efficacy in the antipsychotic treatment in rats.

    Science.gov (United States)

    Benvegnú, Dalila M; Barcelos, Raquel C S; Boufleur, Nardeli; Reckziegel, Patrícia; Pase, Camila S; Ourique, Aline F; Beck, Ruy Carlos R; Bürger, Marilise E

    2011-02-01

    Haloperidol is an antipsychotic drug associated with the development of movement disorders. We evaluated the effect of its nanoencapsulation on its pharmacological activity and motor side effects. Haloperidol-loaded polysorbate-coated nanocapsules (H-NC) showed nanometric size, negative zeta potential and low polydispersity indices and high encapsulation efficiency (>95%). Rats received a single dose of H-NC (0.2mg/kg ip) and four doses of D,L-amphetamine, AMPH (8.0mg/kg ip), injected every 3h (0, 3, 6 and 9h). The AMPH-induced stereotyped movements were quantified in the intervals of 15 min after each of four doses of AMPH, demonstrating greater pharmacological efficacy of the H-NC over free haloperidol (FH). The acute motor side effects were evaluated 1h after a single dose of H-NC or its free solution (0.2mg/kg ip). The group treated with H-NC presented lower extrapyramidal effects (catalepsy and oral dyskinesia) than those treated with FH. In the last experimental set, rats sub-chronically treated with a daily dose of H-NC (0.2mg/kg ip) for 28 days showed a lower incidence of extrapyramidal effects than those treated with the free drug (0.2mg/kg ip). Our findings showed the potential of using H-NC in the development of a nanomedicine aimed at increasing the efficacy of this antipsychotic drug and reducing its side effects.

  17. Anticataleptic activity of cathinone and MDMA (Ecstasy) upon acute and subchronic administration in rat.

    Science.gov (United States)

    Banjaw, Mehret Yerdaw; Mayerhofer, Andreas; Schmidt, Werner J

    2003-09-15

    It was recently demonstrated that acute administration of 3,4-methylenedioxymethamphet-amine (MDMA, "Ecstasy") is capable of counteracting haloperidol-induced catalepsy in rats. The present study was done with another psychostimulant, S-(-)-cathinone. In these experiments, 32 male Sprague-Dawley rats, 225 +/- 25 g, were used. They were divided into three groups. All groups received 0.5 mg/kg haloperidol in normal saline (s.c.) as a first injection. Then 30 min later each group received either isotonic phosphate-buffered saline, 1 mg/kg S-(-)-cathinone, or 2.5 mg/kg (RS)-MDMA (s.c.) as a second injection. The results of descent latency on both the horizontal bar and vertical grid showed that S-(-)-cathinone or (RS)-MDMA upon acute administration induces a strong anticataleptic activity (P mechanism of the observed strong anticataleptic activity of S-(-)-cathinone (which is considered a potent dopamine releaser) requires further investigation.

  18. Ultrapure ajulemic acid has improved CB2 selectivity with reduced CB1 activity.

    Science.gov (United States)

    Tepper, Mark A; Zurier, Robert B; Burstein, Sumner H

    2014-07-01

    Ajulemic acid, a side-chain analog of Δ(8)-THC-11-oic acid, was designed as a potent therapeutic agent free of the psychotropic adverse effects typical of most cannabinoids. Subsequent studies of ajulemic acid have yielded widely divergent findings on the occurrence of these adverse effects. To help resolve these discrepancies, we have prepared highly purified ajulemic acid using a different synthetic method than previously reported in the literature and compared its cannabinoid receptor binding constants with those obtained using several other preparations from different sources. Whereas CB2 binding did not vary greatly among all of the samples, the CB1 binding showed a wide range of affinities. The highly purified product (JBT-101) reported here had the weakest affinity for CB1 while the original preparation (HU-239) showed the strongest affinity for CB1. The CB1/CB2 ratio of affinities was 12.3 for JBT-101 whereas that for HU-239 was 0.19, a 65-fold difference. Functional responses such as catalepsy and hypothermia using JBT-101 versus HU-239 displayed reduced CB1 activity in keeping with the receptor binding data. Thus, earlier conclusions on the limited therapeutic index for ajulemic acid need to be reconsidered in the light of the data now obtained using JBT-101.

  19. Preliminary phytochemical, pharmacological and antibacterial studies of the alkaloidal extracts of the leaves of Synclisia scabrida Miers.

    Science.gov (United States)

    Sokomba, E; Wambebe, C; Chowdhury, B K; Iriah, J; Ogbeide, O N; Orkor, D

    1986-11-01

    Preliminary phytochemical investigation of the leaves of Synclisia scabrida indicated the presence of two alkaloids in the water extracts and five alkaloids in the ethanol extracts. The alkaloidal fraction obtained from the cold ethanol extract furnished on column-chromatography, a homogeneous amorphous solid which has been designated as alkaloid C. Alkaloid C showed positive test for alkaloids. The UV and IR spectra and colour reactions of alkaloid C indicated that the compound may be a phenolic bisbenzylisoquinoline alkaloid. All the extracts delayed the onset and shortened the duration of apomorphine-induced stereotyped behaviour in chicks. In addition, 40 mg kg-1 i.p. of the ethanolic extract induced catalepsy in rats. The cold water extract (CWE) synchronized the EEG of the hyperstriatum, optic tectum and the reticular formation while the EMG activity was slightly enhanced. The hot ethanol alkaloidal extract (HEE) inhibited the growth of Pseudomonas aeruginosa and Staphylococcus aureus. The minimum inhibitory concentration of HEE on Pseudomonas aeruginosa strains I and II were 5 and 2.5 micrograms/ml while for Staphylococcus aureus strains I and II were 5 and 10 micrograms/ml, respectively. Up to 1 g kg-1 i.p. of the extract failed to induce any lethal effect in chicks and rats. These effects of the leaf extracts of Synclisia scabrida Miers support some of the local uses of the plant by traditional medical practitioners.

  20. Endocytosis following dopamine D2 receptor activation is critical for neuronal activity and dendritic spine formation via Rabex-5/PDGFRβ signaling in striatopallidal medium spiny neurons.

    Science.gov (United States)

    Shioda, N; Yabuki, Y; Wang, Y; Uchigashima, M; Hikida, T; Sasaoka, T; Mori, H; Watanabe, M; Sasahara, M; Fukunaga, K

    2016-12-06

    Aberrant dopamine D2 receptor (D2R) activity is associated with neuropsychiatric disorders, making those receptors targets for antipsychotic drugs. Here, we report that novel signaling through the intracellularly localized D2R long isoform (D2LR) elicits extracellular signal-regulated kinase (ERK) activation and dendritic spine formation through Rabex-5/platelet-derived growth factor receptor-β (PDGFRβ)-mediated endocytosis in mouse striatum. We found that D2LR directly binds to and activates Rabex-5, promoting early-endosome formation. Endosomes containing D2LR and PDGFRβ are then transported to the Golgi apparatus, where those complexes trigger Gαi3-mediated ERK signaling. Loss of intracellular D2LR-mediated ERK activation decreased neuronal activity and dendritic spine density in striatopallidal medium spiny neurons (MSNs). In addition, dendritic spine density in striatopallidal MSNs significantly increased following treatment of striatal slices from wild-type mice with quinpirole, a D2R agonist, but those changes were lacking in D2LR knockout mice. Moreover, intracellular D2LR signaling mediated effects of a typical antipsychotic drug, haloperidol, in inducing catalepsy behavior. Taken together, intracellular D2LR signaling through Rabex-5/PDGFRβ is critical for ERK activation, dendritic spine formation and neuronal activity in striatopallidal MSNs of mice.Molecular Psychiatry advance online publication, 6 December 2016; doi:10.1038/mp.2016.200.

