Further evaluation of the tropane analogs of haloperidol.

Science.gov (United States)

Sampson, Dinithia; Bricker, Barbara; Zhu, Xue Y; Peprah, Kwakye; Lamango, Nazarius S; Setola, Vincent; Roth, Bryan L; Ablordeppey, Seth Y

2014-09-01

Previous work from our labs has indicated that a tropane analog of haloperidol with potent D2 binding but designed to avoid the formation of MPP(+)-like metabolites, such as 4-(4-chlorophenyl)-1-(4-(4-fluorophenyl)-4-oxobutyl)pyridin-1-ium (BCPP(+)) still produced catalepsy, suggesting a strong role for the D2 receptor in the production of catalepsy in rats, and hence EPS in humans. This study tested the hypothesis that further modifications of the tropane analog to produce compounds with less potent binding to the D2 receptor than haloperidol, would produce less catalepsy. These tests have now revealed that while haloperidol produced maximum catalepsy, these compounds produced moderate to low levels of catalepsy. Compound 9, with the least binding affinity to the D2R, produced the least catalepsy and highest Minimum Adverse Effective Dose (MAED) of the analogs tested regardless of their affinities at other receptors including the 5-HT1AR. These observations support the hypothesis that moderation of the D2 binding of the tropane analogs could reduce catalepsy potential in rats and consequently EPS in man. Published by Elsevier Ltd.

Effects of lipopolysaccharide and interleukin-6 on cataleptic immobility and locomotor activity in mice.

Science.gov (United States)

Bazovkina, Daria V; Tibeikina, Marina A; Kulikov, Alexander V; Popova, Nina K

2011-01-10

Catalepsy (animal hypnosis, tonic immobility) is a type of passive defensive behavior. Its exaggerated form is a syndrome of some psychopathological disorders. Numerous neurotransmitters have impact on the regulation of catalepsy. In this paper we demonstrated the involvement of interleukin-6 (IL-6) in the mechanism of cataleptic immobility. Effects of exogenous IL-6 treatment (7.5 and 10μg/kg, i.p) or stimulation of endogenous IL-6 secretion with lipopolysaccharide (LPS) administration (50, 100 and 200μg/kg, i.p.) on catalepsy and locomotor activity were studied in adult C57BL/6 male mice. IL-6 induced catalepsy in 70% (7.5μg/kg) or 72.7% (10μg/kg) of animals with no effect on locomotor activity. LPS administration reduced distance travelled and number of rears in the open field at any dose used, however, only high doses (100 or 200μg/kg) of the toxin induced catalepsy in 50% of mice. This result indicates that IL-6 is involved in the regulation of catalepsy, this effect is specific and does not arise from inhibition of locomotor activity. The study provides a new evidence on participation of IL-6 in mechanisms of abnormal behavior. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Inhibition of the cataleptic effect of tetrahydrocannabinol by other constituents of Cannabis sativa L.

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Formukong, E A; Evans, A T; Evans, F J

1988-02-01

Tetrahydrocannabinol (THC) induced catalepsy in mice, whereas a cannabis oil (6.68% w/w THC), four cannabinoids and a synthetic mixture did not. Cannabinol (CBN) and olivetol inhibited THC-induced catalepsy in the mornings and the evenings, but cannabidiol (CBD) exhibited this effect only in the evenings. A combination of CBN and CBD inhibited THC-induced catalepsy equal to that of CBN alone in the mornings, but this inhibition was greater than that produced by CBN alone in the evenings.

Radiation-induced increases in sensitivity of cataleptic behavior to haloperidol: possible involvement of prostaglandins

International Nuclear Information System (INIS)

Joseph, J.A.; Kandasamy, S.B.; Hunt, W.A.; Dalton, T.K.; Stevens, S.

1988-01-01

The effects of radiation exposure on haloperidol-induced catalepsy were examined in order to determine whether elevated prostaglandins, through an action on dopaminergic autoreceptors, could be involved in the radiation-induced increase in the potency of this neuroleptic. Cataleptic behavior was examined in animals irradiated with various doses of gamma photons (1-150 Gy) and pretreated with a subthreshold dose of haloperidol (0.1 mg/kg). This approach was chosen to maximize any synergistic effects of radiation and haloperidol. After irradiation with doses less than or equal to 30 Gy, the combined treatment of haloperidol and radiation produced catalepsy, whereas neither treatment alone had an effect. This observed catalepsy could be blocked with prior administration of indomethacin, a prostaglandin synthesis inhibitor. Animals exposed to doses of radiation less than or equal to 50 Gy and no haloperidol, however, displayed apparent catalepsy. This effect was also antagonized by indomethacin. Prostaglandins can induce catalepsy and when administered in subthreshold doses along with subthreshold doses of haloperidol, catalepsy was observed. In order to assess a possible action of prostaglandins and radiation on dopaminergic activity, the functioning of striatal dopaminergic autoreceptors was examined by determining the effects of varying concentrations of haloperidol on the K+-evoked release of dopamine from striatal slices obtained from parallel groups of animals treated as above. Results indicated that sensitivity to haloperidol increased (higher K+-evoked dopamine release) in slices from irradiated or prostaglandin-treated animals and that this increase in sensitivity was blocked by indomethacin

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.

Comparative study between two animal models of extrapyramidal movement disorders: prevention and reversion by pecan nut shell aqueous extract.

Science.gov (United States)

Trevizol, Fabiola; Benvegnú, Dalila M; Barcelos, Raquel C S; Pase, Camila S; Segat, Hecson J; Dias, Verônica Tironi; Dolci, Geisa S; Boufleur, Nardeli; Reckziegel, Patrícia; Bürger, Marilise E

2011-08-01

Acute reserpine and subchronic haloperidol are animal models of extrapyramidal disorders often used to study parkinsonism, akinesia and tardive dyskinesia. In humans, these usually irreversible and disabling extrapyramidal disorders are developed by typical antipsychotic treatment, whose pathophysiology has been related to oxidative damages development. So far, there is no treatment to prevent these problems of the psychiatric clinic, and therefore further studies are needed. Here we used the animal models of extrapyramidal disorders cited above, which were performed in two distinct experiments: orofacial dyskinesia (OD)/catalepsy induced by acute reserpine and subchronic haloperidol after (experiment 1) and before (experiment 2) oral treatment with pecan shell aqueous extract (AE), a natural and promissory antioxidant. When administered previously (exp.1), the AE prevented OD and catalepsy induced by both reserpine and haloperidol. When reserpine and haloperidol were administered before the extract (exp.2), the animals developed OD and catalepsy all the same. However, the orofacial parameter (but not catalepsy) in both animal models was reversed after 7 and 14 days of AE treatment. These results indicate that, acute reserpine and subchronic haloperidol administrations induced similar motor disorders, although through different mechanisms, and therefore are important animal models to study the physiopathology of extrapyramidal disorders. Comparatively, the pecan shell AE was able to both prevent and reverse OD but only to prevent catalepsy. These results reinforce the role of oxidative stress and validate the two animal models used here. Our findings also favor the idea of prevention of extrapyramidal disorders, rather than their reversal. Copyright © 2011 Elsevier B.V. All rights reserved.

Synthesize, characterization, and anti-Parkinson activity of silver-Indonesian velvet beans (Mucuna pruriens) seed extract nanoparticles (AgMPn)

Science.gov (United States)

Sardjono, R. E.; Khoerunnisa, F.; Musthopa, I.; Akasum, N. S. M. M.; Rachmawati, R.

2018-05-01

Parkinson is one of the progressive neurodegenerative diseases. Various efforts are made in handling this disease, one of them is the utilization of plant extracts that have anti-Parkinson activity, for example, velvet bean (Mucuna pruriens L.). Changing the particle size of the extract into nanoscale particle is expected to increase its anti-parkinson activity. The research was conducted to synthesize silver-velvet bean (Mucuna pruriens L.) seed extract nanoparticles (AgMPn) and to evaluate its antiparkinson activity through the catalepsy test in mice. The research consisted of several stages i.e. extraction of velvet bean seed powder, synthesis and characterization of AgMPn, and catalepsy test of AgMPn. Velvet bean seed powder was extracted by maceration method using ethanol-water (1:1) at pH 3 adjusted with citric acid. AgMPn was synthesized by reacting the silver nitrate (AgNO3) solution with the extract of velvet bean seed for 40 min, dispersibility of solution during the reaction was controlled by using sonication and ultrasonic processor homogenizer. Characterization of AgMPn was done by using Fourier transform infrared (FT-IR), scanning electron microscopy-energy dispersive X-ray (SEM-EDX), and transmission electron microscopy (TEM). Catalepsy test was conducted on AgMpn at the doses of 5, 10, 15, 20 and 25 mg/kg body weight. The results of SEM-EDX and TEM showed that AgMPn formed aggregates with several shapes such as rectangle, oval, and spherical, with the average particle diameter was 36.5 nm. FT-IR spectra showed a band at 464.8 cm-1 absorbance area which is typical band indicated the interaction of Ag-O of AgMPn. Catalepsy test demonstrated that AgMPn at the doses of 5, 15, and 20 mg/kg body weight lowered the catalepsy symptoms in mice significantly, with the best dose was 5 mg/kg body weight.

Design, synthesis, spectroscopic characterization and anti-psychotic investigation of some novel Azo dye/Schiff base/Chalcone derivatives

Directory of Open Access Journals (Sweden)

Chandravadivelu Gopi

2017-12-01

Full Text Available The purpose of the study is to design, synthesise and assess the antipsychotic activity of a set of the novel (5-(10-(3-N, N-Dimethylamino propyl-10H-phenothiazine-3-yl-1,3,4-thiadiazo-2-yl Azodye/Schiff base/Chalcone derivatives. The newly synthesised compound structure was characterised by FT-IR, 1H NMR, Mass spectroscopy and elemental analysis. Each compound has been shown an excellent anti-psychotic activity in a haloperidol-induced catalepsy metallic bar test. The results found are firmly similar to docking study. Among the synthesised derivatives, compound 2-Amino-6-(3-hydroxy-4-methylphenyl pyrimidine-4-yl (7-chloro-10-(3-(N, N-dimethylamino propyl-10H-phenothiazine-3-yl methanone (GC8 exhibiting high potency of catalepsy induction. Therefore, the derivative of GC8 has been considered that a potent anti-psychotic agent among the synthesised compounds. Keywords: Design, MVD, Catalepsy, Antipsychotic agent, X-ray crystallography

Rat brain CYP2D enzymatic metabolism alters acute and chronic haloperidol side-effects by different mechanisms.

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Miksys, Sharon; Wadji, Fariba Baghai; Tolledo, Edgor Cole; Remington, Gary; Nobrega, Jose N; Tyndale, Rachel F

2017-08-01

Risk for side-effects after acute (e.g. parkinsonism) or chronic (e.g. tardive dyskinesia) treatment with antipsychotics, including haloperidol, varies substantially among people. CYP2D can metabolize many antipsychotics and variable brain CYP2D metabolism can influence local drug and metabolite levels sufficiently to alter behavioral responses. Here we investigated a role for brain CYP2D in acutely and chronically administered haloperidol levels and side-effects in a rat model. Rat brain, but not liver, CYP2D activity was irreversibly inhibited with intracerebral propranolol and/or induced by seven days of subcutaneous nicotine pre-treatment. The role of variable brain CYP2D was investigated in rat models of acute (catalepsy) and chronic (vacuous chewing movements, VCMs) haloperidol side-effects. Selective inhibition and induction of brain, but not liver, CYP2D decreased and increased catalepsy after acute haloperidol, respectively. Catalepsy correlated with brain, but not hepatic, CYP2D enzyme activity. Inhibition of brain CYP2D increased VCMs after chronic haloperidol; VCMs correlated with brain, but not hepatic, CYP2D activity, haloperidol levels and lipid peroxidation. Baseline measures, hepatic CYP2D activity and plasma haloperidol levels were unchanged by brain CYP2D manipulations. Variable rat brain CYP2D alters side-effects from acute and chronic haloperidol in opposite directions; catalepsy appears to be enhanced by a brain CYP2D-derived metabolite while the parent haloperidol likely causes VCMs. These data provide novel mechanistic evidence for brain CYP2D altering side-effects of haloperidol and other antipsychotics metabolized by CYP2D, suggesting that variation in human brain CYP2D may be a risk factor for antipsychotic side-effects. Copyright © 2017 Elsevier Inc. All rights reserved.

Developmental plasticity in the D1- and D2-mediation of motor behavior in rats depleted of dopamine as neonates.

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Byrnes, E M; Ughrin, Y; Bruno, J P

1996-12-01

D1- and D2-like antagonist-induced catalepsy and dorsal immobility were studied in pups (Day 10) and weanlings (Days 20, 28, or 35) that received intraventricular injection of 6-OHDA (50 micrograms/hemisphere) or its vehicle solution or postnatal Day 3. The ability of the D1 of D2 antagonists to induce immobility differed as a function of the lesion condition and the age at the time of testing. Moreover, the two behavioral measures exhibited differences in their specific D1 and D2 receptor modulation. Administration of the D1 antagonist SCH 23390 (0.2 or 1.0 mg/kg) or the D2 antagonist clebopride (1.0, 10.0, or 20.0 mg/kg) led to catalepsy and dorsal immobility in intact rats, regardless of test age. Both antagonists induced catalepsy and dorsal immobility in rats depleted of DA when tested on Day 10. However, the effects of each antagonist in DA-depleted rats were ether negligible or significantly less than in controls when animals were tested as weanlings. These data suggest lesion-induced changes in the DA receptor modulation of motor behavior and that this plasticity requires more than a week to become apparent.

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...

An ethanolic extract of Desmodium adscendens exhibits antipsychotic-like activity in mice.

