Neuroprotective Effects of P-Coumaric Acid on Haloperidol-Induced Catalepsy Through Ameliorating Oxidative Stress and Brain Dopamine Level

Objective To evaluate the effect of p-coumaric acid (p-CA) on haloperidol-induced catalepsy in Swiss albino male mice. Method To induce catalepsy, haloperidol (1 mg/kg i.p.) was administered for 21 consecutive days. p-CA (50, 75, and 100 mg/kg, PO) was administered 30 min before haloperidol injection for 21 consecutive days. For catalepsy, locomotor activity and motor coordination scores were recorded on the 17, 14, and 21 days of drug treatment, while the gait analysis score was recorded on day 21. After behavioral testing, animals were sacrificed, and various biochemical and histopathology tests of the brain were conducted. Dopamine, malondialdehyde, reduced glutathione (GSH), superoxide dismutase (SOD), and catalase activity were examined in the brain. Results Chronic administration of haloperidol significantly increased catalepsy in mice. It also produced hypolocomotion, motor coordination, and gait disturbance in mice. p-CA significantly inhibited haloperidol-induced catalepsy. Haloperidol significantly increased malondialdehyde levels in the brain. While dopamine levels in the brain dropped along with GSH, SOD, and catalase activity levels, which also had an impact on the histology of the brain. p-CA significantly reduced haloperidol-induced increases in brain oxidative stress, dopamine levels in the brain, and brain histology in mice. Discussion p-CA significantly reduced haloperidol-induced catalepsy, possibly through reducing oxidative stress and increasing brain dopamine levels. It can be a good candidate drug for extrapyramidal symptoms in Parkinson’s disease and adjuvant therapy with antipsychotic drugs.

Effect of methonolic extract of Vitex negundo on haloperidol induced catalepsy in albino mice

Background: Plants are being used in traditional medicine since history of mankind. The knowledge of these medicinal plants has accrued in the course of many centuries leading to medicinal systems in India such as Ayurveda, Unani and Siddha. Objective: In the present study, we evaluated the anticataleptic efficacy of Vitex negundo, a polyherbal formulation in haloperidol induced catalepsy in mice.Methods: Five groups (n=6) of male albino mice were used in the study. Catalepsy was induced by i.p. administration of haloperidol (1 mg/kg). The degree of catalepsy (cataleptic score) was measured as the time the animal maintained an imposed posture. We compared the anticataleptic efficacy of Vitex negundo (50, 100, 200 mg/kg) with standard received Pheniramine maleate 10 mg/kg, i.p.Results: In vehicle treated animals, haloperidol (1 mg/kg. i.p.) produced the maximum catalepsy at 180 min (46.78�78 min). Standard treated as Pheniramine maleate 10 mg/kg, i.p. shows maximum at 120 min. 19.24�32. Test herb, i.p. Methanolic extract of Vitex negundo (50, 100, 200 mg/kg, i.p.) significantly potentiated haloperidol induced catalepsy at each time interval, in a dose dependent manner. At dose 50, 100 and 200mg/kg, extract of Vitex negundo (Linn.) roots showed maximum cataleptic score 12.34�78, 14.43�43 and 15.43�67 min, respectively at 120 minutes in haloperidol treated animals.Conclusions: The present study indicates that the methanolic extract of Vitex negundo reduces haloperidol-induced catalepsy in mice.

Neuroprotective Effect Of Methanolic Extract Of Sargassum Wightii On Haloperidol Induced Catalepsy And Tardive Dyskinesia In Albino Rats

