Aspectos farmacológicos, efeitos anticonvulsivantes e neuroprotetores da buspirona / Pharmacological study of buspirone and its anticonvulsant and neuroprotective effects

A buspirona é o primeiro fármaco da classe das azapironas e a única comercializada no Brasil. O objetivo do presente trabalho foi conduzir uma revisão de literatura sobre os aspectos farmacológicos da buspirona, bem como demonstrar seus efeitos anticonvulsivantes e neuroprotetores no modelo de convulsão induzido por pilocarpina. Para tanto, foi realizada uma revisão da literatura usando as palavras-chaves buspirone, action mechanism, pharmacokinetics, indications, adverse effects, nomenclature e structure, por intermédio do MEDLINE e LILACS, bem como foram inseridos os resultados experimentais encontrados em camundongos pré-tratados com buspirona no modelo de convulsão induzido por pilocarpina. A busca incluiu todos os artigos completos, resumos, estudos de caso, pré-clínicos e clínicos nos idiomas português e inglês compreendidos entre os anos de 1982 e 2010. Com base na revisão, pode se perceber que ainda existem muitas questões sem respostas sobre a farmacologia da buspirona. Somente a descrição do mecanismo de ação é insuficiente para explicar todos os efeitos produzidos pela buspirona. Além disso, em nossos estudos farmacológicos demonstramos que a buspirona apresenta efeitos anticonvulsivantes e neuroprotetores em camundongos no modelo de convulsão induzido por pilocarpina. Existem poucas informações na literatura sobre o mecanismo de ação que explicaria os efeitos adversos da buspirona, bem como suas propriedades anticonvulsivantes e neuroprotetoras. Dessa forma, são necessários mais estudos para fornecer as informações necessárias, bem como para esclarecer as suas propriedades farmacológicas, contribuindo com o conhecimento dos profissionais, a fim de prevenir os efeitos adversos durante o tratamento clínico com a buspirona.

Buspirone was the first drug in the class of azapirones and is the only one marketed in Brazil. The objective of this study was to conduct a literature review on the pharmacology of buspirone, as well as to demonstrate its neuroprotective and anticonvulsant effects in the model of seizures induced by pilocarpine. To this end, we employed the keywords buspirone, action mechanism, pharmacokinetics, indications, adverse effects, nomenclature and structure to perform a search of the literature, through MEDLINE and LILACS, and inserted the experimental results obtained in mice pretreated with buspirone in the model of seizures induced by pilocarpine. The search included all full articles, abstracts, case studies, pre-clinical and clinical studies in Portuguese and English, between the years 1982 and 2010. The review revealed that there are still many unanswered questions about the pharmacology of buspirone. A description of the mechanism of action alone is insufficient to explain all the effects produced by buspirone. Moreover, our pharmacological studies have shown that buspirone has anticonvulsant and neuroprotective effects in a mouse model of seizures induced by pilocarpine. There is little information in the literature about mechanisms that would explain either the adverse effects of buspirone or its anticonvulsant and neuroprotective properties. Thus, further studies are needed to provide the necessary information, as well as to clarify its pharmacological properties, in order to enable professionals to prevent adverse effects during clinical treatment with buspirone.

[Study the effect of buspirone and trazodone on hematological damage induced by long-term exposure to noise in mice]

The study investigated the effect of stress induced by long-term exposure to noise on body immunity through total white blood cell and lymphatic cell count, and on neutrophil-to-lymphatic cell ratio as a physiological marker of noise-induced stress in rats. In addition, the effect of both buspirone and trazodone in alleviating this negative outcome induced by noise was also investigated on 32 rats aged 90-100 days at the beginning of the study period. Results of the study was consistent with previous theories that noise may be considered as a causative agent which influences body's immune system when it reduces both total white blood cell and lymphatic cell count. Results also showed that the ration of neutrophil-to-lymphatic cell was increased as a result of long-term exposure to noise. Furthermore, the study presented a new evidence of antagonizing and therapeutic effect of buspirone and trazodone to stress-induced physiological damage

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.

Involvement of central serotonergic systems in dextromethorphan-induced behavioural syndrome in rats.