  1. Solcoseryl stimulates behavioural activity of rats.

    Science.gov (United States)

    Braszko, J J; Winnicka, M M; Wiśniewski, K

    1996-01-01

    The influence of Solcoseryl (S), a protein-free extract of calves' blood given intraperitoneally (i.p.) on the behavioural measures of activity of the central nervous system of male Wistar rats was examined. The drug (1.0 ml/kg i.p.) given 60 min before testing the animals in electromagnetic motimeter significantly enhanced overall and vertical motility of rats. S at the doses of 0.5, 1.0 and 2.0 ml/kg did not significantly influence the activity of rats in "open field". 1.0 ml/kg of S given 15, 45 and 60 min before thiopental (30 mg/kg i.p.) did not change the onset and time of sleep following the latter drug, except for the significant shortening of the time of sleep of animals injected with S 15 min before thiopental. S at the dose of 1.0 ml/kg did not change stereotypies produced by apomorphine (2.0 mg/kg i.p.) and amphetamine (6.5 mg/kg i.p.) but decreased intensity of haloperidol (1.0 mg/kg i.p.) catalepsy.

  2. Systemic administration of the neurotensin NTS₁-receptor agonist PD149163 improves performance on a memory task in naturally deficient male brown Norway rats.

    Science.gov (United States)

    Keiser, Ashley A; Matazel, Katelin S; Esser, Melissa K; Feifel, David; Prus, Adam J

    2014-12-01

    Agonists for the neurotensin NTS₁ receptor consistently exhibit antipsychotic effects in animal models without producing catalepsy, suggesting that NTS₁-receptor agonists may be a novel class of drugs to treat schizophrenia. Moreover, studies utilizing NTS₁ agonists have reported improvements in some aspects of cognitive functioning, including prepulse inhibition and learning procedures, which suggest an ability of NTS₁-receptor agonists to diminish neurocognitive deficits. The present study sought to assess both baseline delay-induced memory performance and the effects of NTS₁-receptor activation on learning and memory consolidation in male Long-Evans and Brown Norway rats using a delayed nonmatch-to-position task radial arm-maze task. In the absence of drugs, Brown Norway rats displayed a significant increase in spatial memory errors following 3-, 7-, and 24-hr delay, whereas Long-Evans rats exhibited an increase in spatial memory errors following only a 7-, and 24-hr delay. With Brown Norway rats, administration of PD149163 before or after an information trial significantly reduced errors during a retention trial after a 24 hr delay. Administration of the NTS(1/2)-receptor antagonist SR142948 prior to the information trial did not affect retention-trial errors. These data are consistent with previous findings that Brown Norway rats have natural cognitive deficits and that they may be useful for assessing putative antipsychotic drugs for cognitive efficacy. Moreover, the results of this study support previous findings suggesting that NTS₁-receptor agonists may improve some aspects of cognitive functioning.

  3. In Vitro Opioid Receptor Affinity and in Vivo Behavioral Studies of Nelumbo nucifera Flower

    Science.gov (United States)

    Kumarihamy, Mallika; León, Francisco; Pettaway, Sara; Wilson, Lisa; Lambert, Janet A.; Wang, Mei; Hill, Christopher; McCurdy, Christopher R.; ElSohly, Mahmoud A.; Cutler, Stephen J.; Muhammad, Ilias

    2015-01-01

    Ethnopharmacological relevance Nelumbo nucifera Geartn., known as sacred lotus, has been used traditionally in South East Asia as a traditional medicine for various CNS disorders including stress, fever, depression, insomnia, and cognitive conditions. Aim of the study To investigate the in vitro cannabinoid and opioid receptor binding affinities, and in vivo behavioral actions of Nelumbo flower extracts and to isolate the potential compounds to treat CNS associated disorders. Materials and methods The white and pink flowers of N. nucifera were extracted with 95% EtOH, followed by acid-base partitioning using CHCl3 to give acidic and basic partitions. These partitions were subjected to Centrifugal Preparative TLC (CPTLC) to yield benzyltetrahydroisoquinoline (BTIQ) alkaloids and long chain fatty acids, identified by physical and spectroscopic methods. In addition, EtOH extracts and partitions were analyzed for chemical markers by UHPLC/MS and GC/MS. In vitro neuropharmacological effects were evaluated by cannabinoid (CB1 and CB2) and opioid [delta (δ), kappa (κ), and mu (μ)] competitive radioligand binding and GTPγS functional assays. The in vivo behavioral effect was studied through the use of the mouse tetrad assay at 10, 30, 75 and 100 mg/kg/ip doses that revealed the effect on locomotion, catalepsy, body temperature, and nociception of acidic and basic CHCl3 partitions, fractions, and compounds. Results Three aporphines, nuciferine (1), N-nor-nuciferine (2), asimilobine (3), and five BTIQs, armepavine (4), O-methylcoclaurine (5), N-methylcoclaurine (6), coclaurine (7), neferine (10), and a mixture of linoleic and palmitic acids (LA and PA), were identified and evaluated for cannabinoid and opioid receptor displacement activities. Compounds 5–7 showed binding affinities for the κ opioid receptor with equilibrium dissociation constant (Ki) values of 3.5±0.3, 0.9±0.1, 2.2±0.2 µM, respectively. Compound 10 displayed affinities for δ-and μ- opioid

  4. In Vitro and In Vivo Characterization of the Alkaloid Nuciferine.

    Directory of Open Access Journals (Sweden)

    Martilias S Farrell

    Full Text Available The sacred lotus (Nelumbo nucifera contains many phytochemicals and has a history of human use. To determine which compounds may be responsible for reported psychotropic effects, we used in silico predictions of the identified phytochemicals. Nuciferine, an alkaloid component of Nelumbo nucifera and Nymphaea caerulea, had a predicted molecular profile similar to antipsychotic compounds. Our study characterizes nuciferine using in vitro and in vivo pharmacological assays.Nuciferine was first characterized in silico using the similarity ensemble approach, and was followed by further characterization and validation using the Psychoactive Drug Screening Program of the National Institute of Mental Health. Nuciferine was then tested in vivo in the head-twitch response, pre-pulse inhibition, hyperlocomotor activity, and drug discrimination paradigms.Nuciferine shares a receptor profile similar to aripiprazole-like antipsychotic drugs. Nuciferine was an antagonist at 5-HT2A, 5-HT2C, and 5-HT2B, an inverse agonist at 5-HT7, a partial agonist at D2, D5 and 5-HT6, an agonist at 5-HT1A and D4 receptors, and inhibited the dopamine transporter. In rodent models relevant to antipsychotic drug action, nuciferine blocked head-twitch responses and discriminative stimulus effects of a 5-HT2A agonist, substituted for clozapine discriminative stimulus, enhanced amphetamine induced locomotor activity, inhibited phencyclidine (PCP-induced locomotor activity, and rescued PCP-induced disruption of prepulse inhibition without induction of catalepsy.The molecular profile of nuciferine was similar but not identical to that shared with several approved antipsychotic drugs suggesting that nuciferine has atypical antipsychotic-like actions.