Objective: The present study was designed to evaluate the neuroprotective effect of methanolic extract of Sargassum wightii on haloperidol-induced catalepsy and tardive dyskinesia in Wistar albino rats. Methods: In this study, thirty Wistar albino rats were randomly divided into six groups. Gr-I served as control. Haloperidol (1 mg/kg intraperitoneally) was administered to rats of Gr-II to Gr-V for twenty-one consecutive days to induce catalepsy and tardive dyskinesia. Animals of Gr-II to Gr-V were orally administered with vehicle, levodopa carbidopa combination (30 mg/kg), Sargassum extract 200 and 400 mg/kg respectively. All the drugs and vehicles were given orally one hour before haloperidol injection for twenty one consecutive days. The cataleptic scores were recorded using standard bar test. Tardive dyskinesia was assessed in terms of vacuous chewing movement (VCM) and tongue protrusion (TP) scores. After behavioural testing, all animals were sacrificed on twenty-second day and various biochemical parameters like MDA, SOD and GSH were estimated in brain tissue. Results: Chronic administration of haloperidol significantly increased cataleptic scores, VCM and TP scores. (p<0.001) Sargassum wightii extract (400 mg/kg) significantly inhibited haloperidol-induced catalepsy, VCM and TP (p<0.001) Haloperidol increased MDA and decreased SOD and GSH in brain tissue to a highly significant extent (p<0.001) Sargassum extract at 400 mg/kg also significantly reversed the haloperidol-induced alteration in brain oxidative stress markers. Conclusion: Sargassum wightii inhibits haloperidol-induced catalepsy and tardive dyskinesia. Thus it may be used as a unique therapeutic adjunct for the prevention of neuroleptic-induced extrapyramidal symptoms, however, it has to be explored more.

Assessment of Morus alba (mulberry) leaves extract for anti-psychotic effect in rats

Background: Morus alba commonly known as white mulberry has been widely cultivated to feed silkworms. This widely grown plant has been in use by tribals of this country for ailments such as asthma, cough, bronchitis, edema, insomnia, wound healing, diabetes, influenza, eye infections and nose bleeds. Various parts of morus alba linn are used as an cardioprotective, hepatoprotective anti-inflammatory, hypoglycemic, free radical scavenging activity and neuro-protective agent. In this study, anti-psychotic property of M. alba leaves extract (MAE) was evaluated by Haloperidol induced catalepsy model in rats.Methods: In this study Haloperidol induced catalepsy model was used to evaluate antipsychotic effects in rats. Haloperidol (1 mg/kg) was injected intraperitoneally to rats (n=6) pretreated with vehicle (0.5 mg/kg, i.p.) or MAE (100, 200 and 400 mg/kg, i.p).Results: In control treated animals, haloperidol produced the maximum catalepsy at 90 min 212.66 ±10.23. In animals treated with MAE at dose of 100 mg/kg, 200 mg/kg and 400 mg/kg significantly potentiated haloperidol induced catalepsy at each time interval, in a dose dependent manner. At dose 100, 200 and 400 mg/kg, animals treated with MAE showed maximum cataleptic score of 228.33±12.29, 265.66±7.33 and 274.16±8.86 respectively at 120 min (p<0.001).Conclusions: Results indicate that the MAE have anti-psychotic effects in haloperidol induced catalepsy model in rats.

Effect of Mirtazapine Pre-treatment on Haloperidol, Ergometrine and Fluoxetine Induced Behaviours in Albino Rats.

