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.

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

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.

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.

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.

Dopaminergic profile of new heterocyclic N-phenylpiperazine derivatives

Dopamine constitutes about 80 percent 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

Gender-related differences in the effects of nitric oxide donors on neuroleptic-induced catalepsy in mice

It has been suggested that nigrostriatal dopaminergic transmission is modulated by nitric oxide (NO). Since there is evidence that gonadal hormones can affect extrapyramidal motor behavior in mammals, we investigated the effects of isosorbide dinitrate (ISD), linsidomine (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP), three pharmacologically different NO donors, on neuroleptic-induced catalepsy in 60- to 80-day-old male and female albino mice. Catalepsy was induced with haloperidol (1 mg/kg, ip) and measured at 30-min intervals by means of a bar test. Drugs (or appropriate vehicle) were injected ip 30 min before haloperidol, with each animal being used only once. ISD (5, 20 and 50 mg/kg) caused a dose-dependent inhibition of catalepsy in male mice (maximal effect 120 min after haloperidol: 64 percent inhibition). In the females only at the highest dose of ISD was an attenuation of catalepsy observed, which was mild and short lasting. SIN-1 (10 and 50 mg/kg) did not significantly affect catalepsy in female mice, while a significant attenuation was observed in males at the dose of 50 mg/kg (maximal inhibition: 60 percent). SNAP (20 mg/kg) significantly attenuated catalepsy in males 120 min after haloperidol (44 percent inhibition), but had no significant effect on females. These results basically agree with literature data showing that NO facilitates central dopaminergic transmission, although the mechanisms are not fully understood. They also reveal the existence of gender-related differences in this nitrergic modulation in mice, with females being less affected than males

Cataleptic postures in thalamic hemorrhage: case report

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

Evidence of interaction between fluoxetine and isosorbide dinitrate on neuroleptic-induced catalepsy in mice

Drugs which influence 5-HTergic mechanisms can modify neuroleptic-induced catalepsy (NC) in rodents, a phenomenon produced by striatal dopamine (DA) receptor blockade. Previous research also suggests a role for endogenous nitric oxide (NO) in the modulation of striatal DAergic neurotransmission; in addition, NO seems to play a role in the 5-HT reuptake mechanism. It is known that clomipramine potentiates NC in mice, but the reported effects of selective 5-HT reuptake inhibitors(SSRIs) in this model are rather contradictory. We then decided to re-address this issue, investigating the effect of fluoxetine (FX), an SSRI, on NC. In view of the ubiquitous role of NO as a central neuromodulator, we also studied the effect of isosorbide dinitrate (ID), a centrally active NO donor, and how both drugs interact to effect the phenomenon of NC. Catalepsy was induced in male albino mice with haloperidol (H; 1 mg/kg, ip) and measured at 30-min interval by means of a bar test. Drugs (FX, ID and FX + ID) or saline (controls) were injected ip 30 min before H, with each animal used only once. FX (5 mg/kg) significantly reduced NC, with maximal attenuation (about 74 percent) occurring at 150 min after H. ID (5 mg/kg) also inhibited NC (150 min: 62 percent attenuation). The combined drugs (FX + ID group), however caused a great potentiation of NC (4.7-fold at its maximum, at 90 min). The effect observed with ID is compatible with the hypothesis that NO increases DA release in the striatum. The attenuation of NC observed with FX may be due to a preferential net effect oon the raphe somatodendritic synapse, where inhibitory 5-HT(1A) autoreceptors are operative. The enhancement of NC caused by combined administration of FX and ID suggests the presence of a pharmacodynamic interaction, whose mechanism, still unclear, may be related to a decrease in striatal DA release.

Effects of losartan on neuroleptic-induced catalepsy in mice

Neuroleptic-induced catalepsy remains a useful method to study central dopaminergic function in rodents. Evidence obtained in several studies indicates that this phenomenon can be modified by cholinergic, histaminergic and serotonergic manipulation. Angiotensin II is a central neurotransmitter acting through AT1 and AT2 receptors. There are few data on the effect of angiotensinergic drugs on dopaminergic transmission. We investigated the effect of losartan, a nonpeptide antagonist of central and peripheral AT1 receptors, on neuroleptic-induced catalepsy. Adult male albino mice, 26-35 g, were used. Catalepsy was induced with haloperidol (H; l mg/kg, ip) and measured at 30-min intervals by means of a bar test. Losartan (10 or 100 ng/kg) or saline (control; 0.13 ml) was injected intraperitoneally 20 min before H, with each animal (7 per group) being used only once. Losartan (10 and 100 ng/kg) significantly (P<0.05) potentiated the cataleptic effect of H in comparison to the control group (e.g. 264 ñ 26 and 299 ñ 68 sec, respectively, vs 89 ñ 24 sec for the control group, 90 min after H). No differences were demonstrable 120, 150 or 180 min after H. Considering the high selectivity and the pharmacokinetic properties of losartan, these data suggest that central angiotensin AT1 receptors play a role in neuroleptic-induced catalepsy. However, further studies are necessary to confirm this hypothesis and to clarify the mechanism(s) involved in this process.