  5. Antiasthmatic and antiallergic potential of methanolic extract of leaves of Ailanthus excelsa

    Directory of Open Access Journals (Sweden)

    Dinesh Kumar

    2011-02-01

    Full Text Available The aim of study was antiasthmatic potential of methanolic extract of leaves of Ailanthus excelsa Roxb., Simaroubaceae. Traditionally or in Indian system of medicine, A. excelsa is used in the treatment of asthma, cough, colic pain, cancer, diabetes and also used as antispasmodic, antifertility, bronchodilator. Stem bark of A. excelsa already reported for its potential against asthma. The pollens of Ailanthus excelsa reported allergic in nature and the time of collection of leaves were important in this study, generally the flowering stage of plant was avoided for the collection due to maximum chance of pollens at that time. Methanolic extract of leaves of A. excelsa was evaluated using in vitro goat tracheal chain preparation model and in vivo- Milk induced leucocytosis, eosinophilia, Clonidine induced catalepsy in mice model while Passive paw anaphylaxis and Clonidine induced mast cell degranulation in rat model. The extract showed the presence of flavonoids, terpenoids, saponins, quassonoids and test was also positive for alkaloids and steroids. The extract also showed the presence of quercetin which is flavonoid and detected on the preparative TLC plate with the help of standard quercetin. Dose response studies of methanolic extract of leaves of A. excelsa Roxb. were conducted at 100 µg mL-1 in vitro and 100, 200, 400 mg kg-1 p.o. in vivo models. The treatment with methanolic extract of A. excelsa at different dose level showed the significant (*p<0.05, **p<0.01, ***p<0.001 antiasthmatic activity. Inhibition or decrease the release of inflammatory mediators potentiates the antiasthmatic as well as antiallergic activity of methanolic extract of leaves of A. excelsa.

  6. Evaluation of anti-parkinson’s activity of gentisic acid in different animal models

    Institute of Scientific and Technical Information of China (English)

    Kabra MP; Bhandari SS; Sharma A; Gupta RB

    2014-01-01

    Objective:To evaluate the neuroprotective activity ofGentisic acid inPD.The study was conducted on swiss albinFo mice(20-25 g) & wistar rats(200-250 g).Methods:Three behavioural models namely,Haloperidol induced catalepsy,Reserpine antagonism andHaloperidol induce orofacial dyskinesia were employed in this study,SwissAlbino mice(20-25 g) were used in first two models whileWistar rats(200-250 g) used in last one model.There are five group(n=6) in each animal model.Various behavior activity/parameter(cataleptic behavior, horizontal movements, rearing & grooming frequencies andDyskinesia activity like vacuous chewing & tongue protrusion) in different animal models were used to evaluate the anti-Parkinson’s activity ofGentisic acid.Results:Gentisic acid showed a significant(P<0.01) reduction in the duration of cataleptic behavior dose dependently when compared to haloperidol control group.Gentisic acid shows dose dependant increase in the frequency of horizontal movement and rearing behavior when compared to theReserpine control group.But, the effect ofGentisic acid on the frequency of grooming behavior was found to be insignificant.Gentisic acid(80 mg/kg) showed a significant (P<0.05) decrease in the frequency of vacuous chewing & tongue protrusion but the other dose tested were found to be insignificant in this respect.Conclusions:Results shows that the Gentisic acid produced dose dependent neuroprotective activity in different animal models ofPD.

  7. A behavioural comparison of acute and chronic Delta9-tetrahydrocannabinol and cannabidiol in C57BL/6JArc mice.

    Science.gov (United States)

    Long, Leonora E; Chesworth, Rose; Huang, Xu-Feng; McGregor, Iain S; Arnold, Jonathon C; Karl, Tim

    2010-08-01

    Cannabis contains over 70 unique compounds and its abuse is linked to an increased risk of developing schizophrenia. The behavioural profiles of the psychotropic cannabis constituent Delta9-tetrahydrocannabinol (Delta9-THC) and the non-psychotomimetic constituent cannabidiol (CBD) were investigated with a battery of behavioural tests relevant to anxiety and positive, negative and cognitive symptoms of schizophrenia. Male adult C57BL/6JArc mice were given 21 daily intraperitoneal injections of vehicle, Delta9-THC (0.3, 1, 3 or 10 mg/kg) or CBD (1, 5, 10 or 50 mg/kg). Delta9-THC produced the classic cannabinoid CB1 receptor-mediated tetrad of hypolocomotion, analgesia, catalepsy and hypothermia while CBD had modest hyperthermic effects. While sedative at this dose, Delta9-THC (10 mg/kg) produced locomotor-independent anxiogenic effects in the open-field and light-dark tests. Chronic CBD produced moderate anxiolytic-like effects in the open-field test at 50 mg/kg and in the light-dark test at a low dose (1 mg/kg). Acute and chronic Delta9-THC (10 mg/kg) decreased the startle response while CBD had no effect. Prepulse inhibition was increased by acute treatment with Delta9-THC (0.3, 3 and 10 mg/kg) or CBD (1, 5 and 50 mg/kg) and by chronic CBD (1 mg/kg). Chronic CBD (50 mg/kg) attenuated dexamphetamine (5 mg/kg)-induced hyperlocomotion, suggesting an antipsychotic-like action for this cannabinoid. Chronic Delta9-THC decreased locomotor activity before and after dexamphetamine administration suggesting functional antagonism of the locomotor stimulant effect. These data provide the first evidence of anxiolytic- and antipsychotic-like effects of chronic but not acute CBD in C57BL/6JArc mice, extending findings from acute studies in other inbred mouse strains and rats.

  8. A Cannabinoid CB1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects.

    Science.gov (United States)

    Ignatowska-Jankowska, Bogna M; Baillie, Gemma L; Kinsey, Steven; Crowe, Molly; Ghosh, Sudeshna; Owens, Robert A; Damaj, Imad M; Poklis, Justin; Wiley, Jenny L; Zanda, Matteo; Zanato, Chiara; Greig, Iain R; Lichtman, Aron H; Ross, Ruth A

    2015-12-01

    The CB1 receptor represents a promising target for the treatment of several disorders including pain-related disease states. However, therapeutic applications of Δ(9)-tetrahydrocannabinol and other CB1 orthosteric receptor agonists remain limited because of psychoactive side effects. Positive allosteric modulators (PAMs) offer an alternative approach to enhance CB1 receptor function for therapeutic gain with the promise of reduced side effects. Here we describe the development of the novel synthetic CB1 PAM, 6-methyl-3-(2-nitro-1-(thiophen-2-yl)ethyl)-2-phenyl-1H-indole (ZCZ011), which augments the in vitro and in vivo pharmacological actions of the CB1 orthosteric agonists CP55,940 and N-arachidonoylethanolamine (AEA). ZCZ011 potentiated binding of [(3)H]CP55,940 to the CB1 receptor as well as enhancing AEA-stimulated [(35)S]GTPγS binding in mouse brain membranes and β-arrestin recruitment and ERK phosphorylation in hCB1 cells. In the whole animal, ZCZ011 is brain penetrant, increased the potency of these orthosteric agonists in mouse behavioral assays indicative of cannabimimetic activity, including antinociception, hypothermia, catalepsy, locomotor activity, and in the drug discrimination paradigm. Administration of ZCZ011 alone was devoid of activity in these assays and did not produce a conditioned place preference or aversion, but elicited CB1 receptor-mediated antinociceptive effects in the chronic constriction nerve injury model of neuropathic pain and carrageenan model of inflammatory pain. These data suggest that ZCZ011 acts as a CB1 PAM and provide the first proof of principle that CB1 PAMs offer a promising strategy to treat neuropathic and inflammatory pain with minimal or no cannabimimetic side effects.