Background: Central 5-HT and 5-HT serotonergic 2A 2Creceptors are mainly involved in the control ofnigrostriatal and mesolimbic dopaminergic neuronalactivity has been well proved and established. 5-HThas facilitatory effect on stimulated dopamine releaseby stimulating central 5-HT receptors and inhibitory 2Aeffect by stimulating 5-HT receptors. Aim and 2CObjectives: To evaluate 5-HT and 5-HT receptor 2A 2Cblocking activity of Mirtazapine (MIR) and the effectof mirtazapine pre-treatment on Ergometrine (ERG)induced behaviours, Fluoxetine (FLU) induced penileerections and Haloperidol (HAL) induced catalepsy inrats. Material and Methods: Each group wassubdivided into different subgroups consisting 6animals in each. Control group received DimethylSulfoxide (DMSO) and other groups received differentdoses of mirtazapine one hour before ERG/FLU/HAL.Values obtained from control group were comparedwith all remaining groups pre-treatment with differentdoses of MIR. Results: MIR (MIR) at 2.5, 5, 10 and 20mg/kg intraperitoneally (i.p) did not produce any per seeffects. Pre-treatment with 5, 10 and 20 mg/kg i.p. MIRsignificantly antagonised ERG induced behaviours. 5mg/kg i.p. MIR significantly antagonised whereas 10and 20 mg/kg i.p. MIR abolished FLU (10 mg/kg)induced penile erections in rats. MIR 5 and 20 mg/kgi.p. significantly antagonised HAL (1mg/kg) inducedcatalepsy at 1 hr testing time interval while 10 and 20mg/kg MIR significantly antagonised HAL (1 mg/kg)induced catalepsy at 2 hr testing time interval.Conclusion: Our results indicate that MIR at 5, 10 and20 mg/kg possesses 5-HT and 5-HT receptors 2A 2Cblocking activity. At 5, 10 and 20 mg/kg MIR, byblocking central 5-HT receptors predominantly, 2Ccauses release of dopamine from nigrostriataldopaminergic neurons and therefore antagonizes HALinduced catalepsy

Evaluation of the effect of piperine per se and its interaction with ondansetron on haloperidol induced catalepsy in Albino mice

Background: This study aims to evaluate the per se effect of piperine and its interaction with ondansetron on haloperidol induced catalepsy in swiss albino mice.Methods: The piperine crystals were separated from crude extract of Piper nigrum. Catalepsy was induced by haloperidol (1mg/kg, i.p.). Control group received 2% gum acacia (10ml/kg), standard group ondansetron (0.5mg/kg), test group piperine (10mg/kg) and combination group ondansetron plus piperine (0.5mg/kg + 10mg/kg), per oral, respectively. In acute study, drugs were administered only once, one hour prior to the haloperidol administration. Whereas in chronic study, catalepsy was determined on the seventh day of treatment.Results: In acute study, from 60 min onwards after haloperidol administration, ondansetron and ondansetron plus piperine group resulted in significantly lower cataleptic scores than the control treated group. On the other hand, 120 min onwards ondansetron group showed significantly lower cataleptic scores (24.62) as compared to the ondansetron plus piperine group (31.50). In the chronic study, from 60 min onwards, ondansetron and the ondansetron plus piperine resulted in significantly lower cataleptic scores than the control treated group. Also the combination of ondansetron plus piperine was more significantly protective compared to ondansetron alone (P <0.05).Conclusions: Piperine has the potential to be used as a bioenhancer when combined with other drugs which would reduce the dose of drugs and thereby adverse effects. It may act probably by enhancing the bioavailability as well as by inhibiting the metabolic pathways of other drugs.

Effect of Phyllanthus Amarus on Haloperidol Induced Catalepsy in Experimental Animal Models.

Objectives: The aim of the study was to investigate the anticataleptic effect of Phyllanthus amarus ethanolic extract in Swiss albino mice. Methods: The ethanolic extract of leaves of Phyllanthus amarus [PAEE] at a dose of 100mg/kg/body weight was administered orally for ten days. On tenth day, one hour later Haloperidol [1 mg/ kg IP] was administered to induce catalepsy. Results: The results indicate that induction of catalepsy by Haloperidol in Swiss albino mice was significantly prevented by PAEE. Conclusions: The anticataleptic activity of Phyllanthus amarus can be due to its effect on brain neurotransmitters or due to antioxidant property.

Anti-NMDA Receptor Encephalitis in an Adolescent.

Background: Anti N-methyl-D-aspartate (NMDA) receptor encephalitis is an immune mediated disorder. Case characteristics: A previously healthy 14-year-old girl presenting with generalized tonic clonic seizures and altered behavior. Observation: In view of refractory seizures, hallucinations, psychobehavioral and catalepsy like symptoms, and CSF showing lymphocytic pleocytosis, possibility of autoimmune encephalitis was considered. Serum was positive for anti-NMDA receptor antibodies. Outcome: She recovered completely in six months without any sequelae. Conclusion: Anti-NMDA receptor encephalitis - a potentially treatable disease - should be considered in differential diagnosis of encephalitis when acute behavioral changes, seizures or dyskinesias are present.

