Coumarin analogue 3-methyl-7H-furo[3,2-g]chromen-7-one as a possible antiparkinsonian agent / El análogo de cumarina 3-metil-7H-furo[3,2-g]cromen-7-ona, un posible agente antiparkinsoniano

Abstract Introduction: Parkinson's disease is the second most common neurodegenerative disease. Monoamine oxidase B inhibitors are used in the treatment of this disease concomitantly with levodopa or as monotherapy. Several substituted coumarins have shown activity as inhibitors of monoamine oxidase B. Objective: To evaluate the possible antiparkinsonian effects of the coumarin analogue FCS005 (3-methyl-7H-furo[3,2-g]chromen-7-one) in mouse models, as well as its inhibitory activity towards monoamine oxidases (MAO) and its antioxidant activity. Materials and methods: FCS005 was synthesized and the reversal of hypokinesia was evaluated in the reserpine and levodopa models. Moreover, in the haloperidol model, its anticataleptic effects were evaluated. Additionally, the monoamine oxidase inhibitory activity and antioxidant activity of FCS005 were evaluated using in vitro and ex vivo studies, respectively. Results: FCS005 (100 mg/kg) caused the reversal of hypokinesia in the reserpine and levodopa models. This furocoumarin also presented anti-cataleptic effects at the same dose. Besides, it showed selective inhibitory activity towards the MAO-B isoform and antioxidant activity. Conclusion: These results attribute interesting properties to the compound FCS005. It is important to continue research on this molecule considering that it could be a potential antiparkinsonian agent.

Resumen Introducción. El segundo trastorno neurodegenerativo más común es la enfermedad de Parkinson. Los inhibidores de la monoamino oxidasa B se emplean en el tratamiento de esta enfermedad en monoterapia o concomitantemente con levodopa. Varios compuestos cumarínicos han mostrado actividad como inhibidores de la monoamino oxidasa B. Objetivo. Evaluar los posibles efectos antiparkinsonianos del análogo de la cumarina FCS005 (3-methyl-7H-furo [3,2-g ] chromen-7-one) en modelos de ratones, la actividad inhibitoria frente a las monoamino oxidasas (MAO) y la actividad antioxidante. Materiales y métodos. Se sintetizó la furanocumarina FCS005 y, en los modelos de reserpina y levodopa, se evaluó si producía reversión de la hipocinesia; en el modelo de haloperidol se evaluaron sus efectos anticatalépticos. Además, se evaluó in vitro la actividad inhibidora de MAO y, ex vivo, la actividad antioxidante del compuesto FCS005. Resultados. El compuesto FCS005 en dosis de 100 mg/kg produjo la remisión de la hipocinesia en los modelos de reserpina y de levodopa. Esta furanocumarina presentó efectos anticatalépticos con la misma dosis. Además, mostró tener actividad inhibitoria selectiva sobre la MAO B, así como efectos antioxidantes. Conclusión. Los resultados evidenciaron propiedades interesantes del compuesto FCS005. Es importante continuar investigando esta molécula porque puede ser un potencial agente antiparkinsoniano.

Catatonia y delirium: síndromes que pueden confluir en el paciente neuropsiquiátrico / Catatonia and Delirium: Syndromes that may Converge in the Neuropsychiatrie Patient