  9. Nicotine reduces antipsychotic-induced orofacial dyskinesia in rats.

    Science.gov (United States)

    Bordia, Tanuja; McIntosh, J Michael; Quik, Maryka

    2012-03-01

    Antipsychotics are an important class of drugs for the management of schizophrenia and other psychotic disorders. They act by blocking dopamine receptors; however, because these receptors are present throughout the brain, prolonged antipsychotic use also leads to serious side effects. These include tardive dyskinesia, repetitive abnormal involuntary movements of the face and limbs for which there is little treatment. In this study, we investigated whether nicotine administration could reduce tardive dyskinesia because nicotine attenuates other drug-induced abnormal movements. We used a well established model of tardive dyskinesia in which rats injected with the commonly used antipsychotic haloperidol develop vacuous chewing movements (VCMs) that resemble human orofacial dyskinesias. Rats were first administered nicotine (minipump; 2 mg/kg per day). Two weeks later, they were given haloperidol (1 mg/kg s.c.) once daily. Nicotine treatment reduced haloperidol-induced VCMs by ∼20% after 5 weeks, with a significant ∼60% decline after 13 weeks. There was no worsening of haloperidol-induced catalepsy. To understand the molecular basis for this improvement, we measured the striatal dopamine transporter and nicotinic acetylcholine receptors (nAChRs). Both haloperidol and nicotine treatment decreased the transporter and α6β2* nAChRs (the asterisk indicates the possible presence of other nicotinic subunits in the receptor complex) when given alone, with no further decline with combined drug treatment. By contrast, nicotine alone increased, while haloperidol reduced α4β2* nAChRs in both vehicle and haloperidol-treated rats. These data suggest that molecular mechanisms other than those directly linked to the transporter and nAChRs underlie the nicotine-mediated improvement in haloperidol-induced VCMs in rats. The present results are the first to suggest that nicotine may be useful for improving the tardive dyskinesia associated with antipsychotic use.

  10. Behavioral indices in antipsychotic drug discovery.

    Science.gov (United States)

    Porsolt, Roger D; Moser, Paul C; Castagné, Vincent

    2010-06-01

    Schizophrenia is characterized by three major symptom classes: positive symptoms, negative symptoms, and cognitive deficits. Classical antipsychotics (phenothiazines, thioxanthenes, and butyrophenones) are effective against positive symptoms but induce major side effects, in particular, extrapyramidal symptoms (EPS). The discovery of clozapine, which does not induce EPS and is thought effective against all three classes of symptom, has driven research for novel antipsychotics with a wider activity spectrum and lower EPS liability. To increase predictiveness, current efforts aim to develop translational models where direct parallels can be drawn between the processes studied in animals and in humans. The present article reviews existing procedures in animals for their ability to predict compound efficacy and EPS liability in relation to their translational validity. Rodent models of positive symptoms include procedures related to dysfunction in central dopamine and glutamatergic (N-methyl-D-aspartate) and serotonin (5-hydroxytryptamine) neurotransmission. Procedures for evaluating negative symptoms include rodent models of anhedonia, affective flattening, and diminished social interaction. Cognitive deficits can be assessed in rodent models of attention (prepulse inhibition) and of learning/memory (object and social recognition, Morris water maze and operant-delayed alternation). The relevance of the conditioned avoidance response is also discussed. A final section reviews procedures for assessing EPS liability, in particular, parkinsonism (catalepsy in rodents), acute dystonia (purposeless chewing in rodents, dystonia in monkeys), akathisia (defecation in rodents), and tardive dyskinesia (long-term antipsychotic treatment in rodents and monkeys). It is concluded that, with notable exceptions (attention, learning/memory, EPS liability), current predictive models for antipsychotics fall short of clear translational validity.

  11. Despite strong behavioral disruption, Delta9-tetrahydrocannabinol does not affect cell proliferation in the adult mouse dentate gyrus.

    Science.gov (United States)

    Kochman, Linda J; dos Santos, Angela Amancio; Fornal, Casimir A; Jacobs, Barry L

    2006-10-01

    Marijuana is a widely abused illicit drug known to cause significant cognitive impairments. Marijuana has been hypothesized to target neurons in the hippocampus because of the abundance of cannabinoid receptors present in this structure. While there is no clear evidence of neuropathology in vivo, suppression of brain mitogenesis, and ultimately neurogenesis, may provide a sensitive index of marijuana's more subtle effects on neural mechanisms subserving cognitive functions. We examined the effects of different doses and treatment regimens of Delta(9)-tetrahydrocannabinol (THC), the main active ingredient in marijuana, on cell proliferation in the dentate gyrus of adult male mice. Following drug treatment, the thymidine analog 5-bromo-2'-deoxyuridine (BrdU; 200 mg/kg, i.p.) was administered two hours prior to sacrifice to assess cell proliferation, the first step in neurogenesis. Administration of THC produced dose-dependent catalepsy and suppression of motor activity. The number of BrdU-labeled cells was not significantly changed from vehicle control levels following either acute (1, 3, 10, 30 mg/kg, i.p.), sequential (two injections of 10 or 30 mg/kg, i.p., separated by 5 h), or chronic escalating (20 to 80 mg/kg, p.o.; for 3 weeks) drug administration. Furthermore, acute administration of the potent synthetic cannabinoid receptor agonist R-(+)-WIN 55,212-2 (WIN; 5 mg/kg, i.p.) also had no significant effect on cell proliferation. These findings provide no evidence for an effect of THC on hippocampal cell proliferation, even at doses producing gross behavioral intoxication. Whether marijuana or THC affects neurogenesis remains to be explored.

  12. Design Expert® supported optimization and predictive analysis of selegiline nanoemulsion via the olfactory region with enhanced behavioural performance in Parkinson’s disease

    Science.gov (United States)

    Kumar, Shobhit; Ali, Javed; Baboota, Sanjula

    2016-10-01

    Selegiline is a monoamine oxidase B (MAO-B) inhibitor and is used in the treatment of Parkinson’s disease. The main problem associated with its oral administration is its low oral bioavailability (10%) due to its poor aqueous solubility and extensive first pass metabolism. The aim of the present research work was to develop a nanoemulsion loaded with selegiline for direct nose-to-brain delivery for the better management of Parkinson’s disease. A quality by design (QbD) approach was used in a statistical multivariate method for the preparation and optimization of nanoemulsion. In this study, four independent variables were chosen, in which two were compositions and two were process variables, while droplet size, transmittance, zeta potential and drug release were selected as response variables. The optimized formulation was assessed for efficacy in Parkinson’s disease using behavioural studies, namely forced swimming, locomotor, catalepsy, muscle coordination, akinesia and bradykinesia or pole test in Wistar rats. The observed droplet size, polydispersity index (PDI), refractive index, transmittance, zeta potential and viscosity of selegiline nanoemulsion were found to be 61.43 ± 4.10 nm, 0.203 ± 0.005, 1.30 ± 0.01, 99.80 ± 0.04%, -34 mV and 31.85 ± 0.24 mPas respectively. Surface characterization studies demonstrated a spherical shape of nanoemulsion which showed 3.7 times enhancement in drug permeation as compared to drug suspension. The results of behaviour studies showed that treatment of haloperidol induced Parkinson’s disease in rats with selegiline nanoemulsion (administered intranasally) showed significant improvement in behavioural activities in comparison to orally administered drug. These findings demonstrate that nanoemulsion could be a promising new drug delivery carrier for intranasal delivery of selegiline in the treatment of Parkinson’s disease.

  13. Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity.