Science.gov (United States)

Amoateng, Patrick; Adjei, Samuel; Osei-Safo, Dorcas; Kukuia, Kennedy K E; Karikari, Thomas K; Nyarko, Alexander K

2017-09-26

Desmodium adscendens extract (DAE) is used traditionally in Ghana for the management of psychosis. The present study aimed at providing pharmacological evidence for its ethnomedical use by testing the hypothesis that an ethanolic extract of Desmodium adscendens may possess antipsychotic properties. The primary behavioral effects of DAE on the central nervous system of mice were investigated using Irwin's test paradigm. Novelty-induced and apomorphine-induced locomotor and rearing behaviors in mice were explored in an open-field observational test system. Apomorphine-induced cage climbing test in mice was used as the antipsychotic animal model. The ability of DAE to induce catalepsy and enhance haloperidol-induced catalepsy was also investigated in mice. The DAE produced sedation, cholinergic-, and serotonergic-like effects in mice when evaluated using the Irwin's test. No lethality was observed after 24 h post-treatment. The LD50 in mice was estimated to be greater than 3000 mg/kg. The DAE significantly decreased the frequency of novelty- and apomorphine-induced rearing and locomotor activities in mice. It also significantly lowered the frequency and duration of apomorphine-induced climbing activities in mice. It did not induce any cataleptic event in naïve mice but only significantly enhanced haloperidol-induced catalepsy at a dose of 1000 mg/kg. The ethanolic extract of Desmodium adscendens exhibited antipsychotic-like activities in mice. Motor side effects are only likely to develop at higher doses of the extract.

Opiate and non-opiate aspects of morphine induced seizures.

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Frenk, H; Liban, A; Balamuth, R; Urca, G

1982-12-16

The intraperitoneal administration of morphine hydrochloride at doses of 300 mg/kg produced analgesia, catalepsy, and electrographic spiking in rats that developed into electrographic seizure patterns after approximately 2.5 h. Whereas naltrexone (12 mg/kg) reversed analgesia and catalepsy, and diminished electrographic spiking, it precipitated electrographic seizure activity similar to that observed following intraperitoneal morphine alone. These seizures were accompanied by behavioral convulsions. No tolerance to these seizures developed with repeated paired administration of morphine and naltrexone or in morphine tolerant rats, but rather potentiation was observed. The epileptogenic effects were found to be potentiated in amygdaloid kindled rats, as well. It was concluded that morphine at these doses activates two different epileptogenic mechanisms, one mediated by opiate receptors, the other not. The possibility of the simultaneous activation of a morphine sensitive anticonvulsant mechanism is discussed.

Ameliorative effect of the hydroethanolic whole plant extract of ...

African Journals Online (AJOL)

At the end of the study, biochemical markers of nitrosative and oxidative stress status were determined. Results: DH (12.5, 50 and 100 mg/kg) significantly ameliorated haloperidol-induced catalepsy (bar test), spontaneous motor and working memory deficits (open field and elevated plus maze tests, respectively), ...

[Effects of chronic fluoxetine treatment on manifestation of sexual motivation and social behavior in mice of ASC line].

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Tikhonova, M A; Otroshchenko, E A; Kulikov, A V

2010-02-01

Sexual dysfunctions are the typical symptoms accompanying depressive disorders. However antidepressants which improve general state of the patients have no effect on sexual disorders. Mice of ASC (Antidepressant Sensitive Catalepsy) line with high hereditary predisposition to catalepsy were proposed as a model of genetically associated depressive-like condition. The work was aimed at comparison of behavioral indices of sexual motivation and social interest of ASC mice with those of mice of parental inbred AKR and CBA strains, and at the study of the effects of chronic fluoxetine treatment in doses of 10 and 20 mg/kg on these parameters in ASC mice. ASC males demonstrated reduced sexual motivation which was not corrected by fluoxetine. ASC mice did not differ in the expression of social interest and aggression towards juvenile intruder from mice of parental strains. Fluoxetine failed to alter social behavior of ASC mice in social interaction test but its higher dose decreased percentage of aggressors. ASC mouse line seems to be a perspective model to study genetic mechanisms of sexual dysfunctions associated with depressive conditions.

Behavioral and neurochemical effects of alpha lipoic acid associated with omega-3 in tardive dyskinesia induced by chronic haloperidol in rats.

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de Araújo, Dayane Pessoa; Camboim, Thaisa Gracielle Martins; Silva, Ana Patrícia Magalhães; Silva, Caio da Fonseca; de Sousa, Rebeca Canuto; Barbosa, Mabson Delâno Alves; Oliveira, Lucidio Clebeson; Cavalcanti, José Rodolfo Lopes de Paiva; Lucena, Eudes Euler de Souza; Guzen, Fausto Pierdoná

2017-07-01

Tardive dyskinesia (TD) is characterized by involuntary movements of the lower portion of the face being related to typical antipsychotic therapy. TD is associated with the oxidative imbalance in the basal ganglia. Lipoic acid (LA) and omega-3 (ω-3) are antioxidants acting as enzyme cofactors, regenerating antioxidant enzymes. This study aimed to investigate behavioral and neurochemical effects of supplementation with LA (100 mg/kg) and ω-3 (1 g/kg) in the treatment of TD induced by chronic use of haloperidol (HAL) (1 mg/kg) in rats. Wistar male rats were used, weighing between 180-200 g. The animals were treated chronically (31 days) with LA alone or associated with HAL or ω-3. Motor behavior was assessed by open-field test, the catalepsy test, and evaluation of orofacial dyskinesia. Oxidative stress was accessed by determination of lipid peroxidation and concentration of nitrite. LA and ω-3 alone or associated caused an improvement in motor performance by increasing locomotor activity in the open-field test and decreased the permanence time on the bar in the catalepsy test and decreased the orofacial dyskinesia. LA and ω-3 showed antioxidant effects, decreasing lipid peroxidation and nitrite levels. Thus, the use of LA associated with ω-3 reduced the extrapyramidal effects produced by chronic use of HAL.

Anticataleptic and antiepileptic activity of ethanolic extract of leaves of Mucuna pruriens: A study on role of dopaminergic system in epilepsy in albino rats.

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Champatisingh, D; Sahu, P K; Pal, A; Nanda, G S

2011-04-01

To assess the anticataleptic and antiepileptic activity of leaves of Mucuna pruriens in albino rats. Haloperidol-induced catalepsy (HIC), maximum electro-shock (MES) method, pilocarpine-induced Status epilepticus (PISE) and single-dose effect of M. pruriens were employed. M. pruriens (100 mg/kg) had significant anticataleptic and antiepileptic activity in HIC, MES, and PISE. M. pruriens extract has the potential to be an anticataleptic and antiepileptic drug. Dopamine and 5-HT may have a role in such activity.

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

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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.

Stress-opioid interactions: a comparison of morphine and methadone.

Science.gov (United States)

Taracha, Ewa; Mierzejewski, Paweł; Lehner, Małgorzata; Chrapusta, Stanisław J; Kała, Maria; Lechowicz, Wojciech; Hamed, Adam; Skórzewska, Anna; Kostowski, Wojciech; Płaźnik, Adam

2009-01-01

The utility of methadone and morphine for analgesia and of methadone for substitution therapy for heroin addiction is a consequence of these drugs acting as opioid receptor agonists.We compared the cataleptogenic and antinociceptive effects of single subcutaneous doses of methadone hydrochloride (1-4 mg/kg) and morphine sulfate (2.5-10 mg/kg) using catalepsy and hot-plate tests, and examined the effects of the highest doses of the drugs on Fos protein expression in selected brain regions in male Sprague-Dawley rats. Methadone had greater cataleptogenic and analgesic potency than morphine. Fos immunohistochemistry revealed substantial effects on the Fos response of both the stress induced by the experimental procedures and of the drug exposure itself. There were three response patterns identified: 1) drug exposure, but not stress, significantly elevated Fos-positive cell counts in the caudate-putamen; 2) stress alone and stress combined with drug exposure similarly elevated Fos-positive cell counts in the nucleus accumbens and cingulate cortex; and 3) methadone and morphine (to a lesser extent) counteracted the stimulatory effect of nonpharmacological stressors on Fos protein expression in the somatosensory cortex barrel field, and Fos-positive cell counts in this region correlated negatively with both the duration of catalepsy and the latency time in the hot-plate test. The overlap between brain regions reacting to nonpharmacological stressors and those responding to exogenous opioids suggests that stress contributes to opioid-induced neuronal activation.

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.

Reboxetine Enhances the Olanzapine-Induced Antipsychotic-Like Effect, Cortical Dopamine Outflow and NMDA Receptor-Mediated Transmission

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Marcus, Monica M; Jardemark, Kent; Malmerfelt, Anna; Björkholm, Carl; Svensson, Torgny H

2010-01-01

Preclinical data have shown that addition of the selective norepinephrine transporter (NET) inhibitor reboxetine increases the antipsychotic-like effect of the D2/3 antagonist raclopride and, in parallel, enhances cortical dopamine output. Subsequent clinical results suggested that adding reboxetine to stable treatments with various antipsychotic drugs (APDs) may improve positive, negative and depressive symptoms in schizophrenia. In this study, we investigated in rats the effects of adding reboxetine to the second-generation APD olanzapine on: (i) antipsychotic efficacy, using the conditioned avoidance response (CAR) test, (ii) extrapyramidal side effect (EPS) liability, using a catalepsy test, (iii) dopamine efflux in the medial prefrontal cortex and the nucleus accumbens, using in vivo microdialysis in freely moving animals and (iv) cortical N-methyl--aspartate (NMDA) receptor-mediated transmission, using intracellular electrophysiological recording in vitro. Reboxetine (6 mg/kg) enhanced the suppression of CAR induced by a suboptimal dose (1.25 mg/kg), but not an optimal (2.5 mg/kg) dose of olanzapine without any concomitant catalepsy. Addition of reboxetine to the low dose of olanzapine also markedly increased cortical dopamine outflow and facilitated prefrontal NMDA receptor-mediated transmission. Our data suggest that adjunctive treatment with a NET inhibitor may enhance the therapeutic effect of low-dose olanzapine in schizophrenia without increasing EPS liability and add an antidepressant action, thus in principle allowing for a dose reduction of olanzapine with a concomitant reduction of dose-related side effects, such as EPS and weight gain. PMID:20463659

Effects of sigma(1) receptor ligand MS-377 on D(2) antagonists-induced behaviors.

Science.gov (United States)

Karasawa, Jun-ichi; Takahashi, Shinji; Takagi, Kaori; Horikomi, Kazutoshi

2002-10-01

(R)-(+)-1-(4-Chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate (MS-377) is a novel antipsychotic agent with selective and high affinity for sigma(1) receptor. The present study was carried out to clarify the interaction of MS-377 with dopamine D(2) receptor antagonists (D(2) antagonists) in concurrent administration, and then the involvement of sigma receptors in the interaction. The effects of MS-377 on haloperidol- or sultopride-induced inhibition of apomorphine-induced climbing behavior and catalepsy were investigated in mice and rats, respectively. In addition, the effects of (+)-SKF-10,047 and SA4503, both of which are sigma receptor agonists, and WAY-100,635, which is a 5-HT(1A) receptor antagonist, on the interaction due to the concurrent use were also investigated. MS-377 potentiated the inhibitory effects of haloperidol or sultopride on apomorphine-induced climbing behavior in a dose-dependent manner. In contrast, MS-377 did not affect the catalepsy induction by these drugs. The potentiation of the inhibitory effects of haloperidol or sultopride on apomorphine-induced climbing behavior by MS-377 was not inhibited by WAY-100,635, but was inhibited by (+)-SKF-10,047 and SA4503. These findings showed that MS-377 potentiates the efficacy of D(2) antagonists, but it does not deteriorate the adverse effect. Moreover, sigma(1) receptors are involved in this potentiation of the efficacy of D(2) antagonists by MS-377.

High fat diet and food restriction differentially modify the behavioral effects of quinpirole and raclopride in rats.

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Baladi, Michelle G; France, Charles P

2009-05-21

Nutritional status can impact dopamine systems in a manner that might be important to understanding possible common neurobiological mechanisms that mediate abnormal compulsive food (e.g., obesity) and drug taking. Limiting food intake, for example, can increase sensitivity to the behavioral effects of indirect-acting dopamine receptor agonists. Much less is known regarding possible diet-induced changes in sensitivity to direct-acting dopamine receptor drugs. The present study investigated the effects of a high fat diet and of food restriction on sensitivity of rats to the behavioral effects of a direct-acting dopamine receptor agonist and a dopamine receptor antagonist. Free access to high fat chow increased sensitivity to quinpirole-induced yawning without changing sensitivity to raclopride-induced catalepsy or quinpirole-induced hypothermia. Food restriction (10 g/day) decreased sensitivity to quinpirole-induced yawning and raclopride-induced catalepsy without affecting sensitivity to quinpirole-induced hypothermia. Free access to a standard chow restored sensitivity to the behavioral effects of both drugs in rats that were previously food-restricted but not in rats that previously ate a high fat diet. These data confirm that food restriction can decrease sensitivity to behavioral effects of direct-acting dopamine receptor drugs, they provide evidence (i.e., no change in hypothermic effects) indicating that these changes are not due to pharmacokinetic mechanisms, and they provide initial evidence showing enhanced sensitivity to behavioral effects of dopamine receptor drugs in rats eating a high fat diet. These changes in sensitivity of dopamine systems could be relevant to understanding the impact of nutrition on therapeutic and recreational drug use.

Exposure to an enriched environment facilitates motor recovery and prevents short-term memory impairment and reduction of striatal BDNF in a progressive pharmacological model of parkinsonism in mice.