Dextromethorphan, a noncompetitive blocker of the N-methyl-D-aspartate (NMDA) type of glutamate receptor, at 45, 60 and 75 mg/kg, ip doses induced a behavioural syndrome characterised by reciprocal forepaw treading, lateral head-weaving, hind-limb abduction and flat body posture. Such type of behavioural syndrome is induced by 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT) by directly stimulating the central postsynaptic 5-hydroxytryptamine (5-HT, serotonin) receptors of the 5-HT1A type. Pretreatment with buspirone (5, 10 mg/kg, ip) and l-propranolol (10, 20 mg/kg, ip) antagonised the behavioural syndrome induced by 8-OH-DPAT and dextromethorphan. Pretreatment with p-chlorophenylalanine (100 mg/kg/day x 4 days) antagonised the behavioural syndrome induced by dextromethorphan and dexfenfluramine but had no significant effect on 8-OH-DPAT induced behavioural syndrome. This indicates that dextromethorphan induces the behavioural syndrome by releasing 5-HT from serotonergic neurons with resultant activation of the postsynaptic 5-HT1A receptors by the released 5-HT. Pretreatment with fluoxetine (10 mg/kg, ip) significantly potentiated the behavioural syndrome induced by dextromethorphan and 5-hydroxytryptophan but significantly antagonised dexfenfluramine induced behavioural syndrome. This indicates that dextromethorphan releases 5-HT by a mechanism which differs from that of dexfenfluramine. Dextromethorphan may be releasing 5-HT by blocking the NMDA receptors and thereby counteracting the inhibitory influence of l-glutamate on 5-HT release.

Effects of injection of serotonin into nucleus caudatus on food and water intake and body weight in albino rats.

Serotonin is known to inhibit food and water intake. However, the effect of its injection into nucleus caudatus on food and water intake is not known. In the present study, serotonin hydrochloride, buspirone (the serotonin 5-HT1A agonist) and ondensetron (the 5HT3 antagonist) were injected into nucleus caudatus through stereotaxically implanted cannulae in three different dosages (1, 2 and 5 microg) and their effects on 24 h food and water intake, and body weight were recorded. The injection of serotonin hydrochloride resulted in a dose- dependent decrease in food intake attaining maximum of 27.3% at 5 microg dose, whereas water intake and body weight were decreased 12% and 4.3% respectively only at the highest does. Buspirone elicited a dose dependent inhibition of food and water intake and body weight (22.3%, 19.8% and 5.1% respectively), whereas ondensetron elicited an increase in food and water intake (37.8% and 36.3% respectively) without significantly altering bodyweight. It was concluded that serotonin hydrochloride injected into nucleus caudatus inhibits food and water intake significantly. These effects are mediated via 5-HT1A and 5HT3 receptors. The effect of injections of 5-HT1A receptor agonist is more pronounced on water intake. The effect of injections of 5HT3 receptor antagonist is also more pronounced on water intake.

A buspirona no tratamento da fobia social Parte II - Revisäo farmacológica e terapêutica da buspirona / The buspirone in the social phobie treatment Part 2 - Pharmacological and therapeutical review of the buspirone

Cinco pacientes com fobia social foram tratados com buspirona nas doses máximas toleradas por um período igual ou superior a seis semanas. Três pacientes fizeram uso de doses de 50-60 miligramas/dia durante um período superior a oito semanassem obterem qualquer vantagem perceptível. Um paciente, após oito semanas de tratamento e tendo atingido a dose de 40 mg/dia, experimentou "tonteiras" que a levaram a pedir a interrupçäo do uso da buspirona; tampouco neste caso foi registrado qualquer benefício terapêutico. A quinta paciente, após 6 semanas de tratamento, estando em uso de 30 mg/dia de buspirona, relatou melhora moderada da fobia social. Contudo, esta dose lhe causou sensaçÆes de "rotaçäo da cabeça", obrigando-nos a interromper o tratamento. embora seja necessário estudar os efeitos da administraçäo da buspirona em número maior de pacientes, os resultados preliminares sugerem que a buspirona é pouco efetiva na maior parte dos casos de fobia social

A buspirona no tratamento da fobia social Parte I - Revisäo farmacológica e terapêutica da buspirona / Buspirone in the treatment of the social fobhie Part I - Terapeutical and pharmacological review of the buspirone

Objetivo:A buspirona é um ansiolítico näo benzodiazepínico com perfil de efeitos colaterais benigno. Este trabalho pretende rever as propriedades farmacológicas da buspirona, seus efitos colaterais e suas indicaçöes clínicas no tratamento no tratamento dos trantornos depressivos e ansiosos, visando determinar em quis destes transtornos a buspirona representa uma alternativa terapêutica efetiva aos medicamentos atualmente empregados

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

Ansiedade e ansiolíticos na prática clínica / Anxiety and anxiolitics in clinical practice