Resumen Introducción: La catatonia y el delírium son 2 síndromes diferentes e independientes. La catatonia es un síndrome psicomotor asociado a una variedad de enfermedades de diferentes causas médicas y está caracterizado por ausencia de actividad, inducción de posturas pasivas contra gravedad, la oposición o ausencia de respuesta ante estímulos externos, flexibilidad cérea, estereotipias, manierismos y ecofenómenos, entre otros. El delirium se caracteriza por alteraciones de la conciencia y cognitivas, principalmente atención y orientación, habitualmente de aparición aguda, que tiende a fluctuar durante el día y con evidencia de que la alteración es una consecuencia fisiológica directa de una enfermedad, una intoxicación o la abstinencia de alguna sustancia. A pesar de las diferencias y que las clasificaciones excluyen la posibilidad de que estos síndromes puedan presentarse juntos, varios reportes de casos y estudios en grupos de pacientes han planteado que pueden darse las 2 condiciones conjuntamente. Material y métodos: En el presente estudio se detectó a 16 pacientes hospitalizados en quienes concomitaban ambos síndromes, identificados mediante la escala Delirium rating scale-R (DRS-98) y la escala de Bush y Francis de Catatonia (BFCRS). Resultados: Se siguió el desenlace durante la hospitalización y su condición clínica al egreso. Estos pacientes en su mayoría tenían diagnósticos neurológicos, tuvieron una hospitalización larga, requirieron tratamiento con antipsicóticos y benzodiacepinas y sufrieron frecuentes complicaciones. Conclusiones: Catatonia y delirium son síndromes que pueden presentarse al mismo tiempo, lo que lleva a que los pacientes tengan peor desenlace y mayor riesgo de complicaciones.

Abstract Introduction: Catatonia and delirium are two different and independent syndromes. Catatonia is a psychomotor syndrome associated with a variety of diseases of different medical causes and is characterised by lack of activity, induction of passive postures against gravity, opposition or absence of response to external stimuli, waxy flexibility, stereotypies, mannerisms and echophenomena. Delirium is characterised by consciousness and cognitive alterations, mainly attention and orientation and usually of acute onset, which tend to fluctuate during the day and with evidence that the alteration is a direct physiological consequence of a disease, intoxication or substance withdrawal. Despite the differences and the fact that the classifications exclude the possibility that these syndromes may manifest together, several case reports and studies in groups of patients have postulated that the two conditions can occur together. Material and methods: In this study we identified 16 hospitalised patients who experienced both syndromes at the same time as confirmed by the Delirium Rating Scale-Revised (DRS-98) and the Bush-Francis Catatonia Rating Scale (BFCRS). Results: Patient outcome was followed during hospitalisation and the patients' clinical condition upon discharge. These patients had mostly neurological diagnoses, long hospital stays, required treatment with antipsychotics and benzodiazepines and had frequent complications. Conclusions: Catatonia and delirium are syndromes that can present at the same time, resulting in worse patient outcome and an increased risk of complications.

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.

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

Role of 5-hydroxytryptamine 1a receptors in 6-hydroxydopamine-induced catalepsy-like immobilization in rats: a therapeutic approach for treating catalepsy of parkinson's disease

We have shown that buspirone, a partial agonist of 5-hydroxytryptamine 1A [5-HT[1A]] receptors, improves motor dysfunctions induced by 6-hydroxydopamine [6-OHDA] and haloperidol in rats. The present work extends these findings by investigating the role of 5-HT[1A] receptors on catalepsy-like immobilization in rats, a model of Parkinson's disease. Catalepsy was induced by unilateral infusion of 6-OH-dopamine [8 micro g/2 micro L/rat] into the central region of the substantia nigra, compact part [SNc] and assayed by bar-test method 5, 60, 120 and 180 min after the drugs administration. The involvement of 5-HT[1A] receptors in 6-OHDA-induced catalepsy was studied through intraperitoneal [0.25, 0.5 and 1mg/Kg IP] and intrasubstantia nigra, compact part [10 micro g/rat, intra-SNc] injection of 8-hydroxy-2-[di-n-propylamino] tetralin [8-OHDPAT] as well as administration of 1-[2-methoxyphenyl]-4-[4-[2-pthalimmido] butyl] piperazine hydrobromide [0.1, 0.5 and 1 mg/Kg, NAN-190, IP]. NAN-190 [1 mg/Kg, IP] and 8-OHDPAT [1 mg/Kg, IP and 10 micro g/rat, intra-SNc] increased and decreased 6-OHDA-induced catalepsy respectively. In normal [non 6-OHDA-lesioned] rats, NAN-190 [1 mg/Kg, IP] increased the elapsed time in bar-test while 8-OHDPAT did not produce any significant effect. The anticataleptic effect of 8-OHDPAT [1 mg/Kg, IP] was reversed markedly by co-injection with NAN-190 [1 mg/Kg, IP]. These findings suggest that 5-HT1A receptors are involved in 6-OHDA-induced catalepsy-like immobilization