    Science.gov (United States)

    Brents, Lisa K; Gallus-Zawada, Anna; Radominska-Pandya, Anna; Vasiljevik, Tamara; Prisinzano, Thomas E; Fantegrossi, William E; Moran, Jeffery H; Prather, Paul L

    2012-04-01

    K2 and several similar purported "incense products" spiked with synthetic cannabinoids are abused as cannabis substitutes. We hypothesized that metabolism of JWH-073, a prevalent cannabinoid found in K2, contributes to toxicity associated with K2 use. Competition receptor binding studies and G-protein activation assays, both performed by employing mouse brain homogenates, were used to determine the affinity and intrinsic activity, respectively, of potential monohydroxylated (M1, M3-M5) and monocarboxylated (M6) metabolites at cannabinoid 1 receptors (CB1Rs). Surprisingly, M1, M4 and M5 retain nanomolar affinity for CB1Rs, while M3 displays micromolar affinity and M6 does not bind to CB1Rs. JWH-073 displays equivalent efficacy to that of the CB1R full agonist CP-55,940, while M1, M3, and M5 act as CB1R partial agonists, and M4 shows little or no intrinsic activity. Further in vitro investigation by Schild analysis revealed that M4 acts as a competitive neutral CB1R antagonist (K(b)∼40nM). In agreement with in vitro studies, M4 also demonstrates CB1R antagonism in vivo by blunting cannabinoid-induced hypothermia in mice. Interestingly, M4 does not block agonist-mediated responses of other measures in the cannabinoid tetrad (e.g., locomotor suppression, catalepsy or analgesia). Finally, also as predicted by in vitro results, M1 exhibits agonist activity in vivo by inducing significant hypothermia and suppression of locomotor activity in mice. In conclusion, the present study indicates that further work examining the physiological effects of synthetic cannabinoid metabolism is warranted. Such a complex mix of metabolically produced CB1R ligands may contribute to the adverse effect profile of JWH-073-containing products.

  14. Antinociceptive effects of the selective CB2 agonist MT178 in inflammatory and chronic rodent pain models.

    Science.gov (United States)

    Vincenzi, Fabrizio; Targa, Martina; Corciulo, Carmen; Tabrizi, Mojgan Aghazadeh; Merighi, Stefania; Gessi, Stefania; Saponaro, Giulia; Baraldi, Pier Giovanni; Borea, Pier Andrea; Varani, Katia

    2013-06-01

    Cannabinoid CB(2) receptor activation by selective agonists has been shown to produce analgesic effects in preclinical models of inflammatory, neuropathic, and bone cancer pain. In this study the effect of a novel CB(2)agonist (MT178) was evaluated in different animal models of pain. First of all, in vitro competition binding experiments performed on rat, mouse, or human CB receptors revealed a high affinity, selectivity, and potency of MT178. The analgesic properties of the novel CB(2) agonist were evaluated in various in vivo experiments, such as writhing and formalin assays, showing a good efficacy comparable with that produced by the nonselective CB agonist WIN 55,212-2. A dose-dependent antiallodynic effect of the novel CB(2) compound in the streptozotocin-induced diabetic neuropathy was found. In a bone cancer pain model and in the acid-induced muscle pain model, MT178 was able to significantly reduce mechanical hyperalgesia in a dose-related manner. Notably, MT178 failed to provoke locomotor disturbance and catalepsy, which were observed following the administration of WIN 55,212-2. CB(2) receptor mechanism of action was investigated in dorsal root ganglia where MT178 mediated a reduction of [(3)H]-d-aspartate release. MT178 was also able to inhibit capsaicin-induced substance P release and NF-κB activation. These results demonstrate that systemic administration of MT178 produced a robust analgesia in different pain models via CB(2) receptors, providing an interesting approach to analgesic therapy in inflammatory and chronic pain without CB(1)-mediated central side effects.

  15. Knockout of NMDA-receptors from parvalbumin interneurons sensitizes to schizophrenia-related deficits induced by MK-801.

    Science.gov (United States)

    Bygrave, A M; Masiulis, S; Nicholson, E; Berkemann, M; Barkus, C; Sprengel, R; Harrison, P J; Kullmann, D M; Bannerman, D M; Kätzel, D

    2016-04-12

    It has been suggested that a functional deficit in NMDA-receptors (NMDARs) on parvalbumin (PV)-positive interneurons (PV-NMDARs) is central to the pathophysiology of schizophrenia. Supportive evidence come from examination of genetically modified mice where the obligatory NMDAR-subunit GluN1 (also known as NR1) has been deleted from PV interneurons by Cre-mediated knockout of the corresponding gene Grin1 (Grin1(ΔPV) mice). Notably, such PV-specific GluN1 ablation has been reported to blunt the induction of hyperlocomotion (a surrogate for psychosis) by pharmacological NMDAR blockade with the non-competitive antagonist MK-801. This suggests PV-NMDARs as the site of the psychosis-inducing action of MK-801. In contrast to this hypothesis, we show here that Grin1(ΔPV) mice are not protected against the effects of MK-801, but are in fact sensitized to many of them. Compared with control animals, Grin1(ΔPV)mice injected with MK-801 show increased stereotypy and pronounced catalepsy, which confound the locomotor readout. Furthermore, in Grin1(ΔPV)mice, MK-801 induced medial-prefrontal delta (4 Hz) oscillations, and impaired performance on tests of motor coordination, working memory and sucrose preference, even at lower doses than in wild-type controls. We also found that untreated Grin1(ΔPV)mice are largely normal across a wide range of cognitive functions, including attention, cognitive flexibility and various forms of short-term memory. Taken together these results argue against PV-specific NMDAR hypofunction as a key starting point of schizophrenia pathophysiology, but support a model where NMDAR hypofunction in multiple cell types contribute to the disease.

  16. Bee Venom Alleviates Motor Deficits and Modulates the Transfer of Cortical Information through the Basal Ganglia in Rat Models of Parkinson’s Disease

    Science.gov (United States)

    Maurice, Nicolas; Deltheil, Thierry; Melon, Christophe; Degos, Bertrand; Mourre, Christiane

    2015-01-01

    Recent evidence points to a neuroprotective action of bee venom on nigral dopamine neurons in animal models of Parkinson’s disease (PD). Here we examined whether bee venom also displays a symptomatic action by acting on the pathological functioning of the basal ganglia in rat PD models. Bee venom effects were assessed by combining motor behavior analyses and in vivo electrophysiological recordings in the substantia nigra pars reticulata (SNr, basal ganglia output structure) in pharmacological (neuroleptic treatment) and lesional (unilateral intranigral 6-hydroxydopamine injection) PD models. In the hemi-parkinsonian 6-hydroxydopamine lesion model, subchronic bee venom treatment significantly alleviates contralateral forelimb akinesia and apomorphine-induced rotations. Moreover, a single injection of bee venom reverses haloperidol-induced catalepsy, a pharmacological model reminiscent of parkinsonian akinetic deficit. This effect is mimicked by apamin, a blocker of small conductance Ca2+-activated K+ (SK) channels, and blocked by CyPPA, a positive modulator of these channels, suggesting the involvement of SK channels in the bee venom antiparkinsonian action. In vivo electrophysiological recordings in the substantia nigra pars reticulata (basal ganglia output structure) showed no significant effect of BV on the mean neuronal discharge frequency or pathological bursting activity. In contrast, analyses of the neuronal responses evoked by motor cortex stimulation show that bee venom reverses the 6-OHDA- and neuroleptic-induced biases in the influence exerted by the direct inhibitory and indirect excitatory striatonigral circuits. These data provide the first evidence for a beneficial action of bee venom on the pathological functioning of the cortico-basal ganglia circuits underlying motor PD symptoms with potential relevance to the symptomatic treatment of this disease. PMID:26571268

  17. Antinociceptive Activity of Trichilia catigua Hydroalcoholic Extract: New Evidence on Its Dopaminergic Effects

    Directory of Open Access Journals (Sweden)