O Distúrbio Generalizado de Ansiedade (DAG) constitui-se em um quadro clínico de grande freqüência, que acarreta sofrimento e pertubaçäo no desempenho do indivíduo. Este estado deve ser diferenciado da ansiedade normal e dos distúrbios ansiosos orgânicos. O autor faz uma análise crítica do emprego dos ansiolíticos no tratamento da DAG em termos de riscos e benefícios, enfatizando a necessidade de uma abordagem global do paciente, através de instrumentos terapêuticos múltiplos

Dorsal raphe nucleus lesions have no effect on neuroleptic-induced catalepsy and on the anticataleptic activity of buspirone

The anxiolytic drug buspirone (BUS) and other central 5-HT-1A receptor ligands are capable of reducing neuroleptic-induced catalepsy in rodents. The dorsal raphe nucleus (DRN) is reported to be an important source of serotonergic projections to the basal ganglia, the site of neuroleptic action. The present study was designed to evaluate the participation of the DRN in the anticataleptic effect of BUS on male Wistar rats. Rats were submitted to electrolytic or sham DRN lesion under barbiturate anesthesia. Ten days later, the animals were injected with BUS (5 mg/kg,ip) or saline ( 1 ml, ip) and catalepsy was induced 20 min later with haloperidol (1 mg/kg, ip). Saline-injected DRN-lesioned and sham-lesioned rats displayed similar catalepsy score and BUS significantly and similarly reduced the catalepsy scores in both groups. The results suggest that, in producing anticataleptic effects, BUS interacts at sites other than the DRN. The participation of other raphe nuclei in the anticataleptic effect of BUS is currently under investigation

Inhibition of chlorpromazine-induced catalepsy by the 5-HT-1A ligands pindolol and Buspirone in mice

Neuroleptcs such as chlorpromazine and haloperidol are capable of inducing catalepsy in rodents. Non-selective 5-hydroxytryptamine (5-HT) antagonists such as methysergide reduce the cataleptic effect of haloperidol. The present study was designed to evaluate the particpation of 5-HT-1A receptors in chlorpromazine-induced catalepsy in mice. Pundolol and buspirone, two putative 5-HT-1A receptor ligands, were used. Pretreatment with these drugs reduced the cataleptic effect of chlorpromazine. Clomipramine, a 5-HT neuronal uptake blocker, reversed the inhibitory effect of buspirone. Pretreatment with clomipramine alone caused a potentiation of neuroleptic-induced catalepsy. These results suggest that central 5-HT-1A receptors play an important role in neuroleptic-induced catalepsy in mice

Efeitos terapêuticos do cloridrato de buspirona na síndrome do climatério / Therapeutic effects of buspirone hydrochloride in climateric syndrome

Vinte pacientes com síndrome do climatério e manifestaçåo de ansiedade generalizada foram estudadas no intuito de avaliar a eficácia e segurança do Cloridrato de buspirona. As idades variaram entre 42 e 58 anos, com média de 50 anos. Foram tratadas durante 4 semanas e a dose inicial utilizada da droga foi de 5 mg três vezes ao dia. A dose média foi de 16,6 mg por dia ao final do estudo. Utilizaram-se as escalas de Hamilton e Covi para avaliar a ansiedade e a de raskin para a depressåo. Duas pacientes nåo completaram o estudo por terem apresentado efeitos colaterais. Concluiu-se que esta nova droga ansiolítica, o Cloridrato de buspirona, foi eficaz e bem tolerada, com indicaçåo especial naquelas pacientes que necessitam estar alerta para exercer suas atividades normais

A simple simulated public speaking test for evaluating anxiolytic drugs

We evaluated the feasibility of using a simulated public (SPS) test to assess the activity of anxiolytic drugs. SPS was achieved by requesting subjects to present a speech to an audiocassette recorder. Thirty volunteers were randomly assigned to one of three groups treated with 10 mg diazepam, 10 mg buspirone or placebo, under double-blind conditions. One h after drug adminsitration, subjective states were measured by the Visual Analogue Mood Scale (VAMS), the State-Trait Anxiety Inventory (STAI) and by a Bodily Symptoms Scale (BSS). Heart rate and blood pressure were also recorded. SPS induced both physiological and subjective changes characteristic of anxiety. Moreover, diazepam attenuated experimentally induced increases in excitement (as measured by VAMS) and agitation (as measured by BSS). Therefore, SPS using an audiocassette recorder is sensitive to a prototypical anxiolytic and may thus be a useful test for evaluating putative anxiolytics. No effect was observed with the new anxiolytic drug buspirone. However, the present negative result may be explained by clinical data indicating that patients may experience a longer lag period before the onset of the anxiolytic effect of buspirone