RESUMO
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.
Assuntos
Animais , Ansiolíticos/administração & dosagem , Buspirona/administração & dosagem , Catalepsia/induzido quimicamente , Relação Dose-Resposta a Droga , Haloperidol/administração & dosagem , Masculino , Camundongos , Receptores de Dopamina D2/antagonistas & inibidores , Agonistas do Receptor de Serotonina/administração & dosagem , Comportamento Estereotipado/efeitos dos fármacos , Triptofano/administração & dosagemRESUMO
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.
Assuntos
Animais , Apomorfina/farmacologia , Buspirona/farmacologia , Catalepsia/induzido quimicamente , Dextroanfetamina/farmacologia , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Haloperidol/farmacologia , Masculino , Ratos , Ratos Wistar , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D2/antagonistas & inibidores , Comportamento Estereotipado/efeitos dos fármacosRESUMO
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.
Assuntos
Animais , Antitussígenos/farmacologia , Apomorfina/farmacologia , Comportamento Animal/efeitos dos fármacos , Catalepsia/induzido quimicamente , Dextroanfetamina/farmacologia , Dextrometorfano/farmacologia , Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacocinética , Inibidores da Captação de Dopamina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Haloperidol/toxicidade , Masculino , Ratos , Ratos Wistar , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Comportamento Estereotipado/efeitos dos fármacosRESUMO
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.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/toxicidade , Animais , Antitussígenos/toxicidade , Comportamento Animal/efeitos dos fármacos , Buspirona/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Dexfenfluramina/toxicidade , Dextrometorfano/toxicidade , Fluoxetina/farmacologia , Masculino , Propranolol/farmacologia , Ratos , Ratos Wistar , Serotonina/fisiologia , Agonistas do Receptor de Serotonina/toxicidade , SíndromeRESUMO
5-hydroxytryptamine (5-HT) inhibits the synthesis and release of dopamine (DA) from rat nigrostriatal DAergic neurons. Dexfenfluramine releases 5-HT from brain 5-HTergic neurons. The present study was undertaken to determine whether dexfenfluramine, through the released 5-HT, modulates the intensity of the behaviours dependent on the functional status of the nigrostriatal DAergic system. The effect of pretreatment with dexfenfluramine on dexamphetamine and apomorphine stereotypies of the oral movement variety and on catalepsy induced by haloperidol and small doses (0.05 and 0.1 mg/kg ip) of apomorphine was studied in rats. We also investigated whether dexfenfluramine induces catalepsy in rats. Dexfenfluramine at 2.5, 5 and 10 mg/kg ip did not induce catalepsy and did not antagonise apomorphine stereotypy. However, 1 h pretreatment with 5-HT releasing doses of dexfenfluramine ie 5 and 10 mg/kg ip, antagonized dexamphetamine stereotypy and potentiated catalepsy induced by haloperidol and small doses of apomorphine. Our results, that dexfenfluramine at 2.5, 5 and 10 mg/kg ip neither induced catalepsy nor antagonised apomorphine stereotypy, indicate that dexfenfluramine at these doses does not block the postsynaptic striatal D2 and D1 DA receptors. They also indicate that the 5-HT released by 5 and 10 mg/kg dexfenfluramine does not exert an inhibitory effect at or beyond the postsynaptic striatal D2 and D1 DA receptor sites. However, 5 and 10 mg/kg doses of dexfenfluramine, through the released 5-HT, inhibit the synthesis and release of DA from the nigrostriatal DAergic neurons and thus antagonise dexamphetamine stereotypy and potentiate catalepsy induced by haloperidol and small doses of apomorphine.