Effect of various extracts of Tabernaemontana divaricata on haloperidol induced catalepsy in rats.

Parkinson’s disease (PD) is one of the neurodegenerative diseases with selective loss of dopamine neurons of the substantia nigra pars compacta. In the present study, anti-cataleptic activity of Tabernaemontana divaricata leaves extracts viz. aqueous and ethanolic at different doses (50, 100 and 150 mg/kg i.p.) were studied using haloperidol (1 mg/kg, i.p.) induced catalepsy in rats which is a useful animal model for screening drugs for Parkinson’s disease. Both the extracts were found to reduce catalepsy significantly (P<0.001) as compared to the haloperidol treated rats showing greater effect at 150 mg/kg i.p. dose. Thus the present study reveals the anti-cataleptic activity of Tabernaemontana divaricata evaluating the traditional folklore medicinal use of the plant.

Effect of various extracts of Tabernaemontana divaricata on haloperidol induced catalepsy in rats.

Parkinson’s disease (PD) is one of the neurodegenerative diseases with selective loss of dopamine neurons of the substantia nigra pars compacta. In the present study, anti-cataleptic activity of Tabernaemontana divaricata leaves extracts viz. aqueous and ethanolic at different doses (50, 100 and 150 mg/kg i.p.) were studied using haloperidol (1 mg/kg, i.p.) induced catalepsy in rats which is a useful animal model for screening drugs for Parkinson’s disease. Both the extracts were found to reduce catalepsy significantly (P<0.001) as compared to the haloperidol treated rats showing greater effect at 150 mg/kg i.p. dose. Thus the present study reveals the anti-cataleptic activity of Tabernaemontana divaricata evaluating the traditional folklore medicinal use of the plant.

Antidepressant Activity of Methanolic Extract of Foeniculum Vulgare (Fennel) Fruits in Experimental Animal Models.

The present study was undertaken to investigate the effects of methanolic extract of Foeniculum vulgare fruits (family: umbelifereae), popularly known as fennel, on depression using force swim test in rats, potentiation of norepinephrine toxicity in mice and haloperidol induce catalepsy in mice. The extract of F.vulgare (250 and 500 mg/kg) was administered orally to rats used in FST and 500mg/kg was administered in HIC and same dose administered in NE toxicity in mice. The dose of 250mg/kg and 500mg/kg of extract significantly (p<0.001) reduced the immobility times in rats but dose of 500 mg/kg showed more potent effect than imipramine (30mg/kg). So this dose was used in HIC and NE toxicity in mice. But in NE toxicity model it was observed that MEFV is not good adrenergic component. A significant (P<0.001) reduction in the duration of catalepsy was observed in the MEFV treated group and Fluoxetine group as compared to the haloperidol treated group. In HIC, mice were sacrificed on the seventh day and TBARS, glutathione, nitrite activities were estimated. Monoamine oxidase inhibiting effect and anti-oxidant effect of Foeniculum vulgare may be contributing favorably to the antidepressant-like activity. Thus, it is concluded that Foeniculum vulgare extract may possess an antidepressant-like effect.

Influência da prática de exercícios físicos sobre a flexibilidade, força muscular manual e mobilidade funcional em idosos / Influence of physical exercise on the flexibility, hand muscle strength and functional mobility in the elderly

O processo de envelhecimento envolve alterações em todo o organismo humano, com declínio em quase todas as funções. A prática regular de exercício físico é uma estratégia atrativa e eficaz para retardar essas perdas. O objetivo deste estudo foi avaliar os resultados da prática de exercícios físicos, sobre a força muscular manual, flexibilidade e mobilidade funcional em idosos usuários de unidades de saúde da cidade de Uberaba-MG. Participaram 74 idosos (56 mulheres e 18 homens), pareados por sexo e idade, divididos em dois grupos com 37 indivíduos cada um. Foram avaliadas a força muscular manual, flexibilidade e mobilidade funcional. Os dados foram analisados utilizando o teste de Mann-Whitney (p<0,05). Houve diferença significativa entre os grupos com relação à flexibilidade. Evidencia-se a eficácia do exercício físico supervisionado nas unidades de saúde com relação à flexibilidade e indica-se a importância de modificar os treinos, implementando-se um protocolo mais definido com relação à força.