    Alice F. Viana

    2011-01-01

    Full Text Available Trichilia catigua is a native plant of Brazil; its barks are used by some local pharmaceutical companies to prepare tonic drinks, such as Catuama. The present study was addressed to evaluate the effects of T. catigua hydroalcoholic extract in mouse nociception behavioral models, and to evaluate the possible mechanisms involved in its actions. Male Swiss mice were submitted to hot-plate, writhing and von Frey tests, after oral treatment with T. catigua extract (200 mg kg−1, p.o.. The extract displayed antinociceptive effect in all three models. For characterization of the mechanisms involved in the antinociceptive action of the extract, the following pharmacological treatments were done: naloxone (2.5 mg kg−1, s.c., SR141716A (10 mg kg−1, i.p., SCH23390 (15 μg kg−1, i.p., sulpiride (50 mg kg−1, i.p., prazosin (1 mg kg−1, i.p., bicuculline (1 mg kg−1, i.p. or dl-p-chlorophenylalanine methyl ester (PCPA, 100 mg kg−1, i.p.. In these experiments, the action of T. catigua extract was evaluated in the hot-plate test. The treatment with SCH23390 completely prevented the antinociceptive effect, while naloxone partially prevented it. The possible involvement of the dopaminergic system in the actions of T. catigua extract was substantiated by data showing the potentiation of apomorphine-induced hypothermia and by the prevention of haloperidol-induced catalepsy. In conclusion, the antinociceptive effects of T. catigua extract seem to be mainly associated with the activation of dopaminergic system and, to a lesser extent, through interaction with opioid pathway.

  18. 发作性睡病与癫(癎)共患的诊断与治疗分析%Diagnosis and treatment of epilepsy and narcolepsy comorbid

    Institute of Scientific and Technical Information of China (English)

    杨志仙; 韩芳; 秦炯; 刘晓燕

    2013-01-01

    Objective To analyze the clinical diagnosis and treatment process of narcolepsy and epilepsy co-existence,and thereby to improve awareness of such cases.Method The clinical manifestations of 2 cases were observed,and video-electroencephalogram (VEEG),multiple sleep latency tests (MSLT) were performed.Hypocretin 1 level in cerebrospinal fluid was examined in one case.Result The onset of disease of case one was started with epilepsy with myoclonic seizure.After half a year,catalepsy induced by emotion especially laughing and excessive daytime sleepiness appeared.MSLT was positive and hypocretin 1 level decreased.Narcolepsy-cataplexy was definitely diagnosed in this case.Valproate was given and seizure was controlled completely,but the excessive daytime sleepiness was aggravated.Combination of valproate,methylphenidate and clomipramine treatment improved the symptoms of narcolepsy and the patient was still free of epileptic seizures.The onset symptoms of case 2 were catalepsy and excessive daytime sleepiness.MSLT was positive.The treatment was ineffective because of bad compliance.After 2 years,episodes of impairment of consciousness with automatism occurred.VEEG showed slow waves and spikes in right temporal area.Complex partial seizure was determined.Oxcarbazepine was used and then the patients became seizures free,but the symptoms of narcolepsy were still obvious.Conclusion Comorbidity of narcolepsy and epilepsy is a rare phenomenon.Clinical symptoms,predisposing factor,VEEG and MSLT can help diagnosis and differential diagnosis.The antiepileptic drugs might aggravate drowsiness.Based on therapy of epilepsy by using antiepileptic drugs,low dosage of central nervous system stimulants might improve the drowsiness and catalepsy symptoms of narcolepsy.%目的 观察发作性睡病与癫(癎)共患的临床诊断及治疗过程,提高对此类共患病例的认识.方法 分析2例发作性睡病与癫(癎)共患患儿临床资料、视频脑电图监测(VEEG)及多次

  19. Effects of substance P in globus pallidus on haloperidol-induced Parkinsonian model rats%苍白球P物质对帕金森病僵直模型大鼠的影响

    Institute of Scientific and Technical Information of China (English)

    郑长民; 薛雁; 陈蕾

    2010-01-01

    To investigate the effects of substance P in globus pallidus on haloperidol-induced Parkinson's disease model rat.Methods In behavioral experiments,guide cannulae constructed from stainless steel were implanted into the globus pallidus.After five days recovery,0.5 μl drugs(normal saline,SMSP,SR140333B,SR140333B + SMSP)were bilaterally microinjected into the globus pallidus in awake rats with haloperidol administration intraperitoneally.The catalepsy was then observed within 60 min.In electrophysiological study,an in vivo extracellular recording was performed to observe the effects of substance P on the firing rate of pallidal neurons.Resuits Haloperidol induced catalepsy in rats with intrapallidal saline microinjection.The maximum average latency was(259.8±34.8)s at the time point of 30th min.The minimum average latency was(145.2±54.8)s at 50th min.Bilateral microinjection of SMSP into globus pallidus significantly attenuated haloperidol-induced catalepsy (The average latency was(10.4±3.4)s at lOth rain and(58.4±38.8)s at 60th min,P<0.01).This anticataleptic effect was completely counteracted by selective NK-1 receptors antagonist SR140333B(The average latency was(176.4±64.4)s at 10th min and(139.2±59.7)s at 60th rain,P<0.01).Furthermore,micropressure ejection of SMSP significantly increased the firing rate of pallidal neurons(Basal:(13.4±4.2)Hz,SMSP:(17.5±5.6)Hz).The average increase was(29.4±8.6)%(P<0.05,n=13).SR140333 B completely blocked SMSPinduced increase in firing rate(SR140333B:(10.3±2.5)Hz,SR140333 B + SMSP:(11.3±3.0)Hz,P>0.05,n=8).Conclusion Based on the action of substance P in globus pallidus of parkinsonian rats,it is we hypothesized that activation of substance P receptor in globus pallidus may play a role in the treatment of Parkinson's disease.%目的 观察苍白球P物质对氟哌啶醇帕金森病僵直模型大鼠的影响.方法 行为学实验采用大鼠腹腔注射氟哌啶醇诱发帕金森病僵直模犁,苍白球分

  20. Pharmacological characterization of LY233053: A structurally novel tetrazole-substituted competitive N-methyl-D-aspartic acid antagonist with a short duration of action

    Energy Technology Data Exchange (ETDEWEB)

    Schoepp, D.D.; Ornstein, P.L.; Leander, J.D.; Lodge, D.; Salhoff, C.R.; Zeman, S.; Zimmerman, D.M. (Eli Lilly and Company, Indianapolis, IN (USA))

    1990-12-01

    This study reports the activity of a structurally novel excitatory amino acid receptor antagonist, LY233053 (cis-(+-)-4-((2H-tetrazol-5-yl)methyl)piperidine-2-carboxylic acid), the first tetrazole-containing competitive N-methyl-D-aspartic acid (NMDA) antagonist. LY233053 potently inhibited NMDA receptor binding to rat brain membranes as shown by the in vitro displacement of (3H) CGS19755 (IC50 = 107 +/- 7 nM). No appreciable affinity in (3H)alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or (3H)kainate binding assays was observed (IC50 values greater than 10,000 nM). In vitro NMDA receptor antagonist activity was further demonstrated by selective inhibition of NMDA-induced depolarization in cortical wedges (IC50 = 4.2 +/- 0.4 microM vs. 40 microM NMDA). LY233053 was effective after in vivo systemic administration in a number of animal models. In neonatal rats, LY233053 selectively blocked NMDA-induced convulsions (ED50 = 14.5 mg/kg i.p.) with a relatively short duration of action (2-4 hr). In pigeons, LY233053 potently antagonized (ED50 = 1.3 mg/kg i.m.) the behavioral suppressant effects of 10 mg/kg of NMDA. However, a dose of 160 mg/kg, i.m., was required to produce phencyclidine-like catalepsy in pigeons. In mice, LY233053 protected against maximal electroshock-induced seizures at lower doses (ED50 = 19.9 mg/kg i.p.) than those that impaired horizontal screen performance (ED50 = 40.9 mg/kg i.p.). Cholinergic and GABAergic neuronal degenerations after striatal infusion of NMDA were prevented by single or multiple i.p. doses of LY233053. In summary, the antagonist activity of LY233053 after systemic administration demonstrates potential therapeutic value in conditions of neuronal cell loss due to NMDA receptor excitotoxicity.