Os êxtases da irmã germana: diferentes interpretações em torno das doenças nervosas no Brasil / The ecstasies of sister germana: different interpretations of nervous diseases in Brazil / Les extases de la sœur germana: les différentes interprétations des maladies nerveuses au Brésil / Los éxtasis de sor germana: diferentes interpretaciones acerca de las enfermedades nerviosas en Brasil

Apresenta diferentes concepções em torno dos êxtases de uma beata (Irmã Germana) que viveu em Minas Gerais no século XIX, o parecer do médico Antônio Gonçalves Gomide, seguido do exame de dois cirurgiões e da narrativa do naturalista Auguste de Saint-Hilaire. O objetivo é situar historicamente os textos, investigando as orientações teóricas dos autores e o modo como analisaram os êxtases da beata. A publicação dos documentos pode contribuir para o estudo dos saberes médico-mentais em inícios do século XIX no Brasil.

The article presents two different views of the ecstasies of a nun (Sister Germana) who lived in Minas Gerais, Brazil, in the nineteenth century. The first perspective was the opinion of Dr. Antônio Gonçalves Gomide, together with an examination by two surgeons; the second was a narrative by the naturalist Auguste de Saint-Hilaire. The goal is to historically situate the texts, investigate the theoretical orientations of the authors and note how they analyzed the woman's moments of ecstasy. The publication of these texts contributed to the study of medical and mental knowledge in the early 19th century in Brazil.

Cet article présente les différents aspects de l'extase d'une religieuse (la SŒur Germana) qui a vécu dans l'État de Minas Gerais au XIXe siècle, l'avis de son médecin Antonio Gonçalves Gomide, suivi de l'examen de deux chirurgiens et le récit du naturaliste Auguste de Saint-Hilaire. Notre travail est de situer historiquement les textes, d'enquêter sur les orientations théoriques des auteurs et sur la façon dont ils ont analysé l'extase de la sainte. Cet article a comme but de contribuer à l'étude des connaissances médicales et mentales au Brésil au début du XIXe siècle.

Se presentan diferentes concepciones acerca de los éxtasis de una beata (Sor Germana) que vivió en Minas Gerais en el siglo XIX, la opinión del médico Antônio Gonçalves Gomide, seguido por el examen de dos cirujanos y la narrativa del naturalista Auguste de Saint-Hilaire. El objetivo es situar históricamente los textos, investigando las orientaciones teóricas de los autores y el modo como analizaron los éxtasis de la beata. La publicación de los documentos puede contribuir para el estudio de los saberes médico-mentales en los inicios del siglo XIX en Brasil.

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.

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.

Dietary supplementations of amino acids: evidence for enhanced serotonergic functions following haloperidol withdrawal in rat medial prefrontal cortex