The aging process involves whole bodily changes and decline in almost all functions. The regular practice of physical exercise is an attractive and effective strategy for slowing the losses. This study aimed to evaluate the results of physical exercise on the hand muscle strength, flexibility and functional mobility in elderly users of basic healthcare units in Uberaba, State of Minas Gerais, Brazil. Seventy four elderly participated (56 women and 18 men), matched by sex and age, divided in two groups with 37 individuals each. Hand muscle strength, functional flexibility and mobility were evaluated. Data were analyzed using the Mann-Whitney test (p < 0.05). There were significant differences for the two groups concerning flexibility. This study highlights the effectiveness of supervised exercise in the basic healthcare units with respect to flexibility and indicates the importance of modifying training, implementing a more defined protocol with respect to strength.

Beneficial Effect of Vitamin E in Rotenone Induced Model of PD: Behavioural, Neurochemical and Biochemical Study

Parkinson's disease (PD) a neurodegenerative disorder for which no preventive or long-term effective treatment strategies are available. Epidemiologic studies have failed to identify specific environmental, dietary or lifestyle risk factors for PD. However, oxidative stress in the SN is the most broadly accepted hypothesis for the etiopathology of PD. The Symptoms do not appear until there is a decline of striatal dopamine levels by 80% making it difficult to have early therapeutic interventions. Thus, the present experiment was designed to track down the sequential changes starting from the initiation of motor dysfunction and associated biochemical abnormality in rotenone based PD model. The study also evaluated the neuroprotective efficacy of vitamin E. Rats were treated with rotenone 2 mg/kg b.wt (s.c.) for 35 days. The level of dopamine decreased by 70~80% which was in turn reflected by marked deterioration in motor function such as (Total locomotor activity and catalepsy). Along with these the level of GSH and SOD declined significantly which was associated with elevated lipid peroxidation levels as much as by 60%.Vitamin E co-administration at a dose of 100 I.U/kg b.wt (i.m.) ameliorated rotenone induced changes in motor functions i.e Total locomotor activity and Catalepsy at the end of 5th week. Further, vitamin E supplementation significantly decreased lipid peroxidation and improved associated biochemical parameters i.e SOD and GSH level. Most interestingly the changes appeared as early as 3rd week suggesting that supplementation of vitamin E right at the beginning should be neuroprotective in PD.

Study of interaction of nifedipine with haloperidol on conditioned avoidance response and catalepsy in rats.

Background: To study the interaction of calcium channel blocker (Nifedipine) with Antipsychotic drug (Haloperidol) on Conditioned avoidance Response and catalepsy in Rats. Methods: Every group consisted of 10 healthy albino rats of either sex. Different groups received Nifedipine (5, 10 & 20 mg/kg, i.p.), Haloperidol (ED50 -0.2mg/kg for CAR & 0.4mg/kg for catalepsy) alone and combined doses of both drugs. The Antipsychotic effect of drugs was measured by Conditioned avoidance response (CAR) using Cook’s Pole climbing apparatus and Adverse drug effect (Extra pyramidal syndrome) was measured by Catalepsy. Results: 5 mg/kg i.p. of Nifedipine inhibited CAR in 50 % of Rats (compared to control, p<0.001). 10mg/kg i.p. of Nifedipine inhibited CAR in 60% of Rats (p<0.001) & 20 mg/kg i.p. inhibited CAR in 70% of Rats (p<0.001). When Nifedipine (5 mg/kg i.p) was combined with Haloperidol ED50-0.2mg/kg the CAR was inhibited in 70% of the rats (p<0.01) and after combining Nifedipine (10mg/kg) with Haloperidol ED50-0.2mg/kg the CAR was inhibited in 80% Rats (p<0.001). Nifedipine at the dose of 5 mg/kg and 10 mg/kg (i.p.) did not induce catalepsy in the rats at any testing time interval. At 20 mg/kg i.p., it produced catalepsy in 2 rats at half hour and in 4 rats at 1 hour and 2 hour testing interval each (p<0.01). In the dose of 5, 10 and 20 mg/kg, pretreatment with Nifedipine significantly increased Haloperidol induced cataleptic scores at all testing intervals (p<0.05). Conclusions: Nifedipine blocked CAR. Its higher doses induced catalepsy and it is synergistic with haloperidol in blockade of CAR and catalepsy.