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Campêlo, Clarissa L C; Santos, José R; Silva, Anatildes F; Dierschnabel, Aline L; Pontes, André; Cavalcante, Jeferson S; Ribeiro, Alessandra M; Silva, Regina H

2017-06-15

Previous studies showed that the repeated administration with a low dose of reserpine (RES) induces a gradual appearance of motor signs and cognitive deficits compatible with parkinsonism in rodents. Environmental stimulation has neuroprotective effects in animal models of neurodegenerative damage, including acutely induced parkinsonism. We investigated the effects of exposure to an enriched environment (EE) on motor, cognitive and neuronal (levels of tyrosine hydroxylase, TH and brain derived neurotrophic factor, BDNF) deficits induced by a progressive model of Parkinson's disease (PD) in mice. Male mice were repeatedly treated with vehicle or 0.1mg/kg of RES (s.c) and kept under two housing conditions: standard environment (SE) and EE. In animals kept in SE, the treatment with RES induced deficits in motor function (catalepsy test, open field and oral movements), in novel object recognition (NOR) and plus-maze discriminative avoidance tasks. The environmental stimulation facilitated the recovery of motor deficits assessed by the catalepsy test after the end of treatment. Additionally, exposure to EE prevented the memory deficit in the NOR task. Treatment with RES induced a reduction in the number of TH positive cells in SNpc and VTA, which recovered 30days after the end of treatment. Finally, RES reduced the levels of BDNF in the striatum and the exposure to the EE prevented this effect. These results suggest that plastic brain changes induced by EE promote beneficial effects on the progression of neuronal impairment related to PD. Copyright © 2017 Elsevier B.V. All rights reserved.

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.

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

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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. Copyright © 2011 Wiley Periodicals, Inc.

Effect of brain-derived neurotrophic factor on behavior and key members of the brain serotonin system in genetically predisposed to behavioral disorders mouse strains.

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Naumenko, V S; Kondaurova, E M; Bazovkina, D V; Tsybko, A S; Tikhonova, M A; Kulikov, A V; Popova, N K

2012-07-12

The effect of brain-derived neurotrophic factor (BDNF) on depressive-like behavior and serotonin (5-HT) system in the brain of antidepressant sensitive cataleptics (ASC)/Icg mouse strain, characterized by depressive-like behavior, in comparison with the parental nondepressive CBA/Lac mouse strain was examined. Significant decrease of catalepsy and tail suspension test (TST) immobility was shown 17days after acute central BDNF administration (300ng i.c.v.) in ASC mice. In CBA mouse strain, BDNF moderately decreased catalepsy without any effect on TST immobility time. Significant difference between ASC and CBA mice in the effect of BDNF on 5-HT system was revealed. It was shown that central administration of BDNF led to increase of 5-HT(1A) receptor gene expression but not 5-HT(1A) functional activity in ASC mice. Increased tryptophan hydroxylase-2 (Tph-2) and 5-HT(2A) receptor genes expression accompanied by 5-HT(2A) receptor sensitization was shown in BDNF-treated ASC but not in CBA mouse strain, suggesting BDNF-induced increase of the brain 5-HT system functional activity and activation of neurogenesis in "depressive" ASC mice. There were no changes found in the 5-HT transporter mRNA level in BDNF-treated ASC and CBA mice. In conclusion, central administration of BDNF produced prolonged ameliorative effect on depressive-like behavior accompanied by increase of the Tph-2, 5-HT(1A) and 5-HT(2A) genes expression and 5-HT(2A) receptor functional activity in animal model of hereditary behavior disorders. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

The comparative analysis of antiparkinsonian activity of glycine combined with amantadine in conditions of changing neurosynaptic transmission

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Mamchur V.I.

2017-10-01

Full Text Available Parkinson's disease is traditionally viewed as a disease which affects the human motor sphere. Besides motor manifestations in the clinical picture of the disease, non-motor manifestations with dementia as the most common are present. The purpose of the work – experimental evaluation of the possible antiparkinsonian action of glycine in terms of experimental models of Parkinson's disease equivalents (akinetic-rigid and tremor forms on the background of antiparkinsonian correction by amantadine. Methods: catalepsy model (inhibition of dopaminergic transmission, equivalents of hypokinesia and rigidity states and model of arekolyn tremor (activation of cholinergic transmission that corresponds to parkinsonian tremor on the background of amantadine administration (50 mg/kg, glycine (100 mg/kg and 200 mg/kg and their combined introduction. The research results show a positive dynamic in combined using of amantadine with glycine at a dose of 100 mg/kg and 200 mg/kg, which was is determined by the low percentage of animals with symptoms of catalepsy (50-70% with evaluation criteria of 0.5-1.8 points with maximum possible 6 points. Similar results were obtained in terms of activation of the cholinergic system (arekolyn tremor. Glycine at a dose of 100 mg/kg and 200 mg/kg facilitated to optimization of antitremor action of amantadine, that is registered in increased latent period of tremor, reduction of its duration and intensity attenuation almost by 2,1 times in comparison with indicators of the control group. Thus, studied combinations of amantadine with glycine at a dose of 100 mg/kg and 200 mg/kg are promising in studying of their influence on dementia in Parkinson's syndrome, and this study will be continued.

In vivo effects of synthetic cannabinoids JWH-018 and JWH-073 and phytocannabinoid Δ9-THC in mice: inhalation versus intraperitoneal injection.

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Marshell, R; Kearney-Ramos, T; Brents, L K; Hyatt, W S; Tai, S; Prather, P L; Fantegrossi, W E

2014-09-01

Human users of synthetic cannabinoids (SCBs) JWH-018 and JWH-073 typically smoke these drugs, but preclinical studies usually rely on injection for drug delivery. We used the cannabinoid tetrad and drug discrimination to compare in vivo effects of inhaled drugs with injected doses of these two SCBs, as well as with the phytocannabinoid Δ(9)-tetrahydrocannabinol (Δ(9)-THC). Mice inhaled various doses of Δ(9)-THC, JWH-018 or JWH-073, or were injected intraperitoneally (IP) with these same compounds. Rectal temperature, tail flick latency in response to radiant heat, horizontal bar catalepsy, and suppression of locomotor activity were assessed in each animal. In separate studies, mice were trained to discriminate Δ(9)-THC (IP) from saline, and tests were performed with inhaled or injected doses of the SCBs. Both SCBs elicited Δ(9)-THC-like effects across both routes of administration, and effects following inhalation were attenuated by pretreatment with the CB1 antagonist/inverse agonist rimonabant. No cataleptic effects were observed following inhalation, but all compounds induced catalepsy following injection. Injected JWH-018 and JWH-073 fully substituted for Δ(9)-THC, but substitution was partial (JWH-073) or required relatively higher doses (JWH-018) when drugs were inhaled. These studies demonstrate that the SCBs JWH-018 and JWH-073 elicit dose-dependent, CB1 receptor-mediated Δ(9)-THC-like effects in mice when delivered via inhalation or via injection. Across these routes of administration, differences in cataleptic effects and, perhaps, discriminative stimulus effects, may implicate the involvement of active metabolites of these compounds. Copyright © 2014 Elsevier Inc. All rights reserved.

[Identification and evaluation of the neuroleptic activity of phenotropil].

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Akhapkina, V I; Akhapkin, R V

2013-01-01

The neuroleptic (antipsychotic) activity of phenotropil was studied in an experimental animal model. Phenotropil had a marked neuroleptic activity in models of positive (apomorphine-induced verticalization test) and negative (5-HTP-induced hyperkinesis test) symptoms of psychoses as well as in the m-cholinergic pathway hyperactivation (arecoline-induced tremor test). The compound markedly antagonized haloperidol catalepsy. Used in a single dose or as a course treatment, phenotropil did not provoke aggression nor intensify it. In contrast to typical and atypical antipsychotics, phenotropil had no sedative action and other adverse effects. It exhibited a positive effect on exploratory behavior and motor activity, had anxiolytic and antidepressant action.

The PDE10A inhibitor MP-10 and haloperidol produce distinct gene expression profiles in the striatum and influence cataleptic behavior in rodents.

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Gentzel, Renee C; Toolan, Dawn; Roberts, Rhonda; Koser, Amy Jo; Kandebo, Monika; Hershey, James; Renger, John J; Uslaner, Jason; Smith, Sean M

2015-12-01

Phosphodiesterase 10A (PDE10A) has garnered attention as a potential therapeutic target for schizophrenia due to its prominent striatal expression and ability to modulate striatal signaling. The present study used the selective PDE10A inhibitor MP-10 and the dopamine D2 antagonist haloperidol to compare effects of PDE10A inhibition and dopamine D2 blockade on striatopallidal (D2) and striatonigral (D1) pathway activation. Our studies confirmed that administration of MP-10 significantly elevates expression of the immediate early genes (IEG) c-fos, egr-1, and arc in rat striatum. Furthermore, we demonstrated that MP-10 induced egr-1 expression was distributed evenly between enkephalin-containing D2-neurons and substance P-containing D1-neurons. In contrast, haloperidol (3 mg/kg) selectively activated egr-1 expression in enkephalin neurons. Co-administration of MP-10 and haloperidol (0.5 mg/kg) increased IEG expression to a greater extent than either compound alone. Similarly, in a rat catalepsy assay, administration of haloperidol (0.5 mg/kg) or MP-10 (3-30 mg/kg) did not produce cataleptic behavior when dosed alone, but co-administration of haloperidol with MP-10 (3 and 10 mg/kg) induced cataleptic behaviors. Interestingly, co-administration of haloperidol with a high dose of MP-10 (30 mg/kg) failed to produce cataleptic behavior. These findings are important for understanding the neural circuits involved in catalepsy and suggest that the behavioral effects produced by PDE10A inhibitors may be influenced by concomitant medication and the level of PDE10A inhibition achieved by the dose of the inhibitor. Copyright © 2015. Published by Elsevier Ltd.

Effects of glutamate and α2-noradrenergic receptor antagonists on the development of neurotoxicity produced by chronic rotenone in rats

International Nuclear Information System (INIS)

Alam, Mesbah; Danysz, Wojciech; Schmidt, Werner Juergen; Dekundy, Andrzej

2009-01-01

Systemic inhibition of complex I by rotenone in rats represents a model of Parkinson's disease (PD). The aim of this study was to elucidate whether neramexane (NMDA, nicotinic α9/α10 and 5-HT 3 receptor antagonist), idazoxan (α 2 -adrenoceptor antagonist) or 2-methyl-6-(phenyl-ethyl)-pyrimidine (MPEP, metabotropic glutamate receptor 5 antagonist) prevents rotenone-induced parkinsonian-like behaviours and neurochemical changes in rats. Rotenone (2.5 mg/kg i.p. daily) was administered over 60 days together with saline, neramexane (5 mg/kg i.p., b.i.d.), idazoxan (2.5 mg/kg i.p., b.i.d.) or MPEP (2.5 mg/kg i.p., b.i.d.). The same doses of neramexane, idazoxan and MPEP were administered to rats treated with vehicle instead of rotenone. Treatment-related effects on parkinsonian-like behaviours, such as hypokinesia/rigidity and locomotor activity, were evaluated. Moreover, concentrations of dopamine, serotonin and their metabolites were measured in rats from each experimental group. Over the 60-day treatment period, the rotenone + saline treated animals developed hypokinesia, expressed as an increase in the bar and grid descent latencies in the catalepsy test, and a decrease in locomotor activity. Neramexane and idazoxan partially prevented the development of catalepsy in rotenone-treated rats. Co-administration of MPEP with rotenone resulted only in a decrease in descent latency in the grid test on day 60. Chronic rotenone treatment reduced concentrations of dopamine and serotonin in the anterior striatum, which was blocked by co-treatment with neramexane or idazoxan but not with MPEP. Only neramexane treatment blocked the rotenone-induced decrease in dopamine levels in the substantia nigra pars compacta. In conclusion, neramexane and idazoxan counteracted to some extent the development of parkinsonian symptoms and neurochemical alterations in the rotenone model of Parkinson's disease.

Independent mediation of unconditioned motor behavior by striatal D1 and D2 receptors in rats depleted of dopamine as neonates.

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Bruno, J P; Byrnes, E M; Johnson, B J

1995-11-01

The effects of systemic administration of DA receptor antagonists suggest that unconditioned motor behavior in rats depleted of DA as neonates continues to be dependent upon dopaminergic transmission, yet the specific contribution of D1 and D2 receptors to these behaviors has been altered. The purpose of the present study was to determine whether these depletion-induced receptor changes are occurring at the level of striatal DA terminals and their targets. The ability of bilateral intrastriatal injections (0.5 microliter) of DA receptor antagonists to induce motoric deficits was determined in adult rats treated with vehicle or 6-OHDA (100 micrograms, intraventricular) on postnatal day 3. Administration of the D1-like antagonist SCH 23390 (0.5-2.0 micrograms) or the D2-like antagonist clebopride (1.0-4.0 micrograms) induced dose-dependent akinesia, catalepsy, and somatosensory neglect in vehicle-treated controls. In contrast, neither antagonist produced deficits in rats depleted of forebrain DA as neonates. However, combined administration of SCH 23390 + clebopride induced similar akinesia, catalepsy, and somatosensory neglect in both controls and DA depleted animals. Animals depleted of DA were more sensitive than controls to the low doses of this combined D1 + D2 antagonism. These results demonstrate that activation of striatal DA receptors remains necessary for unconditioned motor behavior in rats depleted of DA as neonates. However, the specific contributions of D1- and D2-like receptors to these behaviors differ between intact animals and those depleted of DA as neonates. The ability of endogenous DA acting at either D1 or D2 receptors to support spontaneous motor behavior in rats depleted of DA as neonates may contribute to their relative sparing from parkinsonian deficits.