To investigate the effects of orally supplemented amino acids L-Tryptophan [Trp] and L-Valine [Val] in rats repeatedly injected with haloperidol following one week of drug withdrawal, with particular reference to extrapyramidal symptoms [EPS] and serotonin [5-hydroxytryptamine; 5-HT] metabolism in medial prefrontal cortex [mPFC]. Experimental study. Place and Duration of Study: Department of Biochemistry, University of Karachi from December 2007 to February 2008. The study was conducted on thirty six locally bred male Albino Wistar rats. Freshly prepared amino acids [Val and Trp] were added in the drinking water of rats on alternate days and haloperidol at doses of 5.0 mg/kg or saline were injected twice daily for three weeks following one week of withdrawal. Locomotor/ exploratory activities were scored in activity boxes and open field apparatuses. Catalepsy was monitored on an inclined surface. The animals tested for locomotor activity and catalepsy for two weeks follow-up post-injections plus one week of drug withdrawal were decapitated to collect mPFC regions of rat brain for neurochemical analysis by high performance liquid chromatography with electrochemical detection [HPLC-EC]. There was significant increase [p < 0.01] in locomotor activity in rats orally supplemented with Val and Trp following one week of drug withdrawal from repeated administration. Marked reduction in cataleptogenic effects of the drug was also observed. Significant [p < 0.01] increases in the brain Trp and mPFC 5-HT metabolism in Val and Trp supplemented animals were also noticed. These findings help to demonstrate the effect of dietary amino acids, in particular, Trp to potentiate mPFC serotonergic modulation of neuroleptic activity

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

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

Variación del tiempo de catalepsia inducida por haloperidol en ratones debido a la administración de c. paradisi / Time variation of catalepsy induced by haloperidol in mice due to administration of c. paradisi

El zumo de pomelo (ZP) (Citrus paradisi) contiene una serie de bioflavonoides (Naringenina, Bergamotina, Furanocumarinas) que afectan la biodisponibilidad de algunos fármacos por medio de la inhibición del sistema enzimático CYP3A (enterico y hepático) que reduce el metabolismo de los mismos aumentado sus niveles plasmáticos. Utilizamos al Itraconazol (IZ), inhibidor de los componentes del sistema CYP450 científicamente comprobado, para comparar dicha actividad. Para poner de manifiesto la inhibición del sistema de isoenzimas por estas sustancias; utilizamos al Haloperidol (Ha), neuroléptico metabolizado por el CYP450 hepático que induce catalepsia, cuadro motor de inmovilización completa; en el cual no hay parálisis, pero tampoco hay movimiento, y tanto el tronco como las extremidades adoptan las posturas que se les impongan. Materiales y métodos: 48 ratones de la raza swiss albinos machos, distribuidos en seis grupos: Administración aguda: Grupo 1: Ha (0,7 mg/kg) ip. con Suero Fisiológico vo; Grupo Nro 2: Ha (0,7 mg/kg) ip. con IZ (1mg/kg) vo, Grupo Nro 3: Ha (0,7 mg/kg) ip. Con ZP vo. Y administración crónica: Grupo Nro 1: Ha (0,7 mg/kg) ip. administración única en el día 7, y Suero Fisiológico vo, Grupo Nro 2: Ha (0,7 mg/kg) ip. Administración única en el día 7, e IZ (1mg/kg) vo., Grupo Nro 3: Ha (0,7 mg/kg) ip. administración única en el día 7, y ZP vo. durante 7 días consecutivos. Existen claras diferencias entre los promedios de los tiempos de catalepsia observados entre la administración aguda y crónica de IZ y ZP. Es probable que lo observado sea producto de que una única exposición al ZP e IZ no sean capaces de inhibir el CYP450 hepático, pero si el entérico. Conclusión: la presencia de flavonoides en el zumo de Citrus paradisi produce una prolongación del tiempo de catalepsia inducida por haloperidol en ratones albinos machos suizos por inhibición del sistema CYP 450 3A4 hepático e intestinal.

Effect of NR-ANX-C (a polyherbal formulation) on haloperidol induced catalepsy in albino mice.