Catalepsia fármaco-inducida en el ratón / Drug-induced catalepsy in mice

La catalepsia fármaco-inducida en roedores es un modelo experimental muy utilizado para evaluar extrapiramidalismo. No existe una estandarización de la técnica, y en ocasiones las metodologías utilizadas son complicadas en su ejecución y en la evaluación de los resultados. También se han señalado diversos factores que pudieran llevar a una pseudocatalepsia o respuesta falsa positiva. El objetivo de este trabajo fue desarrollar una técnica sencilla y fiable donde no se observara pseudocatalepsia y verificar la viabilidad de su aplicación. Se describe un procedimiento utilizando ratones en un dispositivo artesanal y se muestran los resultados obtenidos luego de modificar las variables posición del animal, tiempo para realizar la observación y número de observaciones en un mismo animal. Se empleó haloperidol como droga de referencia. Se concluyó que la técnica propuesta es de fácil aplicación y consistente en sus resultados, sin que se observara pseudocatalepsia en la muestra utilizada

Drug-induced catalepsy in rodents is an experimental model commonly used to study extrapyramidalism. The technique has not been standardized, and the methodologies used are difficult to conduct and do not always facilitate the evaluation of results. Reference has also been made to various factors which might lead to pseudocatalepsy or to a false positive response. The objective of this study was to develop a simple, reliable technique in which pseudocatalepsy would not be observed, and verify the viability of its application. A description is presented of a procedure using mice in a handmade device and the results obtained after modifying the variables posture of the animal, time to make the observation, and number of observations for a given animal. Haloperidol was used as reference drug. It was concluded that the technique proposed is of easy application and yields consistent results, without any evidence of pseudocatalepsy in the sample used

Antônio Gonçalves Gomide: uma semiologia das doenças nervosas no Brasil / Antônio Gonçalves Gomide: a semiotics of nervous illnesses in Brazil

Analisa o parecer médico de Antônio Gonçalves Gomide, publicado em 1814. Trata-se de análise crítica realizada pelo médico, a fim de compreender as manifestações de uma beata, Germana Maria da Purificação, que viveu em Minas Gerais, entre os séculos XVIII e XIX. No texto o médico se contrapõe a um exame realizado por dois cirurgiões que declararam o estado da beata como sobrenatural. A intenção é analisar o parecer situando a concepção da patologia da beata para destacar a importância do documento na compreensão da constituição dos saberes médicos no Brasil. Procura-se ressaltar o fato de o texto ter sido um dos primeiros publicados sobre a medicina mental, podendo ser considerado um dos escritos fundadores dessa medicina que se inaugurava no Brasil no século XIX.