Assuntos
Animais , Dexfenfluramina/farmacologia , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Haloperidol/farmacologia , Masculino , Ratos , Ratos Wistar , Comportamento Estereotipado/efeitos dos fármacosRESUMO
Amantadine, a dopamine agonist is reported to act by releasing dopamine from the dopaminergic nerve terminals as an anti-Parkinsonian drug. In the present behavioural study in the rat, molindone-induced catalepsy and ptosis, which are dopamine dependent-behaviors are reversed by amantadine. Amantadine has also revered molindone-induced inhibition of traction response in mice. Our study indicates that amantadine, like other DA agonists, e.g. amphetamine and apomorphine can antagonize or even reverse the neuroleptic induced dopaminergic behaviors.
Assuntos
Amantadina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Blefaroptose/etiologia , Catalepsia/induzido quimicamente , Modelos Animais de Doenças , Dopamina/metabolismo , Dopaminérgicos/farmacologia , Interações Medicamentosas , Masculino , Camundongos , Camundongos Endogâmicos , Molindona , Probabilidade , Ratos , Ratos Endogâmicos , Valores de Referência , Especificidade da EspécieRESUMO
1. Radio-ligand binding study has demonstrated that flunarizine has a high affinity for the rat striatal D 2 dopamine (DA) receptors. 2. In the present behavioural study conducted in rats it was observed that flunarizine, unlike the postsynaptic striatal D 2 DA receptor agonist apomorphine, did not induce stereotyped behaviour (SB) in rats. This indicates that flunarizine does not act as an agonist at the postsynaptic striatal D 2 DA receptors. 3. Flunarizine however, like the postsynaptic striatal D 2 DA receptor antagonist haloperiodal, inhibited the conditioned avoidance response, induced catalepsy and antagonized the SB induced by the DA agonists apomorphine and methamphetamine. 4. Our findings indicate that flunarizine acts as a postsynaptic striatal D 2 DA receptor antagonist.
Assuntos
Animais , Apomorfina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Catalepsia/induzido quimicamente , Corpo Estriado/efeitos dos fármacos , Dopamina/farmacologia , Quimioterapia Combinada , Flunarizina/farmacologia , Injeções Intraperitoneais , Masculino , Metanfetamina/farmacologia , Ratos , Receptores de Dopamina D2/antagonistas & inibidores , Comportamento Estereotipado/efeitos dos fármacosRESUMO
Metoclopramide (5 to 40 mg/kg, i.p.) induces catalepsy and antagonised apomorphine induced cage climbing behaviour in mice. This further indicate its postsynaptic striatal and mesolimbic D 2 dopamine (DA) receptor blocking activity. Metoclopramide at 1.25 and 2.5 mg/kg, i.p. induced stereotyped cage climbing behaviour in mice. Pretreatment with haloperidol and alpha-methyl-p-tyrosine significantly antagonised metoclopramide (1.25 and 2.5 mg/kg)-induced stereotyped cage climbing behaviour. Metoclopramide at these doses induces stereotyped cage climbing behaviour by releasing DA from the mesolimbic dopaminergic neurons with resultant activation of the postsynaptic mesolimbic D 2 DA receptors by the released DA. DA releasing action of metoclopramide (1.25 and 2.5 mg/kg, i.p.) and the subsequent induction of the stereotyped cage climbing behaviour by these doses of metoclopramide is explained on the basis of selective blockade of the presynaptic D 2 DA autoreceptors by these doses of metoclopramide.
Assuntos
Animais , Antieméticos/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Masculino , Metoclopramida/farmacologia , CamundongosRESUMO
Pentazocine, a kappa opioid receptor agonist, induced catalepsy in mice suggesting thereby that it might possess postsynaptic striatal D 2 dopamine (DA) receptor blocking activity. However, our other findings, that pentazocine pretreatment did not antagonise the cage climbing behaviour induced by the directly acting DA agonist apomorphine in mice and actually potentiated the stereotyped behaviour induced by the indirectly acting DA agonist methamphetamine in mice, indicate that pentazocine does not possess postsynaptic striatal and mesolimbic D 2 DA receptor blocking activity. Pretreatment with naloxone, an antagonist of opioid receptors, antagonised pentazocine-induced catalepsy. This suggests the possible involvement of opioid mechanisms in the induction of catalepsy by pentazocine in mice.