BACKGROUND & OBJECTIVE: Use of typical antipsychotics like haloperidol in treatment of schizophrenia is associated with a high incidence of extrapyramidal side effects. In rodents, administration of haloperidol leads to the development of a behavioural state called catalepsy, in which the animal is not able to correct an externally imposed posture. In the present study we evaluated the anticataleptic efficacy of NR-ANX-C, a polyherbal formulation containing bioactives of Withania somnifera, Ocimum sanctum, Camellia sinensis, triphala and shilajit in haloperidol induced catalepsy in mice. METHODS: Five groups (n = 6) of male albino mice were used in the study. Catalepsy was induced by ip administration of haloperidol (1mg/kg). The degree of catalepsy (cataleptic score) was measured as the time the animal maintained an imposed posture. We compared the anticataleptic efficacy of NR-ANX-C (10, 25 and 50 mg/kg) with scopolamine (1 mg/kg). The superoxide dismutase (SOD) level in brain tissue was also estimated to correlate the levels of oxidative stress and degree of catalepsy in the animal. RESULTS: Significant (P<0.01) reduction in the cataleptic scores was observed in all NR-ANX-C treated groups and maximum reduction was observed in the NR-ANX-C (25 mg/kg) treated group. Significant (P<0.05) reduction in SOD activity was observed in NR-ANX-C (25 and 50 mg/kg) treated groups and maximum reduction was observed in NR-ANX-C (25mg/kg) treated group. INTERPRETATION & CONCLUSION: In our study, maximum reduction in cataleptic score was observed in NR-ANX-C (25 mg/kg) treated group. The maximum reduction in SOD activity was also observed in the same group. These findings suggest a possible involvement of the antioxidant potential of NRANX- C in alleviating haloperidol induced catalepsy.

Effects of buspirone on dopamine dependent behaviours in rats.

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

Effects of dextromethorphan on dopamine dependent behaviours in rats.

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

Effect of BR-16A (Mentat), a polyherbal formulation on drug-induced catalepsy in mice.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the selective loss of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). The events, which trigger and/or mediate the loss of nigral DA neurons, however, remain unclear. Neuroleptic-induced catalepsy has long been used as an animal model for screening drugs for Parkinsonism. Administration of haloperidol (1 mg/kg, ip) or reserpine (2 mg/kg, ip) significantly induced catalepsy in mice. BR-16A (50 and 100 mg/kg, po), a polyherbal formulation or ashwagandha (50 and 100 mg/kg, po), significantly reversed the haloperidol or reserpine-induced catalepsy. The results indicate that BR-16A or ashwagandha has protective effect against haloperidol or reserpine-induced catalepsy and provide hope that BR-16A could be used in preventing the drug-induced extrapyramidal side effects and may offer a new therapeutic approach to the treatment of Parkinson's disease.

Acute effects of selective serotonin reuptake inhibitors on neuroleptic-induced catalepsy in mice

Depression found in Parkinson disease (PD) usually responds to selective serotonin reuptake inhibitors (SSRIs). Drugs that modify experimental neuroleptic catalepsy (NC) might affect extrapyramidal symptoms in PD. Therefore, the effects of SSRIs on NC were tested in mice, 26-36 g, separated by sex. Catalepsy was induced with haloperidol (H; 1 mg/kg, ip) and measured at 30-min intervals using a bar test. An SSRI (sertraline, ST; paroxetine, PX; fluoxetine) or vehicle (C) was injected ip 30 min before H. Dunnett's test was used for comparison of means. ST (1-5 mg/kg) or PX (1-5 mg/kg) attenuated NC, with a similar inhibition found in both sexes (5 mg/kg, 180 min: ST - males: 124 ± 10 vs 714 ± 15 s in C; females: 116 ± 10 vs 718 ± 6 s in C; PX - males: 106 ± 10 vs 714 ± 14 s in C; females: 102 ± 10 vs 715 ± 14 s in C). At 0.3 mg/kg, neither of these drugs affected NC. Fluoxetine (1-25 mg/kg) also inhibited catalepsy, although the effect was not dose-dependent; no differences were observed between males and females (5 mg/kg, 180 min: males, 185 ± 14 vs 712 ± 14 s in C; females, 169 ± 10 vs 710 ± 19 s in C). For these SSRIs, maximal inhibition of NC was obtained with 5 mg/kg, 180 min after H. These results are consistent with the hypothesis that serotonergic mechanisms modulate nigrostriatal transmission, and suggest that SSRIs are possibly safe in depressive PD patients.