Repeated Exposure to the “Spice” Cannabinoid JWH-018 Induces Tolerance and Enhances Responsiveness to 5-HT1A Receptor Stimulation in Male Rats

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Joshua S. Elmore

2018-02-01

Full Text Available Naphthalen-1-yl-(1-pentylindol-3-ylmethanone (JWH-018 is a synthetic compound found in psychoactive “spice” products that activates cannabinoid receptors. Preclinical evidence suggests that exposure to synthetic cannabinoids increases 5-HT2A/2C receptor function in the brain, an effect which might contribute to psychotic symptoms. Here, we hypothesized that repeated exposures to JWH-018 would enhance behavioral responsiveness to the 5-HT2A/2C receptor agonist DOI. Male Sprague-Dawley rats fitted with subcutaneously (sc temperature transponders received daily injections of JWH-018 (1.0 mg/kg, sc or its vehicle for seven consecutive days. Body temperature and catalepsy scores were determined at 1, 2, and 4 h post-injection each day. At 1 and 7 days after the final repeated treatment, rats received a challenge injection of either DOI (0.1 mg/kg, sc or the 5-HT1A receptor agonist 8-OH-DPAT (0.3 mg/kg, sc, then temperature and behavioral responses were assessed. Behaviors induced by DOI included wet dog shakes and back muscle contractions (i.e., skin jerks, while behaviors induced by 8-OH-DPAT included ambulation, forepaw treading, and flat body posture. On the first day of repeated treatment, JWH-018 produced robust hypothermia and catalepsy which lasted up to 4 h, and these effects were significantly blunted by day 7 of treatment. Repeated exposure to JWH-018 did not affect behaviors induced by DOI, but behavioral and hypothermic responses induced by 8-OH-DPAT were significantly augmented 1 day after cessation of JWH-018 treatment. Collectively, our findings show that repeated treatment with JWH-018 produces tolerance to its hypothermic and cataleptic effects, which is accompanied by transient enhancement of 5-HT1A receptor sensitivity in vivo.

Dopaminergic profile of new heterocyclic N-phenylpiperazine derivatives

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Neves G.

2003-01-01

Full Text Available Dopamine constitutes about 80% of the content of central catecholamines and has a crucial role in the etiology of several neuropsychiatric disorders, including Parkinson's disease, depression and schizophrenia. Several dopaminergic drugs are used to treat these pathologies, but many problems are attributed to these therapies. Within this context, the search for new more efficient dopaminergic agents with less adverse effects represents a vast research field. The aim of the present study was to report the structural design of two N-phenylpiperazine derivatives, compound 4: 1-[1-(4-chlorophenyl-1H-4-pyrazolylmethyl]-4-phenylhexahydropyrazine and compound 5: 1-[1-(4-chlorophenyl-1H-1,2,3-triazol-4-ylmethyl]-4-phenylhexahydropyrazine, planned to be dopamine ligands, and their dopaminergic action profile. The two compounds were assayed (dose range of 15-40 mg/kg in three experimental models: 1 blockade of amphetamine (30 mg/kg, ip-induced stereotypy in rats; 2 the catalepsy test in mice, and 3 apomorphine (1 mg/kg, ip-induced hypothermia in mice. Both derivatives induced cataleptic behavior (40 mg/kg, ip and a hypothermic response (30 mg/kg, ip which was not prevented by haloperidol (0.5 mg/kg, ip. Compound 5 (30 mg/kg, ip also presented a synergistic hypothermic effect with apomorphine (1 mg/kg, ip. Only compound 4 (30 mg/kg, ip significantly blocked the amphetamine-induced stereotypy in rats. The N-phenylpiperazine derivatives 4 and 5 seem to have a peculiar profile of action on dopaminergic functions. On the basis of the results of catalepsy and amphetamine-induced stereotypy, the compounds demonstrated an inhibitory effect on dopaminergic behaviors. However, their hypothermic effect is compatible with the stimulation of dopaminergic function which seems not to be mediated by D2/D3 receptors.

Behavioral control by striatal adenosine A2A -dopamine D2 receptor heteromers.

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Taura, J; Valle-León, M; Sahlholm, K; Watanabe, M; Van Craenenbroeck, K; Fernández-Dueñas, V; Ferré, S; Ciruela, F

2018-04-01

G protein-coupled receptors (GPCR) exhibit the ability to form receptor complexes that include molecularly different GPCR (ie, GPCR heteromers), which endow them with singular functional and pharmacological characteristics. The relative expression of GPCR heteromers remains a matter of intense debate. Recent studies support that adenosine A 2A receptors (A 2A R) and dopamine D 2 receptors (D 2 R) predominantly form A 2A R-D 2 R heteromers in the striatum. The aim of the present study was evaluating the behavioral effects of pharmacological manipulation and genetic blockade of A 2A R and D 2 R within the frame of such a predominant striatal heteromeric population. First, in order to avoid possible strain-related differences, a new D 2 R-deficient mouse with the same genetic background (CD-1) than the A 2A R knock-out mouse was generated. Locomotor activity, pre-pulse inhibition (PPI) and drug-induced catalepsy were then evaluated in wild-type, A 2A R and D 2 R knock-out mice, with and without the concomitant administration of either the D 2 R agonist sumanirole or the A 2A R antagonist SCH442416. SCH442416-mediated locomotor effects were demonstrated to be dependent on D 2 R signaling. Similarly, a significant dependence on A 2A R signaling was observed for PPI and for haloperidol-induced catalepsy. The results could be explained by the existence of one main population of striatal postsynaptic A 2A R-D 2 R heteromers, which may constitute a relevant target for the treatment of Parkinson's disease and other neuropsychiatric disorders. © 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Edaravone guards dopamine neurons in a rotenone model for Parkinson's disease.

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Nian Xiong

Full Text Available 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone, an effective free radical scavenger, provides neuroprotection in stroke models and patients. In this study, we investigated its neuroprotective effects in a chronic rotenone rat model for Parkinson's disease. Here we showed that a five-week treatment with edaravone abolished rotenone's activity to induce catalepsy, damage mitochondria and degenerate dopamine neurons in the midbrain of rotenone-treated rats. This abolishment was attributable at least partly to edaravone's inhibition of rotenone-induced reactive oxygen species production or apoptotic promoter Bax expression and its up-regulation of the vesicular monoamine transporter 2 (VMAT2 expression. Collectively, edaravone may provide novel clinical therapeutics for PD.

Edaravone Guards Dopamine Neurons in a Rotenone Model for Parkinson's Disease

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Chen, Chunnuan; Huang, Jinsha; Zhao, Ying; Zhang, Zhentao; Qiao, Xian; Feng, Yuan; Reesaul, Harrish; Zhang, Yongxue; Sun, Shenggang; Lin, Zhicheng; Wang, Tao

2011-01-01

3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone), an effective free radical scavenger, provides neuroprotection in stroke models and patients. In this study, we investigated its neuroprotective effects in a chronic rotenone rat model for Parkinson's disease. Here we showed that a five-week treatment with edaravone abolished rotenone's activity to induce catalepsy, damage mitochondria and degenerate dopamine neurons in the midbrain of rotenone-treated rats. This abolishment was attributable at least partly to edaravone's inhibition of rotenone-induced reactive oxygen species production or apoptotic promoter Bax expression and its up-regulation of the vesicular monoamine transporter 2 (VMAT2) expression. Collectively, edaravone may provide novel clinical therapeutics for PD. PMID:21677777

[Case with difficulty in differentiating between transient neuroleptic malignant syndrome and catatonia after neuroleptic analgesia].

Science.gov (United States)

Yanagawa, Youichi; Miyazaki, Masaki

2010-02-01

An 18-year-old woman was treated with neuroleptic analgesia using fentanyl, morphine, droperidol and haloperidol for general anesthesia and pain control for her knee operation. Postoperatively, she showed emotional unstableness, following dyspnea, tachycardia, fever, hyperhydrosis, muscle rigidity and myoclonus like involuntary movement. She received infusion of 140 mg dantrolene in total under suspicion of having neuroleptic malignant syndrome, but her symptoms improved slightly. After being transferred to our hospital, she exhibited immobility, mutism, rigidity, and catalepsy, and she was suspected of having lethal catatonia. Infusion of diazepam 10 mg resulted in dramatical improvement of her symptoms. Differential diagnosis between neuroleptic malignant syndrome and catatonia is difficult; however, a first line therapy is differential diagnosis. Thus, physician should consider catatonia when treating neuroleptic malignant like syndrome.

Renal Failure in Dementia with Lewy Bodies Presenting as Catatonia

Science.gov (United States)

Fekete, Robert

2013-01-01

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. PMID:23466522

Neuropharmacological profile of ethnomedicinal plants of Guatemala.

Science.gov (United States)

Morales Cifuentes, C; Gómez-Serranillos, M P; Iglesias, I; Villar del Fresno, A M; Morales, C; Paredes, M E; Cáceres, A

2001-08-01

We carried out the Irwin's test with some different extracts of the aerial parts of Thidax procumbens L., the leaves of Neurolaena lobata (L.) R. Br., bark and leaves of Byrsonima crassifolia (L.) Kunth. and Gliricidia sepium Jacq. Walp., and root and leaves of Petiveria alliacea L. At dosage of 1.25 g dried plant/kg weight aqueous extracts of bark and leaves of Byrsonima crassifolia (L.) Kunth. and Gliricidia sepium Jacq. Walp. demonstrated the most activity: decrease in motor activity, back tonus, reversible parpebral ptosis, catalepsy and strong hypothermia. These extracts of both plants were assayed for effects on CNS and they caused very significant reductions in spontaneous locomotor activity, exploratory behavior and rectal temperature and they increased the sodium pentobarbital-induced sleeping time.

Developmental aspects of anandamide: ontogeny of response and prenatal exposure.

Science.gov (United States)

Fride, E; Mechoulam, R

1996-02-01

Recent breakthroughs in cannabinoid research, including the identification of two cannabinoid receptors (CB receptors) and a family of endogenous ligands, the anandamides, may shed new light on the sequelae of pre- and perinatal exposure to cannabinoid receptor ligands and enable the experimental manipulation of the endogenous ligand in the developing organism. In the present study we examined the behavioural response to anandamide (ANA) in developing mice from day 13 into adulthood. We observed that depression of ambulation in an open field and the analgetic response to ANA are not fully developed until adulthood. In a separate set of experiments, we administered five daily injections of ANA (SC, 20 mg/kg) during the last trimester of pregnancy. No effects on birth weight, litter size, sex ratio and eye opening were detected after maternal ANA treatment. Further, no effects on open field performance of the offspring were observed until 4 weeks of age. However, from 40 days of age, a number of differences between the prenatal ANA and control offspring were detected. Thus, the offspring from ANA-treated dams showed impaired responsiveness to a challenge with ANA or delta 0-THC expressed as a lack of immobility in the ring test for catalepsy, hypothermia and analgesia. On the other hand, without challenge, they exhibited a spontaneous decrease in open field activity, catalepsy, hypothermia and a hypoalgetic tendency. These data suggest that exposure to excessive amounts of ANA during gestation alters the functioning of the ANA-CB receptor system. Further experiments investigating responsivity of the immune system suggest an increased inflammatory response to arachidonic acid, and enhanced hypothermic response to lipopolysaccharide in prenatally treated offspring. The results are discussed in relation to other manipulations of the maternal milieu, especially prenatal stress. It is concluded that alterations induced by prenatal exposure to ANA, cannabinoids and other

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.

Dyskinesias differentiate autistic disorder from catatonia.

Science.gov (United States)

Brasic, J R; Barnett, J Y; Will, M V; Nadrich, R H; Sheitman, B B; Ahmad, R; Mendonca, M de F; Kaplan, D; Brathwaite, C

2000-12-01

Autistic disorder and catatonia are neuropsychiatric syndromes defined by impairments in social interaction, communication, and restricted, stereotypical motor routines. Assessments of children with these disorders are typically restricted in scope by the patients' limited ability to comprehend directions. The authors performed systematic assessments of dyskinesias on six prepubertal boys with autistic disorder and mental retardation and on one adolescent male with catatonia to determine if this type of information could be routinely obtained. The boys with autistic disorder had more stereotypies and tics, a greater degree of akathisia and hyperactivity, and more compulsions than the adolescent with catatonia. Catatonia was associated with catalepsy and dystonic postures. The authors conclude that the diagnostic accuracy and specificity of neuropsychiatric syndromes may be enhanced by the systematic assessment of the dyskinesias associated with each condition.

Functionality of colinergic systems in rats pre-treatment with triiodothyronine

International Nuclear Information System (INIS)

Almeida, O.M.S. de.

1990-01-01

In order to investigate the influence of experimental hiperthyroidism in the colinergic activity, rats were injected daily, during 1, 5, 19 or 20 days, with triiodothyronine (0 to 100 ug/kg, s.c.). The hiperthyroidism was evaluated by the decrease of the body weight and the increase of the body temperature and serum hormonal levels (T3). After the administration of the cholinergic agonists (pilocarpine and oxotremorine) or a anticholinesterase drug (eserine), the cholinergic behavioural and pharmacologic activity was evaluated recording the rectal temperature, locomotor activity, catalepsy, tremor and cromodacryorrhea. The results suggests that T3 pre-treatment may induce in rats changes in the functionality of the central cholinergic post-sinaptic receptors. However, the administration of this hormone does not seem to induce any alterations in the periferic cholinergic receptors, implicated in cromodacryorrhea effect. (author)

Pharmacological evaluation of bee venom and melittin

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Camila G. Dantas

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.

The pathophysiological functions mediated by D-1 dopamine receptors

International Nuclear Information System (INIS)

Goldstein, M.; Kuga, S.; Meller, E.; SHimizu, Y.

1986-01-01

This chapter describes some behavioral responses which might be mediated by D 1 and D 2 DA receptors, and the authors discuss their clinical relevance. It was of considerable interest to determine whether a selective D 1 DA antagonist, such as SCH 23390, will induce catalepsy and whether this behavior is mediated by D 1 , or by both D 1 and D 2 DA receptors. Rats were used in the experiments. The authors examined whether the addition of the S 2 antagonist ketanserin affects the displacement of 3 H-Spi by SCH 23390. Induction of self-mutilating biting (SMB) behavior in monkeys with unilateral ventromedial tegmental (VMT) lesions by DA agonists and its prevention by DA antagonists is examined. The authors also discuss the possible relationships between abnormal guanine nucleotide metabolism and dopaminergic neuronal function through the implications in LeschNyhan syndrome and in some mental disorders

Suggestibility, expectancy, trance state effects, and hypnotic depth: II. Assessment via the PCI-HAP.