  1. AB-CHMINACA, AB-PINACA, and FUBIMINA: Affinity and Potency of Novel Synthetic Cannabinoids in Producing Δ9-Tetrahydrocannabinol-Like Effects in Mice.

    Science.gov (United States)

    Wiley, Jenny L; Marusich, Julie A; Lefever, Timothy W; Antonazzo, Kateland R; Wallgren, Michael T; Cortes, Ricardo A; Patel, Purvi R; Grabenauer, Megan; Moore, Katherine N; Thomas, Brian F

    2015-09-01

    Diversion of synthetic cannabinoids for abuse began in the early 2000s. Despite legislation banning compounds currently on the drug market, illicit manufacturers continue to release new compounds for recreational use. This study examined new synthetic cannabinoids, AB-CHMINACA (N-[1-amino-3-methyl-oxobutan-2-yl]-1-[cyclohexylmethyl]-1H-indazole-3-carboxamide), AB-PINACA [N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide], and FUBIMINA [(1-(5-fluoropentyl)-1H-benzo[d]imadazol-2-yl)(naphthalen-1-yl)methanone], with the hypothesis that these compounds, like those before them, would be highly susceptible to abuse. Cannabinoids were examined in vitro for binding and activation of CB1 receptors, and in vivo for pharmacological effects in mice and in Δ(9)-tetrahydrocannabinol (Δ(9)-THC) discrimination. AB-CHMINACA, AB-PINACA, and FUBIMINA bound to and activated CB1 and CB2 receptors, and produced locomotor suppression, antinociception, hypothermia, and catalepsy. Furthermore, these compounds, along with JWH-018 [1-pentyl-3-(1-naphthoyl)indole], CP47,497 [rel-5-(1,1-dimethylheptyl)-2-[(1R,3S)-3-hydroxycyclohexyl]-phenol], and WIN55,212-2 ([(3R)-2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone, monomethanesulfonate), substituted for Δ(9)-THC in Δ(9)-THC discrimination. Rank order of potency correlated with CB1 receptor-binding affinity, and all three compounds were full agonists in [(35)S]GTPγS binding, as compared with the partial agonist Δ(9)-THC. Indeed, AB-CHMINACA and AB-PINACA exhibited higher efficacy than most known full agonists of the CB1 receptor. Preliminary analysis of urinary metabolites of the compounds revealed the expected hydroxylation. AB-PINACA and AB-CHMINACA are of potential interest as research tools due to their unique chemical structures and high CB1 receptor efficacies. Further studies on these chemicals are likely to include research on understanding cannabinoid

  2. Role of the ventromedial nucleus of the thalamus in motor behaviour--I. Effects of focal injections of drugs.

    Science.gov (United States)

    Starr, M S; Summerhayes, M

    1983-12-01

    An assortment of drugs was injected into one or both ventromedial nuclei of the thalamus, to see how these influenced stereotypy, locomotion and posture in spontaneously behaving and actively rotating rats. Unilateral intrathalamic muscimol promoted weak ipsiversive circling, while bilateral treatment gave catalepsy. Similar injections of 4-amino-hex-5-enoic acid, which inhibits gamma-aminobutyrate metabolism, raised gamma-aminobutyrate levels in the ventromedial nuclei more than three-fold yet had none of these behavioural effects. The indirectly acting gamma-aminobutyrate agonists flurazepam and cis-1,3-aminocyclohexane carboxylic acid had little effect on posture and locomotion and, like muscimol and 4-amino-hex-5-enoic acid, elicited only very weak stereotypies. Procaine behaved like the gamma-aminobutyrate antagonist bicuculline, provoking vigorous locomotor hyperactivity and teeth chattering if given uni- or bilaterally. Pretreatment of one ventromedial nucleus with muscimol or 4-amino-hex-5-enoic acid, and to a lesser extent flurazepam or cis- 1,3-aminocyclohexane carboxylic acid, gave rise to pronounced ipsilateral asymmetries when combined with a large systemic dose of apomorphine. Contraversive rotations were initiated by unilateral stereotaxic injection of muscimol into the substantia nigra pars reticulata, or with apomorphine from the supersensitive striatum in unilaterally 6-hydroxydopamine lesioned rats. Drug treatments in the ipsilateral ventromedial nucleus showed a similar rank order of potency at inhibiting these circling behaviours, seemingly by reducing apomorphine-induced posture and muscimol-induced hypermotility. The suppression of circling by muscimol in these tests was highlighted by introducing the compound into the ventromedial nucleus at the height of circling activity. Both types of circling stimulus lost the capacity to increase locomotion, but still caused head turning and stereotypy in rats made cataleptic with bilateral ventromedial

  3. 5-HT1A Receptor Activation Improves Anti-Cataleptic Effects of Levodopa in 6-Hydroxydopamine-Lesioned Rats

    Directory of Open Access Journals (Sweden)

    S. Reyhani-Rad

    2011-12-01

    Full Text Available Background and the purpose of the study: In Parkinsons disease (PD prolong use of L-DOPA causes some motor disorders such as wearing-off and L-DOPA induced dyskinesia (LID. In this investigation the effect of 8-OHDAPT, as a 5-HT1A agonist on anti-cataleptic effect of L-DOPA in 6-hydroxydopamine (6-OHDA lesioned male Wistar rats was investigated. Methods: Catalepsy was induced by unilateral injection of 6-OHDA (8 μg/2μl/rat into the central region of the SNc. After 3 weeks as a recovery period, animals received intraperitoneally (i.p. L-DOPA (15 mg/kg twice daily for 20 days, and anti-cataleptic effect of L-DOPA was assessed by bar-test at days of 5, 10, 15 and 20. Results and major conclusion: The results showed that L-DOPA had anti-cataleptic effect only until the day of 15, and its effect was decreased on the day of 20. On the day of 21, rats were co-injected with three different doses of 8-OHDAPT (0.1, 0.5 and 2.5 mg/kg, i.p. and L-DOPA (15 mg/kg, ip. 8-Hydroxy-2-(di-n-propylamino tetralin (8-OHDAPT improved anti-cataleptic effect of L-DOPA at the dose of 0.5 mg/kg. Moreover the effect of 8-OHDAPT on anti-cataleptic effect of L-DOPA (15 mg/kg, ip was abolished by 1-(2-methyoxyphenyl-4-[4-(2-phthalamido butyl] piperazine hydrobromide (NAN-190; 0.5 mg/kg, i.p. as a 5-HT1A receptor antagonist. According to the obtained results, it may be concluded that activation of 5-HT1A receptors by 8-OHDAPT may improve anti-cataleptic effect of L-DOPA in a 6-OHDA- induced rat model of PD. Further studies are required to clarify the exact mechanism of interaction between 5-HT1A and dopaminergic neurons.