Assuntos
Animais , Antagonistas de Dopamina/farmacologia , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Pentazocina/farmacologia , Receptores Opioides kappa/antagonistas & inibidores , Comportamento Estereotipado/efeitos dos fármacosRESUMO
Racemate pentazocine was found to induce stereotyped behaviour (SB) in rats. Pretreatment with haloperidol and alpha-methyl-p-tyrosine significantly antagonised dl-pentazocine induced SB. This indicates that dl-pentazocine induces SB by releasing dopamine (DA) from the nigrostriatal and mesolimbic dopaminergic neurones with resultant activation of the postsynaptic striatal and mesolimbic D2 DA receptors by the released DA. However, pretreatment with naloxone failed to significantly modify dl-pentazocine induced SB indicating thereby that opioid mechanisms are not involved in the DA releasing action of dl-pentazocine. Our findings are explained on the basis of recent reports that the d-isomer of pentazocine releases DA by stimulating sigma receptors located on the nigrostriatal and mesolimbic dopaminergic neurones.
Assuntos
Analgésicos Opioides/farmacologia , Animais , Dopamina/fisiologia , Masculino , Metiltirosinas/farmacologia , Naloxona/farmacologia , Pentazocina/farmacologia , Ratos , Estereoisomerismo , Comportamento Estereotipado/efeitos dos fármacos , alfa-MetiltirosinaRESUMO
In the present study we have investigated the effect of yohimbine on dopamine-dependent behaviours in rats and mice. Yohimbine (1.25 to 10 mg/kg, ip) failed to block the conditioned avoidance response in rats, to inhibit the traction response in mice and to induce catalepsy in rats and mice. Pretreatment with yohimbine (1.25 to 10 mg/kg, ip) had no significant effect on apomorphine stereotypy in rats and apomorphine induced cage climbing behaviour in mice. However, pretreatment with yohimbine (1.25 to 10 mg/kg. ip) significantly increased the intensity of methamphetamine stereotypy and antagonised haloperidol catalepsy in rats. Our findings indicate that yohimbine does not possess postsynaptic striatal and mesolimbic D-2 dopamine receptor blocking activity.
Assuntos
Animais , Apomorfina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Catalepsia/induzido quimicamente , Dopamina/fisiologia , Haloperidol/farmacologia , Masculino , Metanfetamina/farmacologia , Camundongos , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Comportamento Estereotipado/efeitos dos fármacos , Ioimbina/farmacologiaAssuntos
Animais , Antidepressivos/farmacologia , Bupropiona , Catalepsia/prevenção & controle , Feminino , Haloperidol , Masculino , Morfina , Propiofenonas/farmacologia , RatosRESUMO
Bromocriptine (5-30 mg/kg, ip), 2 hr after administration, induced cage climbing behaviour in mice. Pretreatment with haloperidol, an antagonist of both D-1 and D-2 dopamine receptors, metoclopramide and molindone, the selective D-2 dopamine receptor antagonists, effectively antagonised bromocriptine-induced climbing behaviour. The results indicate that bromocriptine most probably induces climbing behaviour in mice by stimulating the postsynaptic striatal D-2 dopamine receptors.
Assuntos
Animais , Comportamento Animal/efeitos dos fármacos , Bromocriptina/antagonistas & inibidores , Relação Dose-Resposta a Droga , Haloperidol/farmacologia , Masculino , Metoclopramida/farmacologia , Camundongos , Molindona/farmacologia , Atividade Motora/efeitos dos fármacos , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores de Dopamina D2RESUMO
Pretreatment with fenfluramine (5 and 10 mg/kg, ip) in doses which induced head twitches was found to antagonize apomorphine-induced cage climbing behaviour and methamphetamine stereotypy in mice. Since fenfluramine (5 and 10 mg/kg) did not induce catalepsy it indicates that fenfluramine lacks postsynaptic striatal and mesolimbic dopamine receptor blocking activity and it is possible that the fenfluramine-induced enhancement of central 5-hydroxytryptamine neuronal transmission may be responsible for its antagonistic effect on apomorphine-induced climbing behaviour and methamphetamine stereotypy.