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Pekala, Ronald J; Kumar, V K; Maurer, Ronald; Elliott-Carter, Nancy; Moon, Edward; Mullen, Karen

2010-04-01

This study sought to determine if self-reported hypnotic depth (srHD) could be predicted from the variables of the Phenomenology of Consciousness Inventory - Hypnotic Assessment Procedure (PCI-HAP) (Pekala, 1995a, 1995b; Pekala & Kumar, 2007; Pekala et al., 2010), assessing several of the processes theorized by researchers to be associated with hypnotism: trance (altered state effects), suggestibility, and expectancy. One hundred and eighty participants completed the PCI-HAP. Using regression analyses, srHD scores were predicted from the PCI-HAP pre-hypnotic and post-hypnotic assessment items, and several other variables. The results suggested that the srHD scores were found to be a function of imagoic suggestibility, expectancy (both estimated hypnotic depth and expected therapeutic efficacy), and trance state and eye catalepsy effects; effects that appear to be additive and not (statistically) interactive. The results support the theorizing of many investigators concerning the involvement of the aforementioned component processes with this particular aspect of hypnotism, the self-reported hypnotic depth score.

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

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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

Delayed Diagnosis in an Elderly Schizophrenic Patient with Catatonic State and Pulmonary Embolism

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Hsueh-Chin Hu

2013-09-01

Full Text Available Catatonia is a syndrome with any two of five core features: stupor/motoric immobility/catalepsy/waxy flexibility, excitement, negativism/mutism, posturing, and echolalia/echopraxia. We describe a case of delayed diagnosis of pulmonary embolism with an atypical presentation in an elderly schizophrenia male patient, which led to a life-threatening brain infarction. A 75-year-old male was hospitalized in a psychiatric ward because of stupor, poor intake and mutism under a diagnosis of recurrent catatonia. His inability to express his suffering, dehydration, exacerbation of chronic obstructive pulmonary disease, and upper gastrointestinal bleeding, however, made an accurate diagnosis difficult. Finally, the high D-dimer level and further chest computed tomography confirmed pulmonary embolism in the trunk of the bilateral main pulmonary arteries. The brain computed tomography also confirmed brain infarcts. He was transferred to the cardiac intensive care unit and was eventually rescued from near death due to pulmonary embolism and brain infarction. A careful differential diagnosis for pulmonary embolism-induced delirium and catatonic state is important in the treatment of patients with a previous diagnosis of catatonic schizophrenia.

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

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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.

Synthesis and pharmacological characterization of novel N-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)amides as potential multireceptor atypical antipsychotics.

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Chen, Xiao-Wen; Sun, Yuan-Yuan; Fu, Lei; Li, Jian-Qi

2016-11-10

A series of novel benzisothiazolylpiperazine derivatives combining potent dopamine D2 and D3, and serotonin 5-HT1A and 5-HT2A receptor properties were synthesized and evaluated for their potential antipsychotic properties. The most-promising derivative was 9j. The unique pharmacological features of 9j were a high affinity for D2, D3, 5-HT1A, and 5-HT2A receptors, together with a 20-fold selectivity for the D3 versus D2 subtype, and a low affinity for muscarinic M1 (reducing the risk of anticholinergic side effects), and for hERG channels (reducing incidence of QT interval prolongation). In animal behavioral models, 9j inhibited the locomotor-stimulating effects of phencyclidine, blocked conditioned avoidance response, and improved the cognitive deficit in the novel object recognition tests in rats. 9j exhibited a low potential for catalepsy, consistent with results with risperidone. In addition, favorable brain penetration of 9j in rats was detected. These studies have demonstrated that 9j is a potential atypical antipsychotic candidate. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Safety and side effects of cannabidiol, a Cannabis sativa constituent.

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Bergamaschi, Mateus Machado; Queiroz, Regina Helena Costa; Zuardi, Antonio Waldo; Crippa, José Alexandre S

2011-09-01

Cannabidiol (CBD), a major nonpsychotropic constituent of Cannabis, has multiple pharmacological actions, including anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, little is known about its safety and side effect profile in animals and humans. This review describes in vivo and in vitro reports of CBD administration across a wide range of concentrations, based on reports retrieved from Web of Science, Scielo and Medline. The keywords searched were "cannabinoids", "cannabidiol" and "side effects". Several studies suggest that CBD is non-toxic in non-transformed cells and does not induce changes on food intake, does not induce catalepsy, does not affect physiological parameters (heart rate, blood pressure and body temperature), does not affect gastrointestinal transit and does not alter psychomotor or psychological functions. Also, chronic use and high doses up to 1,500 mg/day of CBD are reportedly well tolerated in humans. Conversely, some studies reported that this cannabinoid can induce some side effects, including inhibition of hepatic drug metabolism, alterations of in vitro cell viability, decreased fertilization capacity, and decreased activities of p-glycoprotein and other drug transporters. Based on recent advances in cannabinoid administration in humans, controlled CBD may be safe in humans and animals. However, further studies are needed to clarify these reported in vitro and in vivo side effects.

[Caffeine as a preventive drug for Parkinson's disease: epidemiologic evidence and experimental support].

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Góngora-Alfaro, José Luis

Prospective epidemiologic studies performed in large cohorts of men (total: 374,003 subjects) agree in which the risk of suffering Parkinson's disease diminishes progressively as the consumption of coffee and other caffeinated beverages increases. In the case of women (total: 345,184 subjects) the protective effect of caffeine is only observed in menopausal women which do not receive estrogen replacement therapy. Studies with models of acute parkinsonism in rodents have shown that caffeine reduces the loss of nigrostriatal dopaminergic neurons induced with the neurotoxins 6-hidroxidopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, effect that seems to be mediated through blockade of A(2A) adenosine receptors. Recently, it was shown that male rats treated with moderate doses of caffeine (5 mg/kg/day) during six months, followed by a withdrawal period of at least two weeks, developed a greater resistance to the catalepsy induced with the dopaminergic antagonist haloperidol, which was possibly mediated by an increase of dopaminergic transmission in the corpus striatum. More studies are needed to demonstrate unequivocally that caffeine prevents the degeneration of dopaminergic neurons in animal models of moderate, chronic, and progressive parkinsonism, since it could lead to the discovery of more effective drugs for the prevention of aging-related degenerative diseases of the central nervous system.

An effective novel delivery strategy of rasagiline for Parkinson's disease.

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Fernández, Marcos; Negro, Sofía; Slowing, Karla; Fernández-Carballido, Ana; Barcia, Emilia

2011-10-31

This is the first report on the efficacy of a new controlled release system developed for rasagiline mesylate (RM) in a rotenone-induced rat model of Parkinson's disease (PD). PLGA microspheres in vitro released RM at a constant rate of 62.3 μg/day for two weeks. Intraperitoneal injection of rotenone (2 mg/kg/day) to Wistar rats produced typical PD symptoms. Catalepsy, akinesia and swim tests outcomes in animals receiving RM either in solution or within microspheres showed a reversal in descent latency when compared to rotenone-treated animals, being this reversal specially pronounced in animals receiving RM microspheres (dose equivalent to 1 mg/kg/day RM injected i.p. every 15 days). Nissl-staining of brain sections showed selective degeneration of the substantia nigra (SNc) dopaminergic neurons in rotenone-treated animals which was markedly reverted by RM microspheres. PET/CT with (18)F-DG resulted in mean increases of accumulation of radiotracer in striatum and SNc of around 40% in animals treated with RM microspheres which also had significant beneficial effects on Bcl-2, Bax, TNF-α mRNA and SOD2 levels as detected by real-time RT-PCR. Our results confirm the robust effect achieved by the new controlled release system developed for RM which exhibited better in vivo efficacy than RM given in solution. Copyright © 2011 Elsevier B.V. All rights reserved.

[3H]-beta-endorphin binding in rat brain

International Nuclear Information System (INIS)

Houghten, R.A.; Johnson, N.; Pasternak, G.W.

1984-01-01

The binding of [ 3 H]-beta-endorphin to rat brain homogenates is complex. Although Scatchard analysis of saturation studies yields a straight line, detailed competition studies are multiphasic, suggesting that even at low concentrations of the compound, the 3 H-ligand is binding to more than one class of site. A portion of [ 3 H]-beta-endorphin binding is sensitive to low concentrations of morphine or D-Ala2-Leu5-enkephalin (less than 5 nM). The inhibition observed with each compound alone (5 nM) is the same as that seen with both together (each at 5 nM). Thus, the binding remaining in the presence of both morphine and the enkephalin does not correspond to either mu or delta sites. The portion of [ 3 H]-beta-endorphin binding that is inhibited under these conditions appears to be equally sensitive to both morphine and the enkephalin and may correspond to mu1 sites. Treating membrane homogenates with naloxonazine, a mu1 selective antagonist, lowers [ 3 H]-beta-endorphin binding to the same degree as morphine and D-Ala2-Leu5-enkephalin alone or together. This possible binding of [ 3 H]-beta-endorphin to mu1 sites is consistent with the role of mu1 sites in beta-endorphin analgesia and catalepsy in vivo

(/sup 3/H)-beta-endorphin binding in rat brain

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Houghten, R.A.; Johnson, N.; Pasternak, G.W.

1984-10-01

The binding of (/sup 3/H)-beta-endorphin to rat brain homogenates is complex. Although Scatchard analysis of saturation studies yields a straight line, detailed competition studies are multiphasic, suggesting that even at low concentrations of the compound, the /sup 3/H-ligand is binding to more than one class of site. A portion of (/sup 3/H)-beta-endorphin binding is sensitive to low concentrations of morphine or D-Ala2-Leu5-enkephalin (less than 5 nM). The inhibition observed with each compound alone (5 nM) is the same as that seen with both together (each at 5 nM). Thus, the binding remaining in the presence of both morphine and the enkephalin does not correspond to either mu or delta sites. The portion of (/sup 3/H)-beta-endorphin binding that is inhibited under these conditions appears to be equally sensitive to both morphine and the enkephalin and may correspond to mu1 sites. Treating membrane homogenates with naloxonazine, a mu1 selective antagonist, lowers (/sup 3/H)-beta-endorphin binding to the same degree as morphine and D-Ala2-Leu5-enkephalin alone or together. This possible binding of (/sup 3/H)-beta-endorphin to mu1 sites is consistent with the role of mu1 sites in beta-endorphin analgesia and catalepsy in vivo.

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

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Hwang, Dahren; 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.

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

International Nuclear Information System (INIS)

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

1986-01-01

Three fluorinated derivatives of fentanyl, fluorofentanyl (3), keto-fluorofentanyl (5), and fluorofentanol (6), were synthesized and their abilities to compete with 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 [ 3 H]naltrexone for binding sites in rat brain membranes. Both fentayl and 6 exhibited a similar high ''sodium ratio'' (quotient of the IC 50 's against [ 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 [ 18 F]-6 was developed and the tissue distribution of [ 18 F]-6 in mice was determined 5, 60, and 120 minutes after intravenous injection. The use of this general route to 18 F-labeled derivatives of fentanyl for studies of the opiate receptor using positron emission tomography is planned. (author)

Inhalation Exposure Method for Illegal Drugs.

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Inomata, Akiko; Ogata, Akio; Tada, Yukie; Nagasawa, Akemichi; Yuzawa, Katsuhiro; Ando, Hiroshi; Kubo, Yoshikazu; Takahashi, Hiroshi; Kaihoko, Fujifumi; Tanaka, Kazuyoshi; Nakajima, Jun'ichi; Suzuki, Atsuko; Uemura, Nozomi; Moriyasu, Takako; Watanabe, Daisuke; Ishihara, Kei; Usami, Takashi; Kamei, Satoru; Kohno, Yasuaki

2017-01-01

We developed a new inhalation exposure method to evaluate effects of synthetic cannabimimetics that are being distributed as new, unregulated drugs in the Tokyo area. We selected the commercial product "SOUTOU" containing AB-CHMINACA and 5F-AMB as the test drug and dried marshmallow (Althaea officinalis) leaves as the negative control. A half cigarette packed with dried marshmallow leaves or SOUTOU was ignited, then mainstream smoke from each was delivered to five mice in an exposure box. After the cigarettes were fully consumed, neurobehavioral observations and a catalepsy test were performed at 15, 30 and 60 min after exposure. The effluent air from the exposure box was poured into impingers containing acetonitrile (first impinger) and dimethyl sulfoxide (second impinger). The resulting solutions were analyzed to assess decomposition of the synthetic cannabimimetics. Mice exposed to SOUTOU smoke showed many excitement behaviors and some suppressive behaviors at 15, 30 and 60 min. These clearly included cannabimimetic specific pharmacological actions. Negative control mice also showed some suppressive behaviors at 15 min but these were attenuated at later times, nearly disappearing at 60 min. In addition, the behavioral effects observed in controls were less pronounced than those in SOUTOU exposed mice. The inhalation exposure method developed in our study would be effective for determining cannabinoid specific pharmacological effects of illegal drugs, as well as for assessing the presence of active compound(s) by comparing the test substance with a negative control.

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.

The first fossil leaf insect: 47 million years of specialized cryptic morphology and behavior.

Science.gov (United States)

Wedmann, Sonja; Bradler, Sven; Rust, Jes

2007-01-09

Stick and leaf insects (insect order Phasmatodea) are represented primarily by twig-imitating slender forms. Only a small percentage ( approximately 1%) of extant phasmids belong to the leaf insects (Phylliinae), which exhibit an extreme form of morphological and behavioral leaf mimicry. Fossils of phasmid insects are extremely rare worldwide. Here we report the first fossil leaf insect, Eophyllium messelensis gen. et sp. nov., from 47-million-year-old deposits at Messel in Germany. The new specimen, a male, is exquisitely preserved and displays the same foliaceous appearance as extant male leaf insects. Clearly, an advanced form of extant angiosperm leaf mimicry had already evolved early in the Eocene. We infer that this trait was combined with a special behavior, catalepsy or "adaptive stillness," enabling Eophyllium to deceive visually oriented predators. Potential predators reported from the Eocene are birds, early primates, and bats. The combination of primitive and derived characters revealed by Eophyllium allows the determination of its exact phylogenetic position and illuminates the evolution of leaf mimicry for this insect group. It provides direct evidence that Phylliinae originated at least 47 Mya. Eophyllium enlarges the known geographical range of Phylliinae, currently restricted to southeast Asia, which is apparently a relict distribution. This fossil leaf insect bears considerable resemblance to extant individuals in size and cryptic morphology, indicating minimal change in 47 million years. This absence of evolutionary change is an outstanding example of morphological and, probably, behavioral stasis.