Ginkgo biloba leaf extract (EGb 761) enhances catalepsy induced by haloperidol and L-nitroarginine in mice

Ginkgo biloba extract EGb 761 has been reported to have therapeutic effects which have been attributed to anti-oxidant and free radical-scavenging activities, including a direct action on nitric oxide production. L G-nitro-arginine (L-NOARG), a nitric oxide synthase inhibitor, and haloperidol, a drug that blocks dopamine receptors, are both known to induce catalepsy in rodents. Nitric oxide has been shown to influence dopaminergic transmission in the striatum. The purpose of the present study was to evaluate the effect of the extract obtained from leaves of Ginkgo biloba tree EGb 761 on catalepsy induced by haloperidol or by L-NOARG. Albino Swiss mice (35-45 g, N = 8-12) received by gavage a single or repeated oral dose (twice a day for 4 days) of EGb 761 followed by ip injection of haloperidol or L-NOARG. After the treatments, the animals were submitted to behavioral evaluation using the catalepsy test. Acute treatment with 80 mg/kg EGb did not modify the catalepsy induced by L-NOARG but, the dose of 40 mg/kg significantly enhanced haloperidol-induced catalepsy measured at the 10th min of the test. After repeated treatment with 80 mg/kg EGb 761, a significant increase in the cataleptic effect produced by both haloperidol and L-NOARG was observed. These data show that repeated EGb 761 administration increases the effects of drugs that modify motor behavior in mice. Since the catalepsy test has predictive value regarding extrapyramidal effects, the possibility of pharmacological interactions between haloperidol and Ginkgo biloba extracts should be further investigated in clinical studies.

Effects of tryptophan and valine administration on behavioral pharmacology of haloperidol

Development of antipsychotics with slight/no extra-pyramidal symptoms [EPS] and/or other side effects is one of the exploring fields of drug research. Haloperidol is a high potency typical neuroleptic used in the treatment of schizophrenia but produces muscles related side effects commonly known as EPS. These effects are not produced following the administration of atypical neuroleptics such as clozapine. A severe side effect of clozapine treatment is however, agranulocytosis. This involves investigation on the mechanism by which a typical neuroleptic acting via serotonergic mechanism tends to produce less or no EPS. The present study was, therefore, designed to determine the effect of serotonin precursor tryptophan and a large neutral amino acid other than tryptophan [valine] on the modulation of haloperidol induced catalepsy and akinesia. Cataleptic effects of the drug and activity reducing effects were monitored on inclined surface and in an activity box or open field respectively. The results are discussed in the context of a role of tryptophan and valine induced changes of brain serotonin in modifying the extrapyramidal and monoaminergic effects of the typical neuroleptic haloperidol. In the present study administration of TRP and valine decreased activity in rats, haloperidol-induced catalepsy' was not modulated by prior administration of tryptophan or valine. Brain serotonin levels were elevated by haloperidol treatment and correlated very well with the behavioral response. These findings suggest a possible serotonergic involvement in neuroleptic induced tardive dyskinesia and an amelioration of the disorder through TRP supplementation

Modulation of Dopamine D2 Receptors as a Basis of Antipsychotic Action / 대한정신약물학회지

As comparing to typical antipsychotics, atypical antipsychotics have several characters such as no causing catalepsy in animal models or extrapyramidal side effects in schizophrenia patients, no or transient prolactin elevation (except risperidone, amisulpride), effects on negative symptoms, mood and affective symptoms, and efficacy in refractory schizophrenia. In views of the results of several studies so far achieved, the action at the dopamine D2/3 receptors, is by itself, sufficient to provide the contemporary kind of atypical antipsychotic activity. This review will attempt to address the modulation of dopamine D2 receptors as a basis of atypical antipsychotic action by looking over dopamine receptor occupancy, differential effects at the striatal versus extrastriatal dopamine D2 receptor, D2 receptor affinity and Koff consideration, effects for psychotic symptoms.