Effect of manipulation of the GABA system on dopamine-related behaviors

The interaction between GABAergic and dopaminergic system within the central nervous system was investigated in rats using the open-field apparatus and apomorphine-induced stereotypy, and in mice using haloperidol-induced catalepsy. The single intraperitoneal adminsitration of baclofen 3.0 mg/kg, 4,5,6,7-tetrahydroisoxasolo-(5,4-c) piridin-3-ol (THIP) 10.0 mg/kg and picrotoxin 2.0 mg/kg decreased both ambulation and rearing frequencies of the rats in the open-field; only the GABA agonists increased the duration of animal immobility. THIP (10.0 mg/kg) increased the duration of haloperidol-induced catalepsy. For apomorphine-induced stereotypy, baclofen 3.0 mg/kg and picrotoxin 1.0 mg/kg induced a significant leftward displacement of the control dose-response curve constructed for apomorphine (0.1-10 mg/kg) in relation to the control. In addition, baclofen, THIP, picrotoxin and 3-mercaptopropionic acid (3-MPA) 10.0 mg/kg decreased both rearing and sniffing behaviors elicited by apomorphine and increased licking and/ or gnawing. Different mechanisms seem to be involved in the similar effects induced by GABA agonists and antagonists. Picrotoxin induced stereotyped movements per se with a dose-dependent effect, but baclofen and THIP did not. The present data suggest that GABA manipulation facilitates the progressive activation of the different dopaminergic pathways involved in stereotyped behaviors, thus increasing those stereotyped components (gnawing and licking) that appear after a high level of activation of dopaminergic pathways

5-HT2 receptor blockade by ICI 170.809 does not affect the inhibitory effect of the 5-HT1a receptor ligand gepirone on neuroleptic induced catalepsy

Considerable experimental evidence suggests that central dopaminergic (DA) transmission is under serotonergic (5-HTergic) modulation. For instance, neuroleptic-induced catalepsy (NIC) in rodents, a behavior mainly due to blockade of DA receptors in the striatum, can be affected by 5-HTergic manipulation. It has been shown that ligands of 5-HT1A receptors (e.g. buspirone, gepirone) reduce NIC, while 5-HT2 receptor antagonists (e.g. ritanserin) do not affect this phenomenon. However, the role of 5-HT2 receptors in the modulation of NIC is still controversial and there is evidence from behavioral models other than NIC suggesting the existence of functional interaction between the two subtypes of 5-HT receptors. The present study was designed to evaluate the effect of ICI 170,809 (a selective 5-HT2 receptor antagonist) on NIC and to test the possible effect of this drug on the anticataleptic effect of gepirone (GP). Male Wistar rats weighing 300-350 g were used, and each animal (7 per group, 4 groups) was used only once. Catalepsy was induced with haloperiodol (H; 1 mg/kg, ip) and measured at 30-min intervals by means of a bar test. Animals received either ICI 170,809 (3 mg/kg, ip) or 0.9 percent saline(SL; 0.8 ml, ip) 30 min before H. At 110 min after H, the rats received GP (1 mg/kg, ip) or SL (0.8 ml, ip). GP significantly attenuated NIC (e.g. 739 + or - 106 s vs 1009 + or - 85 s for controls, at 150 min after H), while ICI 170,809 did not significantly affect the phenomenon (e.g. 978 + or - 89 s vs 1009 + or - s for controls, at 150 min after H). Pretreatment with ICI 170,809 did not significantly modify the anticataleptic effect of GP (e.g. 617 + or - 90 s vs 739 + or - 106 s for SL-pretreated animals, at 150 min after H). These results confirm reports of the anticataleptic effect of GP and the lack of effect of 5-HT2 receptor antagonists on NIC. Moreover, these data also suggest the absence of functional interactions between central 5-HT1A and 5-HT2 receptors in this model of DA transmission

Effects of the 5-HT receptor antagonists cyanopindolol, ICI 169,369, cisapride and granisetron on neuroleptic-induced catalepsy in mice