Catalepsia induzida pelo lactato e atividade muscular forçada em ratos privados de sono / Catalepsy induced by lactate administration and forced muscular activity in rats

O estudo comparativo das homologias comportamentais é útil para a compreensão de diferentes aspectos dos transtornos psiquiátricos. Nesta perspectiva, o presente estudo avaliou os efeitos da privação de sono REM sobre a catalepsia. Ratos privados de sono REM por 4 dias foram submetidos à administração i.p. de lactato 10mM/Kg e exercício muscular forçado, sendo, então a catalepsia avaliada. O grupo de animais privados de sono mostrou menor incidência (50 por cento) de animais com catalepsia e média do tempo total de catalepsia menor (11,92 ± 4,12 minutos) em relação aos controles (91,7 por cento e 26,67 ± 5,86 min respectivamente), com significâncias estatísticas no limite (p=0,05). Conclui-se que, em uma situação de perigo prolongado, a catalepsia é disparada em uma segunda instância, após o esgotamento do repertório de enfrentamentos normais da vigília, e que o sono só é compensado após o término da situação de risco

Comparative studies of behavioral homologies help understand several aspects of psychiatric disorders. The present study evaluated the effect of REM-sleep deprivation on the catalepsy induced by lactate administration plus forced muscular activity. Rats deprived of REM-sleep for 96 hs were injected i.p. with lactate solution 10mM/kg and submitted to 5 minutes of forced muscular activity. Catalepsy was then evaluated. The number of animals displaying catalepsy (50%) and mean total catalepsy time (11,92 ± 4,12 minutes) were lower in sleep deprived animals than in controls (91.7% and 26.67 ± 5.86 min respectively), results being statistically significant at the limit level (p=0,05). It is concluded that in long lasting dangerous situations, catalepsy may be triggered after normal wakefulness coping possibilities are exhausted, and sleep being manifested only when the risk situation is over.

Effects of daily chlorpromazine administration on behavioural and physiological parameters in the rat.

Chlorpromazine is a classical neuroleptic drug which produces both therapeutic effects as well as unwanted side effects in human such as sedation, autonomic, endocrine and neurological effects. It is thought that blockade of dopamine D-2 receptors caused by chlorpromazine induces these untoward side effects. Pre-clinical studies on catalepsy has been proposed as an animal model for neuroleptic induced extrapyramidal side effects. The drug also blocks certain stereotypic behaviours in animals induced by dopamine agonists such as apomorphine and amphetamine. These stereotypic behaviours are circling, chewing, rearing, grooming and hyperactivity. Daily administration of chlorpromazine (1, 3 and 10 mg/kg, i.p) to rats for 21 days induced catalepsy, tolerance to catalepsy and locomotor sensitization following PCP (10 mg/kg, i.p) challenge. These results suggest that daily chlorpromazine treatment induced DA/ NMDA-receptor sensitization to total locomotor activity following PCP challenge. Furthermore, there were no changes in other behavioural parameters assessed. Surprisingly daily chlorpromazine administration in rats also produced no changes in other physiological parameters assessed (body weight, food and water intake).

YKP1447, A Novel Potential Atypical Antipsychotic Agent

(S)-Carbamic acid 2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-1-phenyl-ethyl ester hydrochloride (YKP1447) is a novel "atypical" antipsychotic drug which selectively binds to serotonin (5-HT2A, Ki=0.61 nM, 5-HT2C, Ki=20.7 nM) and dopamine (D2, Ki=45.9 nM, D3, Ki=42.1 nM) receptors with over 10~100-fold selectivity over the various receptors which exist in the brain. In the behavioral studies using mice, YKP1447 antagonized the apomorphine-induced cage climbing (ED50=0.93 mg/kg) and DOI-induced head twitch (ED50=0.18 mg/kg) behavior. In the dextroamphetamine-induced hyperactivity and conditioned avoidance response (CAR) paradigm in rats, YKP1447 inhibited the hyperactivity induced by amphetamine (ED50=0.54 mg/kg) and the avoidance response (ED50=0.48 mg/kg); however, unlike other antipsychotic drugs, catalepsy was observed only at much higher dose (ED50=68.6 mg/kg). Based on the CAR and catalepsy results, the therapeutic index (TI) value for YKP1447 is over 100 (i.p.). These results indicate that YKP1447 has an atypical profile and less undesirable side effects than currently available drugs.