Protective Effects of Streblus asper Leaf Extract on H2O2-Induced ROS in SK-N-SH Cells and MPTP-Induced Parkinson’s Disease-Like Symptoms in C57BL/6 Mouse

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Kanathip Singsai

2015-01-01

Full Text Available This study investigated the effects of Streblus asper leaf extract (SA on reactive oxygen species (ROS in SK-N-SH cell culture and on motor functions and behaviors in MPTP-treated C57BL/6 mice. SK-N-SH cell viability after incubation with SA for 24 h was measured by MTT assay. Intracellular ROS levels of SK-N-SH cells were quantified after pretreatment with SA (0, 200, 600, and 1000 µg/mL in the presence of H2O2 (300 µM. Male C57BL/6 mice were force-fed with water or 200 mg/kg/day SA for 32 days. Intraperitoneal injection of MPTP was used to induce Parkinson’s disease-like symptoms. Catalepsy, beam balance ability, olfactory discrimination, social recognition, and spontaneous locomotor activity were assessed on days 19, 21, 23, 26, and 32, respectively. In cell culture, SA at 200, 600, and 1000 µg/mL significantly decreased ROS levels in H2O2-treated SK-N-SH cells. MPTP-treated C57BL/6 mice showed a significant change in all parameters tested when compared to the control group. Pretreatment and concurrent treatment with 200 mg/kg/day SA could antagonize the motor and cognitive function deficits induced by MPTP. The results show that SA possesses anti-Parkinson effects in MPTP-treated C57BL/6 mice and that reduction in ROS levels might be one of the mechanisms.

Frontotemporal dementia with trans-activation response DNA-binding protein 43 presenting with catatonic syndrome.

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Watanabe, Ryohei; Kawakami, Ito; Onaya, Mitsumoto; Higashi, Shinji; Arai, Nobutaka; Akiyama, Haruhiko; Hasegawa, Masato; Arai, Tetsuaki

2017-11-07

Catatonia is a clinical syndrome characterized by symptoms such as immobility, mutism, stupor, stereotypy, echophenomena, catalepsy, automatic obedience, posturing, negativism, gegenhalten and ambitendency. This syndrome occurs mostly in mood disorder and schizophrenic patients, and is related to neuronal dysfunction involving the frontal lobe. Some cases of frontotemporal dementia (FTD) with catatonia have been reported, but these cases were not examined by autopsy. Here, we report on a FTD case which showed catatonia after the first episode of brief psychotic disorder. At the age of 58, the patient had a sudden onset of disorganized behavior and meaningless speech. Psychotropic drugs were effective for catatonic symptoms. However, after remission apathy, hyperorality, socially inappropriate behavior, hoarding, and an instinctive grasp reaction appeared and persisted. Brain MRI showed significant atrophy of the bilateral fronto-temporal lobes. A neuropathological examination revealed extensive trans-activation response DNA-binding protein 43 (TDP-43) positive neurocytoplasmic inclusions and dystrophic neurites in the brain, including the cerebral cortex, basal ganglia, and brainstem. Pathological diagnosis was frontotemporal lobar degeneration (FTLD) with TDP-43 (FTLD-TDP) type C, which was also confirmed by the band pattern of C-terminal fragments of TDP-43 on western blotting of sarkosyl-insoluble fractions extracted from the frozen brain. Dysfunction of the thalamus, globus pallidus, supplementary motor area, amygdala and cingulate cortex have been said to be related to the catatonic syndrome. In this case, these areas were affected, showing abnormal TDP-43-positive structures. Further studies are expected to confirm further clinical - pathological correlations to FTLD. © 2017 Japanese Society of Neuropathology.

2-Phenylethylamine, a constituent of chocolate and wine, causes mitochondrial complex-I inhibition, generation of hydroxyl radicals and depletion of striatal biogenic amines leading to psycho-motor dysfunctions in Balb/c mice.

Science.gov (United States)

Sengupta, T; Mohanakumar, K P

2010-11-01

Behavioral and neurochemical effects of chronic administration of high doses of 2-phenylethylamine (PEA; 25-75 mg/kg, i.p. for up to 7 days) have been investigated in Balb/c mice. Depression and anxiety, as demonstrated respectively by increased floating time in forced swim test, and reduction in number of entries and the time spent in the open arms in an elevated plus maze were observed in these animals. General motor disabilities in terms of akinesia, catalepsy and decreased swimming ability were also observed in these animals. Acute and sub-acute administration of PEA caused significant, dose-dependent depletion of striatal dopamine, and its metabolites levels. PEA caused dose-dependent generation of hydroxyl radicals in vitro in Fenton's reaction in test tubes, in isolated mitochondrial fraction, and in vivo in the striatum of mice. A significant inhibition of NADH-ubiquinone oxidoreductase (complex-I; EC: 1.6.5.3) activity suggests the inhibition in oxidative phosphorylation in the mitochondria resulting in hydroxyl radical generation. Nissl staining and TH immnunohistochemistry in brain sections failed to show any morphological aberrations in dopaminergic neurons or nerve terminals. Long-term over-consumption of PEA containing food items could be a neurological risk factor having significant pathological relevance to disease conditions such as depression or motor dysfunction. However, per-oral administration of higher doses of PEA (75-125 mg/kg; 7 days) failed to cause such overt neurochemical effects in rats, which suggested safe consumption of food items rich in this trace amine by normal population. Copyright © 2010 Elsevier Ltd. All rights reserved.

Cross-talk between an activator of nuclear receptors-mediated transcription and the D1 dopamine receptor signaling pathway.

Science.gov (United States)

Schmidt, Azriel; Vogel, Robert; Rutledge, Su Jane; Opas, Evan E; Rodan, Gideon A; Friedman, Eitan

2005-03-01

Nuclear receptors are transcription factors that usually interact, in a ligand-dependent manner, with specific DNA sequences located within promoters of target genes. The nuclear receptors can also be controlled in a ligand-independent manner via the action of membrane receptors and cellular signaling pathways. 5-Tetradecyloxy-2-furancarboxylic acid (TOFA) was shown to stimulate transcription from the MMTV promoter via chimeric receptors that consist of the DNA binding domain of GR and the ligand binding regions of the PPARbeta or LXRbeta nuclear receptors (GR/PPARbeta and GR/LXRbeta). TOFA and hydroxycholesterols also modulate transcription from NF-kappaB- and AP-1-controlled reporter genes and induce neurite differentiation in PC12 cells. In CV-1 cells that express D(1) dopamine receptors, D(1) dopamine receptor stimulation was found to inhibit TOFA-stimulated transcription from the MMTV promoter that is under the control of chimeric GR/PPARbeta and GR/LXRbeta receptors. Treatment with the D(1) dopamine receptor antagonist, SCH23390, prevented dopamine-mediated suppression of transcription, and by itself increased transcription controlled by GR/LXRbeta. Furthermore, combined treatment of CV-1 cells with TOFA and SCH23390 increased transcription controlled by the GR/LXRbeta chimeric receptor synergistically. The significance of this in vitro synergy was demonstrated in vivo, by the observation that SCH23390 (but not haloperidol)-mediated catalepsy in rats was potentiated by TOFA, thus showing that an agent that mimics the in vitro activities of compounds that activate members of the LXR and PPAR receptor families can influence D1 dopamine receptor elicited responses.

Hypercholesterolemia causes psychomotor abnormalities in mice and alterations in cortico-striatal biogenic amine neurotransmitters: Relevance to Parkinson's disease.

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Paul, Rajib; Choudhury, Amarendranath; Chandra Boruah, Dulal; Devi, Rajlakshmi; Bhattacharya, Pallab; Choudhury, Manabendra Dutta; Borah, Anupom

2017-09-01

The symptoms of Parkinson's disease (PD) include motor behavioral abnormalities, which appear as a result of the extensive loss of the striatal biogenic amine, dopamine. Various endogenous molecules, including cholesterol, have been put forward as putative contributors in the pathogenesis of PD. Earlier reports have provided a strong link between the elevated level of plasma cholesterol (hypercholesterolemia) and onset of PD. However, the role of hypercholesterolemia on brain functions in terms of neurotransmitter metabolism and associated behavioral manifestations remain elusive. We tested in Swiss albino mice whether hypercholesterolemia induced by high-cholesterol diet would affect dopamine and serotonin metabolism in discrete brain regions that would precipitate in psychomotor behavioral manifestations. High-cholesterol diet for 12 weeks caused a significant increase in blood total cholesterol level, which validated the model as hypercholesterolemic. Tests for akinesia, catalepsy, swimming ability and gait pattern (increased stride length) have revealed that hypercholesterolemic mice develop motor behavioral abnormalities, which are similar to the behavioral phenotypes of PD. Moreover, hypercholesterolemia caused depressive-like behavior in mice, as indicated by the increased immobility time in the forced swim test. We found a significant depletion of dopamine in striatum and serotonin in cortex of hypercholesterolemic mice. The significant decrease in tyrosine hydroxylase immunoreactivity in striatum supports the observed depleted level dopamine in striatum, which is relevant to the pathophysiology of PD. In conclusion, hypercholesterolemia-induced depleted levels of cortical and striatal biogenic amines reported hereby are similar to the PD pathology, which might be associated with the observed psychomotor behavioral abnormalities. Copyright © 2017 Elsevier Ltd. All rights reserved.

Protection of dichlorvos induced oxidative stress and nigrostriatal neuronal death by chronic Coenzyme Q10 pretreatment

International Nuclear Information System (INIS)

Binukumar, BK; Gupta, Nidhi; Bal, Amanjit; Gill, Kiran Dip

2011-01-01

Numerous epidemiological studies have shown an association between pesticide exposure and increased risk of developing Parkinson's diseases. Oxidative stress generated as a result of mitochondrial dysfunction has been implicated as an important factor in the etiology of Parkinson's disease. Previously, we reported that chronic dichlorvos exposure causes mitochondrial impairments and nigrostriatal neuronal death in rats. The present study was designed to test whether Coenzyme Q 10 (CoQ 10 ) administration has any neuroprotective effect against dichlorvos mediated nigrostriatal neuronal death, α-synuclein aggregation, and motor dysfunction. Male albino rats were administered dichlorvos by subcutaneous injection at a dose of 2.5 mg/kg body weight over a period of 12 weeks. Results obtained there after showed that dichlorvos exposure leads to enhanced mitochondrial ROS production, α-synuclein aggregation, decreased dopamine and its metabolite levels resulting in nigrostriatal neurodegeneration. Pretreatment by Coenzyme Q 10 (4.5 mg/kg ip for 12 weeks) to dichlorvos treated animals significantly attenuated the extent of nigrostriatal neuronal damage, in terms of decreased ROS production, increased dopamine and its metabolite levels, and restoration of motor dysfunction when compared to dichlorvos treated animals. Thus, the present study shows that Coenzyme Q 10 administration may attenuate dichlorvos induced nigrostriatal neurodegeneration, α-synuclein aggregation and motor dysfunction by virtue of its antioxidant action. - Highlights: → CoQ 10 administration attenuates dichlorvos induced nigrostriatal neurodegenaration. → CoQ 10 pre treatment leads to preservation of TH-IR neurons. → CoQ 10 may decrease oxidative damage and α-synuclin aggregation. → CoQ 10 treatment enhances motor function and protects rats from catalepsy.

Effect of the novel synthetic cannabinoids AKB48 and 5F-AKB48 on "tetrad", sensorimotor, neurological and neurochemical responses in mice. In vitro and in vivo pharmacological studies.

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Canazza, Isabella; Ossato, Andrea; Trapella, Claudio; Fantinati, Anna; De Luca, Maria Antonietta; Margiani, Giulia; Vincenzi, Fabrizio; Rimondo, Claudia; Di Rosa, Fabiana; Gregori, Adolfo; Varani, Katia; Borea, Pier Andrea; Serpelloni, Giovanni; Marti, Matteo

2016-10-01

AKB48 and its fluorinate derivate 5F-AKB48 are two novel synthetic cannabinoids belonging to a structural class with an indazole core structure. They are marketed as incense, herbal preparations or chemical supply for their psychoactive Cannabis-like effects. The present study was aimed at investigating the in vitro and in vivo pharmacological activity of AKB48 and 5F-AKB48 in male CD-1 mice and comparing their in vivo effects with those caused by the administration of Δ 9 -THC and JWH-018. In vitro competition binding experiments performed on mouse and human CB 1 and CB 2 receptors revealed a nanomolar affinity and potency of the AKB48 and 5F-AKB48. In vivo studies showed that AKB48 and 5F-AKB48, induced hypothermia, increased pain threshold to both noxious mechanical and thermal stimuli, caused catalepsy, reduced motor activity, impaired sensorimotor responses (visual, acoustic and tactile), caused seizures, myoclonia, hyperreflexia and promoted aggressiveness in mice. Moreover, microdialysis study in freely moving mice showed that systemic administration of AKB48 and 5F-AKB48 stimulated dopamine release in the nucleus accumbens. Behavioural, neurological and neurochemical effects were fully prevented by the selective CB 1 receptor antagonist/inverse agonist AM 251. For the first time, the present study demonstrates the overall pharmacological effects induced by the administration of AKB48 and 5F-AKB48 in mice and suggests that the fluorination can increase the power and/or effectiveness of SCBs. Furthermore, this study outlines the potential detrimental effects of SCBs on human health.

Dermorphin-related peptides from the skin of Phyllomedusa bicolor and their amidated analogs activate two mu opioid receptor subtypes that modulate antinociception and catalepsy in the rat.