Assuntos
Animais , Apomorfina/antagonistas & inibidores , Catalepsia/induzido quimicamente , Fenfluramina/farmacologia , Humanos , Masculino , Metanfetamina/antagonistas & inibidores , Camundongos , Comportamento Estereotipado/efeitos dos fármacosRESUMO
Pretreatment with alpha-methyl-p-tyrosine, a tyrosine hydroxylase inhibitor, was found to increase the intensity of catalepsy induced by haloperidol, chlorpromazine and molindone. The drug probably decreases the synthesis of dopamine and makes less dopamine available for release and to compete with the neuroleptic for the postsynaptic striatal dopamine receptor sites with resultant potentiation of the neuroleptic-induced catalepsy.
Assuntos
Animais , Antipsicóticos/toxicidade , Catalepsia/induzido quimicamente , Clorpromazina/toxicidade , Dopamina/biossíntese , Sinergismo Farmacológico , Haloperidol/toxicidade , Humanos , Masculino , Metiltirosinas/toxicidade , Molindona/toxicidade , Ratos , alfa-MetiltirosinaRESUMO
Pretreatment with L-tryptophan, a precursor of 5-HT, was found to decrease the intensity of stereotyped behaviour induced by amantadine, while methysergide, a 5-HT antagonist, was found to increase the intensity of amantadine-induced stereotypy. These results suggest that the intensity of amantadine-induced stereotypy depends on the balance between central dopamine and 5-HT systems and that the central 5-HT systems may have an opposing, tonic effect upon central dopamine systems involved in the mediation of stereotypy. In contrast to L-tryptophan, however, pretreatment with quipazine, a 5-HT agonist, and clomipramine, a selective 5-HT neuronal reuptake blocker, was found to potentiate the stereotyped behaviour induced by amantadine.
Assuntos
Amantadina/farmacologia , Animais , Clomipramina/farmacologia , Humanos , Masculino , Metisergida/farmacologia , Quipazina/farmacologia , Ratos , Serotonina/fisiologia , Comportamento Estereotipado/efeitos dos fármacos , Triptofano/farmacologiaRESUMO
Maprotiline, a tetracyclic antidepressant drug, was evaluated for antidepressant and neuroleptic activity. In antidepressant tests, maprotiline antagonized reserpine-induced ptosis in rats but, unlike the tricyclic antidepressants, was found to antagonize methamphetamine stereotypy in rats, to decrease the intensity of L-dopa induced behavioural syndrome in pargyline-pretreated mice and to be ineffective in intensifying the 5-HTP induced behavioural syndrome. In neuroleptic tests, maprotiline was found to, antagonize apomorphine-induced cage climbing behaviour, induce catalepsy, inhibit the CAR and traction response, decrease the spontaneous motor activity and exploratory behaviour, and to potentiate the hypnotic effect of pentobarbitone. Our results indicate that maprotiline exhibits a profile of activity which resembles the neuroleptics and most probably exerts post-synaptic striatal DA receptor blocking activity.
Assuntos
Animais , Antracenos/farmacologia , Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Clomipramina/farmacologia , Desipramina/farmacologia , Imipramina/farmacologia , Masculino , Maprotilina/farmacologia , Metanfetamina/farmacologia , Camundongos , Ratos , Reserpina/farmacologiaRESUMO
Pretreatment with ethosuximide, a drug of choice for petit mal epilepsy, was found to inhibit the conditioned avoidance response in rats and the traction response in mice and to antagonise methamphetamine induced stereotyped behaviour in rats. Our results, which indicate the ethosuximide is capable of inhibiting the dopaminergically mediated behaviours, are in agreement with the recent reports stating that ethosuximide exerts central dopamine receptor blocking activity.