  4. The glycine transporter-1 inhibitors NFPS and Org 24461: a pharmacological study.

    Science.gov (United States)

    Harsing, Laszlo G; Gacsalyi, Istvan; Szabo, Geza; Schmidt, Eva; Sziray, Nora; Sebban, Claude; Tesolin-Decros, Brigitte; Matyus, Peter; Egyed, Andras; Spedding, Michael; Levay, Gyorgy

    2003-03-01

    The in vitro and in vivo pharmacology of two glycine transporter-1 (GlyT1) inhibitors, N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-propyl]sarcosine (NFPS) and R,S-(+/-)N-methyl-N-[(4-trifluoromethyl)phenoxy]-3-phenyl-propylglycine (Org 24461), was studied. NFPS and Org 24461 inhibited the uptake of [3H]glycine in hippocampal synaptosomal preparation with IC(50) values of 0.022 and 2.5 microM. Neither NFPS nor Org 24461 (0.1 microM) showed significant binding to alpha-1, alpha-2, and beta-adrenoceptors, D(1) and D(2) dopamine receptors, and 5-HT(1A) and 5-HT(2A) serotonin receptors in membranes prepared from rat brain or to cloned 5-HT(6) and 5-HT(7) receptors. At 10 microM concentrations, binding affinity was measured for NFPS to 5-HT(2A) and 5-HT(2C) serotonin receptors and alpha-2 adrenoceptors and for NFPS and Org 24461 to 5-HT(7) serotonin receptors. Glycine (0.1 mM) and sarcosine (5 mM) increased [3H]glycine efflux from superfused rat hippocampal slices preloaded with [3H]glycine. NFPS and Org 24461 (0.1 mM) did not influence [3H]glycine efflux, however, they inhibited glycine-induced [3H]glycine release. These findings indicate that NFPS and Org 24461 selectively inhibit glycine uptake without being substrates of the transporter protein. Several antipsychotic tests were used to characterize antipsychotic effects of NFPS and Org 24461 in vivo. These compounds did not alter apomorphine-induced climbing and stereotypy in a dose of 10 mg/kg p.o. in mice and did not induce catalepsy in a dose of 10 mg/kg i.p. in rats. The ID(50) values of NFPS were 21.4 mg/kg and higher than 30 mg/kg i.p. for inhibition of phencyclidine (PCP)- and D-amphetamine-induced hypermotility in mice and these values were 2.5 and 8.6 mg/kg i.p. for Org 24461. NFPS and Org 24461 did not exhibit anxiolytic effects in light-dark test in mice, in the meta-chlorophenylpiperazine (mCPP)-induced anxiety test (minimal effective dose or MED was higher than 3 mg/kg i.p.) and in the Vogel conflict

  5. Study on Anti-depression Effect of Tanshinone%丹参酮的抗抑郁作用研究

    Institute of Scientific and Technical Information of China (English)

    张忠东; 曹莉; 程灶火

    2012-01-01

    OBJECTIVE: To study anti-depression effect of tanshinone. METHODS: Intragastric administration of Tanshinone. Depression model was induced by injection of reserpine (2 mg·kg-1) via tail vein, and the number of heavy-lidded eyes and akine-sia were observed and rectal temperature was determined. Depression model was induced by intraperitoneal injection of tetrabena-zine (40 mg·kg-1), and the number of catalepsy was observed. Mice was injected with reserpine (2 mg·kg-1) via tail vein to conduct tail suspension test and forced swimming test. The time of tail suspension immobility and swimming immobility were observed. The convusion of rats was induced by intravenous injection of MAO inhibitor (tryamine hydrochloride) to observe average value of rat's action and duration of slapping ,and beat. RESULTS: Tanshinone 60,30,20 mg·kg-1 could improve heavy-lidded eyes and swimming immobility and rised rectal temperature in depression symptoms of mice induced by reserpine(P<0.05). Tanshinone 60,30 mg·kg-1 could improve heavy-lidded eyes and swimming immobility in depression symptoms of mice induced by tet-rabenazine(P<0.01,P<0.05). It also shortened the time of tail suspension immobility and swimming immobility in despair symptoms of mice(P<0.01). Tanshinone 42,21,14 mg·kg-1 could depressed actin point in convusions symptoms of rats induced by try-pamine hydrochloride. Tanshinone 42,21 mg·kg-1 could shortened pat duriation in convusions symptoms model rats.CONCLU-SION: Tanshinone have certain anti-depressant effect.%目的:研究丹参酮的抗抑郁作用.方法:丹参酮灌胃给药.通过尾静脉注射利血平(2 mg·kg-1)复制小鼠抑郁模型,观察眼帘下垂动物数、运动不能动物数,测肛温;腹腔注射丁苯那嗪(40 mg·kg-1)复制小鼠抑郁模型,观察眼帘下垂动物数和僵住动物数;尾静脉注射利血平(2 mg·kg-1)后进行悬尾、强迫游泳实验,复制小鼠获得性绝望模型,观察小鼠悬尾不动时间和游泳不

  6. [Catatonia: resurgence of a concept. A review of the international literature].

    Science.gov (United States)

    Pommepuy, N; Januel, D

    2002-01-01

    Catatonia was first described in 1874 by Kahlbaum as being a cyclic disease mixing motor features and mood variations. Because most cases ended in dementia, Kraepelin recognized catatonia as a form of dementia praecox and Bleuler included it within his wide group of schizophrenias. This view influenced the psychiatric practice for more than 70 years. But catatonia was recently reconsidered and this because of the definition of more precise diagnosis criteria, the discovery of a striking association with mood disorders, and the emphasis on effective therapeutics. Peralta et al empirically developed a performant diagnostic instrument with the 11 most discriminant signs among catatonic features. Diagnostic threshold is three or more signs with sensitivity of 100% and specificity of 99%. These signs are: immobility/stupor (extreme passivity, marked hypokinesia); mutism (includes inaudible whisper); negativism (resistance to instructions, contrary comportment to whose asked); oppositionism, other called gegenhalten (resistance to passive movement which increases with the force exerted); posturing (patient adopts spontaneously odd postures); catalepsy (patient retains limb positions passively imposed during examination; waxy flexibility); automatic obedience (exaggerated co-operation to instructed movements); echo phenomena (movements, mimic and speech of the examiner are copied with modification and amplifications); rigidity (increased muscular tone); verbigeration (continuous and directionless repetition of single words or phrases); withdrawal/refusal to eat or drink (turning away from examiner, no eye contact, refusal to take food or drink when offered). Using this diagnostic tool, prevalence of catatonic syndrome appears to be close to 8% of psychiatric admissions. Other signs are also common but less specific: staring, ambitendance, iterations, stereotypes, mannerism, overactivity/excitement, impulsivity, combativeness. Some authors complete this description by

  7. 左旋金黄紫堇碱抗精神分裂症作用研究%On antipsychotic effects of l-Scoulerine

    Institute of Scientific and Technical Information of China (English)

    高赟赟; 米桂芸; 刘帅; 杨征

    2016-01-01

    -bition and cognitive impairment induced by MK-801 (0. 2 mg · kg - 1 , ip), which proposed that l-SLR could improve the negative symptoms and cognitive im-pairment by MK-801. Catalepsy in mice could be caused by the treatment dose of haloperidol (0. 8 mg· kg - 1 , ip), not by that of l-SLR(30 mg·kg - 1 , ip). Conclusion I-SLR has significant effects on the posi-tive and negative symptoms of schizophrenia and cogni-tive impairment and, the effect of l-SLR under effective dose on extrapyramidal system is obviously much less than that of haloperidol and l-SPD.