OpenAIRE

Negri, L; Erspamer, G F; Severini, C; Potenza, R L; Melchiorri, P; Erspamer, V

1992-01-01

Three naturally occurring dermorphin-like peptides from the skin of the frog Phyllomedusa bicolor, the related carboxyl-terminal amides, and some substituted analogs were synthesized, their binding profiles to opioid receptors were determined, and their biological activities were studied in isolated organ preparations and intact animals. The opioid binding profile revealed a very high selectivity of these peptides for mu sites and suggested the existence of two receptor subtypes, of high and ...

Neuroprotective effects of lixisenatide and liraglutide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.

Science.gov (United States)

Liu, W; Jalewa, J; Sharma, M; Li, G; Li, L; Hölscher, C

2015-09-10

Glucagon-like peptide 1 (GLP-1) is a growth factor. GLP-1 mimetics are on the market as treatments for type 2 diabetes and are well tolerated. These drugs have shown neuroprotective properties in animal models of neurodegenerative disorders. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in animal models of Parkinson's disease (PD), and a clinical trial in PD patients showed promising first results. Liraglutide and lixisenatide are two newer GLP-1 mimetics which have a longer biological half-life than exendin-4. We previously showed that these drugs have neuroprotective properties in an animal model of Alzheimer's disease. Here we demonstrate the neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected once-daily (20mg/kg i.p.) for 7 days, and drugs were injected once-daily for 14 days i.p. When comparing exendin-4 (10 nmol/kg), liraglutide (25 nmol/kg) and lixisenatide (10 nmol/kg), it was found that exendin-4 showed no protective effects at the dose chosen. Both liraglutide and lixisenatide showed effects in preventing the MPTP-induced motor impairment (Rotarod, open-field locomotion, catalepsy test), reduction in tyrosine hydroxylase (TH) levels (dopamine synthesis) in the substantia nigra and basal ganglia, a reduction of the pro-apoptotic signaling molecule BAX and an increase in the anti-apoptotic signaling molecule B-cell lymphoma-2. The results demonstrate that in this study, both liraglutide and lixisenatide are superior to exendin-4, and both drugs show promise as a novel treatment of PD. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

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.

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

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Maurice, Nicolas; Deltheil, Thierry; Melon, Christophe; Degos, Bertrand; Mourre, Christiane; Amalric, Marianne; Kerkerian-Le Goff, Lydia

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.

ADN-1184 a monoaminergic ligand with 5-HT(6/7) receptor antagonist activity: pharmacological profile and potential therapeutic utility.

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Kołaczkowski, M; Mierzejewski, P; Bieńkowski, P; Wesołowska, A; Newman-Tancredi, A

2014-02-01

Many dementia patients exhibit behavioural and psychological symptoms (BPSD) that include psychosis, aggressivity, depression and anxiety. Antipsychotic drugs are frequently prescribed but fail to significantly attenuate mood deficits, may interfere with cognitive function and are associated with motor and cardiac side effects, which are problematic in elderly patients. A need therefore exists for drugs that are better suited for the treatment of BPSD. We used in vitro cellular and in vivo behavioural tests to characterize ADN-1184, a novel arylsulfonamide ligand with potential utility for treatment of BPSD. ADN-1184 exhibits substantial 5-HT6 /5-HT7 /5-HT2A /D2 receptor affinity and antagonist properties in vitro. In tests of antipsychotic-like activity, it reversed MK-801-induced hyperactivity and stereotypies and inhibited conditioned avoidance response (MED = 3 mg·kg(-1) i.p.). Remarkably, ADN-1184 also reduced immobility time in the forced swim test at low doses (0.3 and 1 mg·kg(-1) i.p.; higher doses were not significantly active). Notably, up to 30 mg·kg(-1) ADN-1184 did not impair memory performance in the passive avoidance test or elicit significant catalepsy and only modestly inhibited spontaneous locomotor activity (MED = 30 mg·kg(-1) i.p.). ADN-1184 combines antipsychotic-like with antidepressant-like properties without interfering with memory function or locomotion. This profile is better than that of commonly used atypical antipsychotics tested under the same conditions and suggests that it is feasible to identify drugs that improve BPSD, without exacerbating cognitive deficit or movement impairment, which are of particular concern in patients with dementia. © 2013 The British Pharmacological Society.

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

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

2016-01-01

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 (Grin1ΔPV 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 Grin1ΔPV mice are not protected against the effects of MK-801, but are in fact sensitized to many of them. Compared with control animals, Grin1ΔPVmice injected with MK-801 show increased stereotypy and pronounced catalepsy, which confound the locomotor readout. Furthermore, in Grin1ΔPVmice, 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 Grin1ΔPVmice 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. PMID:27070406

Linagliptin potentiates the effect of l-dopa on the behavioural, biochemical and immunohistochemical changes in experimentally-induced Parkinsonism: Role of toll-like receptor 4, TGF-β1, NF-κB and glucagon-like peptide 1.

Science.gov (United States)

Kabel, Ahmed M; Omar, Mohamed S; Alhadhrami, A; Alharthi, Salman S; Alrobaian, Majed M

2018-05-01

Our aim was to assess the effect of different doses of linagliptin with or without l-dopa/Carbidopa on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in mice. Eighty Balb/c mice were divided into 8 equal groups: Control; MPTP; MPTP + l-dopa/Carbidopa; MPTP + linagliptin 3 mg/kg/day; MPTP + linagliptin 10 mg/kg/day; MPTP + Carboxymethyl cellulose; MPTP + l-dopa/Carbidopa + linagliptin 3 mg/kg/day and MPTP + l-dopa/Carbidopa + linagliptin 10 mg/kg/day. Striatal dopamine, tumor necrosis factor alpha (TNF-α), interleukin 10 (IL-10), transforming growth factor beta 1 (TGF-β1), toll-like receptor 4 (TLR4), antioxidant enzymes, adenosine triphosphate (ATP), glucagon-like peptide-1 (GLP-1), receptors of advanced glycation end products (RAGE), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase-1 (HO-1), mitochondrial complex I activity, catalepsy and total swim scores were measured. Also, the substantia nigra was subjected to immunohistochemical examination. The combination of l-dopa/Carbidopa and linagliptin in a dose-dependent manner resulted in significant improvement of the behavioural changes, striatal dopamine, antioxidant parameters, Nrf2/HO-1 content, GLP-1, ATP and mitochondrial complex I activity with significant decrease in striatal RAGE, TGF-β1, TNF-α, IL-10, TLR4 and alleviated the immunohistochemical changes better than the groups that received either l-dopa/Carbidopa or linagliptin alone. The combination of l-dopa/Carbidopa and linagliptin might represent a promising therapeutic modality for management of parkinsonism. Copyright © 2018 Elsevier Inc. All rights reserved.

Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency.

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Korner, Germaine; Noain, Daniela; Ying, Ming; Hole, Magnus; Flydal, Marte I; Scherer, Tanja; Allegri, Gabriella; Rassi, Anahita; Fingerhut, Ralph; Becu-Villalobos, Damasia; Pillai, Samyuktha; Wueest, Stephan; Konrad, Daniel; Lauber-Biason, Anna; Baumann, Christian R; Bindoff, Laurence A; Martinez, Aurora; Thöny, Beat

2015-10-01

Tyrosine hydroxylase catalyses the hydroxylation of L-tyrosine to l-DOPA, the rate-limiting step in the synthesis of catecholamines. Mutations in the TH gene encoding tyrosine hydroxylase are associated with the autosomal recessive disorder tyrosine hydroxylase deficiency, which manifests phenotypes varying from infantile parkinsonism and DOPA-responsive dystonia, also termed type A, to complex encephalopathy with perinatal onset, termed type B. We generated homozygous Th knock-in mice with the mutation Th-p.R203H, equivalent to the most recurrent human mutation associated with type B tyrosine hydroxylase deficiency (TH-p.R233H), often unresponsive to l-DOPA treatment. The Th knock-in mice showed normal survival and food intake, but hypotension, hypokinesia, reduced motor coordination, wide-based gate and catalepsy. This phenotype was associated with a gradual loss of central catecholamines and the serious manifestations of motor impairment presented diurnal fluctuation but did not improve with standard l-DOPA treatment. The mutant tyrosine hydroxylase enzyme was unstable and exhibited deficient stabilization by catecholamines, leading to decline of brain tyrosine hydroxylase-immunoreactivity in the Th knock-in mice. In fact the substantia nigra presented an almost normal level of mutant tyrosine hydroxylase protein but distinct absence of the enzyme was observed in the striatum, indicating a mutation-associated mislocalization of tyrosine hydroxylase in the nigrostriatal pathway. This hypomorphic mouse model thus provides understanding on pathomechanisms in type B tyrosine hydroxylase deficiency and a platform for the evaluation of novel therapeutics for movement disorders with loss of dopaminergic input to the striatum. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

ADN-1184 a monoaminergic ligand with 5-HT6/7 receptor antagonist activity: pharmacological profile and potential therapeutic utility

Science.gov (United States)

Kołaczkowski, M; Mierzejewski, P; Bieńkowski, P; Wesołowska, A; Newman-Tancredi, A

2014-01-01

Background and Purpose Many dementia patients exhibit behavioural and psychological symptoms (BPSD) that include psychosis, aggressivity, depression and anxiety. Antipsychotic drugs are frequently prescribed but fail to significantly attenuate mood deficits, may interfere with cognitive function and are associated with motor and cardiac side effects, which are problematic in elderly patients. A need therefore exists for drugs that are better suited for the treatment of BPSD. Experimental Approach We used in vitro cellular and in vivo behavioural tests to characterize ADN-1184, a novel arylsulfonamide ligand with potential utility for treatment of BPSD. Key Results ADN-1184 exhibits substantial 5-HT6/5-HT7/5-HT2A/D2 receptor affinity and antagonist properties in vitro. In tests of antipsychotic-like activity, it reversed MK-801-induced hyperactivity and stereotypies and inhibited conditioned avoidance response (MED = 3 mg·kg−1 i.p.). Remarkably, ADN-1184 also reduced immobility time in the forced swim test at low doses (0.3 and 1 mg·kg−1 i.p.; higher doses were not significantly active). Notably, up to 30 mg·kg−1 ADN-1184 did not impair memory performance in the passive avoidance test or elicit significant catalepsy and only modestly inhibited spontaneous locomotor activity (MED = 30 mg·kg−1 i.p.). Conclusions and Implications ADN-1184 combines antipsychotic-like with antidepressant-like properties without interfering with memory function or locomotion. This profile is better than that of commonly used atypical antipsychotics tested under the same conditions and suggests that it is feasible to identify drugs that improve BPSD, without exacerbating cognitive deficit or movement impairment, which are of particular concern in patients with dementia. PMID:24199650

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

International Nuclear Information System (INIS)

Schoepp, D.D.; Ornstein, P.L.; Leander, J.D.; Lodge, D.; Salhoff, C.R.; Zeman, S.; Zimmerman, D.M.

1990-01-01

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

Treatment with subthreshold doses of caffeine plus trihexyphenidyl fully restores locomotion and exploratory activity in reserpinized rats.

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Moo-Puc, Rosa E; Villanueva-Toledo, Jairo; Arankowsky-Sandoval, Gloria; Alvarez-Cervera, Fernando; Góngora-Alfaro, José L

2004-09-09

Trihexyphenidyl (THP) is a drug commonly used to reduce parkinsonian symptoms. An important side effect of this agent is memory impairment. Since caffeine enhances the potency of THP to inhibit haloperidol-induced catalepsy, caffeine may be used as an adjuvant of lower doses of THP, in order to improve its antiparkinsonian effects without causing memory disruption. To further assess the synergism between caffeine and THP, both drugs were tested in reserpinized rats, another preclinical model of Parkinson's disease. Four groups of rats (n = 7) were treated with reserpine (5 mg/kg, i.p.). A control group (n = 7) was treated only with the vehicle for reserpine (dimethylsulphoxide). The spontaneous locomotor behavior was tested 24 h later in a box with infrared sensors, 30 min after receiving one of the following treatments: distilled water (1 ml/kg), caffeine (1 mg/kg), THP (0.1 mg/kg) or caffeine plus THP. The levels of horizontal locomotion (14 +/- 5%) and vertical exploration (15 +/- 10%) were significantly lower in reserpinized rats treated with distilled water, compared with the mean activity values (100%) recorded in animals pretreated only with the vehicle for reserpine. The reserpine-induced hypokinesia was neither reversed by caffeine alone nor by THP alone. However, the combination of caffeine plus THP restored locomotion (141 +/- 19%) and vertical exploration (82 +/- 17%) to levels not significantly different to those of non-reserpinized rats. Moreover, the time-course of locomotion and exploration displayed the characteristic habituation over time, in which short-term memory processes are involved. Also, the thigmotaxis index indicated that the combined treatment did not induce anxiety-like behavior. Hence, these results support the proposal that low, subthreshold doses of caffeine plus THP have the potential to alleviate the motor disabilities in parkinsonian patients, with a low risk of causing anxiety or memory impairment.

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

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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.

Role of L-thyroxin in counteracting rotenone induced neurotoxicity in rats.