Typical neuroleptics (e.g. haloperidol) can induce catalepsy in rodents. Selective 5-hydroxytryptamine1A (5-HT1A) receptor antagonists reduce neuroleptic-induced catalepsy (NIC), suggesting that this subtype of serotonin receptor plays a role in the modulation of nigrostriatal dopaminergic transmission. The present study was designed to evaluate the participation of other 5-HT receptor subtypes in NIC. Adult albino mice (both sexes, 26-35 g) were used. Catalepsy was induced with haloperidol (H; 1.5 mg/kg, ip) and measured at 30-min intervals by means of a bar test. Cyanopindolol (a 5-HT1B receptor antagonist), ICI 169,369 (a 5-HT1C/2 receptor antagonist) and granisetron (a 5-HT3 receptor antagonist) were used. Buspirone, a 5-HT1A partial antagonist, cisapride, a 5-HT3/5-HT4 ligand and clomipramine, a 5-HT neuronal uptake blocker, were also employed. These drugs were injected ip, 20 min before H, with each animal (9-10 per group) used only once. Cyanopindolol (0.3 mg/kg) or ICI 169,369 (5 mg/kg) did not significantly affect NIC (375 +/- 39 and 378 +/- 34 s vs 372 +/- 44 s for controls, at 2 h after H). Buspirone (1 mg/kg) reduced, while pretreatments with either granisetron (0.5 mg/kg), cisapride (5 mg/kg) or clomipramine (5 mg/kg) potentiated the cataleptic effect of H (107 +/- 19, 576 +/- 52, 815 +/- 76 and 800 +/- 97 s vs 374 +/- 40 s in the control group, at 2 h after H).(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of median raphe nucleus lesions on neuroleptic-induced catalepsy and on the anticataleptic effect of buspirone

Catalepsy induced by neuroleptics in rats can be modified by 5-hydroxytryptaminergic (5-HTergic) manipulation. For example, buspirone (BUS) and other central 5-HT1A receptor ligands reduce neuroleptic-induced catalepsy (NIC). The dorsal (DRN) and median (MRN) raphe nuclei are reported to be important sources of 5-HTergic projections to the basal ganglia, the site of action of neuroleptics in producing NIC. A previous study showed that lesion of DRN did not affect NIC or the anticataleptic effect of BUS. The present study was designed to evaluate the participation of MRN in NIC and in the anti-NIC effect of BUS. Twenty-four male Wistar rats (N = 6/group) weighing 220-250 g were used. Electrolytic lesion of MRN was carried out in anesthetized rats along with sham operations (electrode inserted but no current applied). Ten days later, the rats were injected with BUS (5 mg/kg, ip) or saline (1 ml, ip). Catalepsy was induced 20 min later with haloperidol (H; 1 mg/kg, ip) and measured at 30-min intervals by means of a bar test. The Costall per cent Naylor method of scoring (range 0-5 points) was used. Saline-injected MRN-lesioned rats displayed significantly lower catalepsy scores than sham-lesioned rats (1.5 +/- 0.2 vs 3.8 +/- 0.3 at 90 min after H). In sham-lesioned rats, BUS significantly reduced the catalepsy scores in comparison with saline-treated animals (1.3 +/- 0.2 vs 3.8 +/- 0.3 at 90 min after H). However, BUS was not able to further reduce NIC in the MRN-lesioned animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of a single administration of buspirone on catalepsy, yawning and stereotypy in rats

In the present study, the effects of a single administration of buspirone (0.1, 0.3, 1.0, and 3.0 mg/kg sc-30 min before testing) on three dopamine-related behaviors were evaluated in 4-month old male Wistar rats (7-10 animals per group). Buspirone decreased haloperidol (2.0 mg/kg ip)-induced catalepsy in a dose-dependent manner (from 7.30 to 5.09 1n of s compared to the untreated control group). Apomorphine (0.06 mg/kg sc)-induced yawning was also dose-dependently reduced (from 26.7 to 0.9 yawns in 30 min) and so was apomorphine (1.0 mg/kg sc)-induced stereotypy (from 32.9 to 5.9, sum of scores). The present results indicate that buspirone presents unique pharmacological effects related to dopaminergic transmission not only in biochemical but also in behavioral terms

Effects of age and isolation on the evolution of catalepsy during chronic haloperidol treatment

Sixteen young (5 months) and 16 old (20-24 months) male Wistar rats, housed together or in individual cages were observed for cataleptic behavior 10, 20 and 30 days after the beginning of chronic haloperidol treatment (1.0 mg/kg, twice daily, for 30 days). Catalepsy was measured by the bar test. Age increased the duration of haloperidol-induced catalepsy of isolated and group-housed rats in the three observation sessions (old-isolated = 7.4 ñ 0.2; old-group housed = 7.5 ñ 0.1; young-isolated =6.3 ñ 0.2; young-group housed = 6.8 ñ 0.2 In seconds in session 1, for example). Conversely, isolation did not modify the sensitivity to the sensitivity to the cataleptic effect of haloperidol. Even more important, no differences in duration of haloperidol-induced catalepsy were observed among the three sessions for each group. The resultss indicate that under the experimental conditions employed the animals did not develop tolerance nor sensitization to haloperidol-induced catalepsy. In addition, neither age nor isolation modified the absence of effects of repeated haloperidol treatment on the catalepsy behavior of rats