Science.gov (United States)

Salama, Mohamed; Helmy, Basem; El-Gamal, Mohamed; Reda, Amr; Ellaithy, Amr; Tantawy, Dina; Mohamed, Mie; El-Gamal, Aya; Sheashaa, Hussein; Sobh, Mohamed

2013-03-01

A key feature of Parkinson's disease is the dopaminergic neuronal cell loss in the substantia nigra pars compacta. Many triggering pathways have been incriminated in the pathogenesis of this disease including inflammation, oxidative stress, excitotoxicity and apoptosis. Thyroid hormone is an essential agent for the growth and maturation of neurons; moreover, it has variable mechanisms for neuroprotection. So, we tested the efficacy of (L)-thyroxin as a neuroprotectant in rotenone model of Parkinson's disease in rats. Thirty Sprague Dawley rats aged 3 months were divided into 3 equal groups. The first received daily intraperitoneal injections of 0.5% carboxymethyl cellulose (CMC) 3 mL/Kg. The second group received rotenone suspended in 0.5% CMC intraperitoneally at a dose of 3 mg/kg, daily. The third group received the same rotenone regimen subcutaneous l-thyroxine at a dose of 7.5 μg daily. All animals were evaluated regarding locomotor disturbance through blinded investigator who monitored akinesia, catalepsy, tremors and performance in open field test. After 35 days the animals were sacrificed and their brains were immunostained against anti-tyrosine hydroxylase and iba-1. Photomicrographs for coronal sections of the substantia nigra and striatum were taken and analyzed using image J software to evaluate cell count in SNpc and striatal fibers density and number of microglia in the nigrostriatal system. The results were then analyzed statistically. Results showed selective protective effects of thyroxin against rotenone induced neurotoxicity in striatum, however, failed to exert similar protection on SN. Moreover, microglial elevated number in nigrostriatal system that was induced by rotenone injections was diminished selectively in striatum only in the l-thyroxin treated group. One of the possible mechanisms deduced from this work was the selective regulation of microglia in striatal tissues. Thus, this study provides an insight into thyroxin neuroprotection

The effect of Ginkgo biloba extract on parkinsonisminduced biochemical changes in brain of irradiated rats

International Nuclear Information System (INIS)

Abd El-Aziz, E.R.

2012-01-01

Parkinson's disease (PD) is the second most common neuro degenerative disorder after Alzheimer's disease. In the present study, neuro modulatory effects of standardized ginkgo biloba extract (EGb 761) and low dose whole-body γ-irradiation in a reserpine model of rat Parkinsonism were investigated. Male Wistar rats were pretreated orally with EGb 761 (100 mg/kg BW/day for 3 weeks) or low dose whole-body γ-irradiation (0.25 Gy once a week for 6 weeks) and their combination (EGb 761 was received during the last three weeks of the irradiation period) and then subjected to intraperitoneal injection of reserpine (5 mg/kg BW dissolved in 1% acetic acid) 24h after last dose of EGb761or radiation. All rats were sacrificed 24h after reserpine injection. Depletion of striatal dopamine (DA) level, increased oxidative stress indicated via depletion of glutathione (GSH), increased malondialdehyde (MDA) and iron levels; decrease of dopamine metabolites metabolizing enzymes; indicated by decrease of glutathione-S transferase (GST) and NADPH-quinone oxidoreductase (NQO) activities; mitochondrial dysfunction; indicated by decline of complex I activity and adenosine triphosphate (ATP) level and increased apoptosis; indicated by the decrease of mitochondrial B cell lymphoma-2 protein (Bcl-2) level and as shown by transmission electron microscope (TEM) were observed in brain of reserpine-induced PD model group, along with behavioral study indicated by increased catalepsy score. Moreover, the level of GSH was correlated with the levels of both DA (r = 0.78) and MDA (r = -0.93). The level of Bcl-2 was correlated with the complex I activity (r = 0.94) and ATP level (r = 0.98). Results revealed that either EGb 761 or irradiation and their combination ameliorated most of the biochemical and behavioral changes induced by reserpine possibly via replenishment of normal glutathione levels. This study revealed that EGb 761, which is a widely used herbal medicine and low dose of whole-body �

Selective dopamine D3 receptor antagonism by SB-277011A attenuates cocaine reinforcement as assessed by progressive-ratio and variable-cost–variable-payoff fixed-ratio cocaine self-administration in rats

Science.gov (United States)

Xi, Zheng-Xiong; Gilbert, Jeremy G.; Pak, Arlene C.; Ashby, Charles R.; Heidbreder, Christian A.; Gardner, Eliot L.

2013-01-01

In rats, acute administration of SB-277011A, a highly selective dopamine (DA) D3 receptor antagonist, blocks cocaine-enhanced brain stimulation reward, cocaine-seeking behaviour and reinstatement of cocaine-seeking behaviour. Here, we investigated whether SB-277011A attenuates cocaine reinforcement as assessed by cocaine self-administration under variable-cost–variable-payoff fixed-ratio (FR) and progressive-ratio (PR) reinforcement schedules. Acute i.p. administration of SB-277011A (3–24 mg/kg) did not significantly alter cocaine (0.75 mg/kg/infusion) self-administration reinforced under FR1 (one lever press for one cocaine infusion) conditions. However, acute administration of SB-277011A (24 mg/kg, i.p.) progressively attenuated cocaine self-administration when: (a) the unit dose of self-administered cocaine was lowered from 0.75 to 0.125–0.5 mg/kg, and (b) the work demand for cocaine reinforcement was increased from FR1 to FR10. Under PR (increasing number of lever presses for each successive cocaine infusion) cocaine reinforcement, acute administration of SB-277011A (6–24 mg/kg i.p.) lowered the PR break point for cocaine self-administration in a dose-dependent manner. The reduction in the cocaine (0.25–1.0 mg/kg) dose–response break-point curve produced by 24 mg/kg SB-277011A is consistent with a reduction in cocaine’s reinforcing efficacy. When substituted for cocaine, SB-277011A alone did not sustain self-administration behaviour. In contrast with the mixed DA D2/D3 receptor antagonist haloperidol (1 mg/kg), SB-277011A (3, 12 or 24 mg/kg) failed to impede locomotor activity, failed to impair rearing behaviour, failed to produce catalepsy and failed to impair rotarod performance. These results show that SB-277011A significantly inhibits acute cocaine-induced reinforcement except at high cocaine doses and low work requirement for cocaine. If these results extrapolate to humans, SB-277011A or similar selective DA D3 receptor antagonists may be

Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice.

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Ghosh, Sudeshna; Kinsey, Steven G; Liu, Qing-Song; Hruba, Lenka; McMahon, Lance R; Grim, Travis W; Merritt, Christina R; Wise, Laura E; Abdullah, Rehab A; Selley, Dana E; Sim-Selley, Laura J; Cravatt, Benjamin F; Lichtman, Aron H

2015-08-01

Inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the primary hydrolytic enzymes for the respective endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonylglycerol (2-AG), produces antinociception but with minimal cannabimimetic side effects. Although selective inhibitors of either enzyme often show partial efficacy in various nociceptive models, their combined blockade elicits augmented antinociceptive effects, but side effects emerge. Moreover, complete and prolonged MAGL blockade leads to cannabinoid receptor type 1 (CB1) receptor functional tolerance, which represents another challenge in this potential therapeutic strategy. Therefore, the present study tested whether full FAAH inhibition combined with partial MAGL inhibition would produce sustained antinociceptive effects with minimal cannabimimetic side effects. Accordingly, we tested a high dose of the FAAH inhibitor PF-3845 (N-​3-​pyridinyl-​4-​[[3-​[[5-​(trifluoromethyl)-​2-​pyridinyl]oxy]phenyl]methyl]-​1-​piperidinecarboxamide; 10 mg/kg) given in combination with a low dose of the MAGL inhibitor JZL184 [4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate] (4 mg/kg) in mouse models of inflammatory and neuropathic pain. This combination of inhibitors elicited profound increases in brain AEA levels (>10-fold) but only 2- to 3-fold increases in brain 2-AG levels. This combination produced significantly greater antinociceptive effects than single enzyme inhibition and did not elicit common cannabimimetic effects (e.g., catalepsy, hypomotility, hypothermia, and substitution for Δ(9)-tetrahydrocannabinol in the drug-discrimination assay), although these side effects emerged with high-dose JZL184 (i.e., 100 mg/kg). Finally, repeated administration of this combination did not lead to tolerance to its antiallodynic actions in the carrageenan assay or CB1 receptor functional tolerance. Thus, full FAAH inhibition

Immunohistochemical evidence for the involvement of gonadotropin releasing hormone in neuroleptic and cataleptic effects of haloperidol in mice.

Science.gov (United States)

Fegade, Harshal A; Umathe, Sudhir N

2016-04-01

Blockade of dopamine D2 receptor by haloperidol is attributed for neuroleptic and cataleptic effects; and also for the release of gonadotropin releasing hormone (GnRH) from the hypothalamus. GnRH agonist is reported to exhibit similar behavioural effects as that of haloperidol, and pre-treatment with GnRH antagonist is shown to attenuate the effects of haloperidol, suggesting a possibility that GnRH might mediate the effects of haloperidol. To substantiate such possibility, the influence of haloperidol on GnRH immunoreactivity (GnRH-ir) in the brain was studied in vehicle/antide pre-treated mice by peroxidase-antiperoxidase method. Initially, an earlier reported antide-haloperidol interaction in rat was confirmed in mice, wherein haloperidol (250μg/kg, i.p.) exhibited suppression of conditioned avoidance response (CAR) on two-way shuttle box, and induced catalepsy in bar test; and pre-treatment with antide (50μg/kg, s.c., GnRH antagonist) attenuated both effects of haloperidol. Immunohistochemical study was carried out to identify GnRH-ir in the brain, isolated 1h after haloperidol treatment to mice pre-treated with vehicle/antide. The morphometric analysis of microphotographs of brain sections revealed that haloperidol treatment increased integrated density units of GnRH-ir in various regions of the limbic system. Considering basal GnRH-ir in vehicle treated group as 100%, the increase in GnRH-ir after haloperidol treatment was by 100.98% in the medial septum; 54.26% in the bed nucleus of the stria terminalis; 1152.85% in the anteroventral periventricular nucleus; 120.79% in the preoptic area-organum vasculosum of the lamina terminalis and 138.82% in the arcuate nucleus. Antide did not influence basal and haloperidol induced increase in GnRH-ir in any of the regions. As significant increase in GnRH-ir after haloperidol treatment was observed in such regions of the brain which are reported to directly or indirectly communicate with the hippocampus and basal

Psychoneuropharmacological activities and chemical composition of essential oil of fresh fruits of Piper guineense (Piperaceae) in mice.

Science.gov (United States)

Oyemitan, Idris Ajayi; Olayera, Omotola Aanuoluwa; Alabi, Akeeb; Abass, Luqman Adewale; Elusiyan, Christianah Abimbola; Oyedeji, Adebola Omowumi; Akanmu, Moses Atanda

2015-05-26

Piper guineense Schum & Thonn (Piperaceae) is a medicinal plant used in the Southern States of Nigeria to treat fever, mental disorders and febrile convulsions. This study aims at determining the chemical composition and the central nervous system (CNS) activities of the essential oil obtained from the plant׳s fresh fruits in order to rationalize its folkloric use. Essential oil of P. guineense (EOPG) obtained by hydrodistillation was analysed by GC/MS. EOPG (50-200mg/kg, i.p.) was evaluated for behavioural, hypothermic, sedative, muscle relaxant, anti-psychotic and anticonvulsant activities using standard procedures. Analysis of the oil reveals 44 compounds of which 30 compounds constituting 84.7% were identified. The oil was characterized by sesquiterpenoids (64.4%) while only four monoterpeneoids (21.3%) were found present in the oil. Major compounds identified were β-sesquiphellandrene (20.9%), linalool (6.1%), limonene (5.8%), Z-β-bisabolene (5.4%) and α-pinene (5.3%). The EOPG (50-200mg/kg, i.p.) caused significant (p<0.01) inhibition on rearing {F(4,20)=43}, locomotor {F(4,20)=22} activity and decreased head dips in hole board {F(4,20)=7} indicating CNS depressant effect; decreased rectal temperature {F(4,20)=7-16}, signifying hypothermic activity; decreased ketamine-induced sleep latency {F(4,20)=7.8} and prolonged total sleeping time {F(4,20)=8.8}, indicating sedative effect; reduced muscular tone on the hind-limb grip test {F(4,20)=22}, inclined board {F(4,20)=4-49} and rota rod {F(4,20)=13-106}, implying muscle relaxant activity; induced catalepsy {F(4,20)=47-136}, inhibited apomorphine-induced climbing behaviour {F(4,20)=9} and inhibited apomorphine-induced locomotor {F(4,20)=16}, suggesting anti-psychotic effect; and protected mice against pentylenetetrazole-induced convulsions, indicating anticonvulsant potential. The most abundant component of the fresh fruits essential oil of P. guineense was β-sesquiphellandrene (20.9%); and the oil possesses

[Catatonia de novo, report on a case: immediate vital prognosis and psychiatric prognosis in longer term].

Science.gov (United States)

Patry, L; Guillem, E; Pontonnier, F; Ferreri, M

2003-01-01

We report on the case of a 20 year old woman with no previous psychiatric history, who displayed a first episode of catatonia with acute onset. Symptoms started plainly with sudden general impairment, intense asthenia, headache, abdominal pain and confusion. After 48 hours, the patient was first admitted to an emergency unit and transferred to an internal medicine ward afterwards. She kept confused. Her behaviour was bizarre with permanent swinging of pelvis, mannerism, answers off the point and increasingly poor. The general clinical examination was normal, except for the presence of a regular tachycardia (120 bpm). The paraclinical investigations also showed normal: biology, EEG, CT Scan, lumbar puncture. Confusion persisted. The patient remained stuporous, with fixed gazing and listening-like attitudes. She managed to eat and move with the help of nurses but remained bedridden. The neurological examination showed hypokinaesia, extended hypotonia, sweating, urinary incontinence, bilateral sharp reflexes with no Babinski's sign and an inexhaustible nasoorbicular reflex. The patient was mute and contrary, actively closed her eyes, but responded occasionally to simple instructions. For short moments, she suddenly engaged in inappropriate behaviors (wandering around) while connecting back to her environment answering the telephone and talking to her parents. The patient's temperature rose twice in the first days but with no specific etiology found. During the first 8 days of hospitalization, an antipsychotic treatment was administered: haloperidol 10 mg per os daily and cyamemazine 37.5 mg i.m. daily. Despite these medications, the patient worsened and was transferred to our psychiatric unit in order to manage this catatonic picture with rapid onset for which no organic etiology was found. On admission, the patient was stuporous, immobile, unresponsive to any instruction, with catalepsy, maintenance of postures, severe negativism and refusal to eat. A first treatment

[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