RESUMO
The effects of systemic administration of the non-competitive N-methyl-D-aspartate (NMDA) antagonists dextrorphan (10-40 mg/kg, i.p.) and [+/-]-5-aminocarbony-10,11-dihydro-5H-dibenzo[a,d]cycloheptan++ +-5,10-imine (ADCI) (25-70 mg/kg, i.p.) on basal ganglia-mediated behaviour and on forebrain dopamine metabolism were investigated in rats. Dextrorphan increased locomotor activity but did not induce stereotyped sniffing. ADCI failed to produce any significant motor stimulant and motor depressant actions. Both dextrorphan and ADCI dose-dependently antagonized catalepsy induced by the D-1 dopamine receptor antagonist SCH 23390 or the D-2 dopamine receptor antagonist haloperidol. Only the highest doses of dextrorphan and ADCI increased dopamine metabolism in the prefrontal cortex and/or in the nucleus accumbens, but not in the dorsal striatum. Our results show that dextrorphan and ADCI produce some of the behavioural effects (antagonism of experimentally induced catalepsy) and neurochemical actions (regionally selective stimulation of dopamine metabolism) that have previously been observed in the prototypical non-competitive NMDA antagonist, dizocilpine. The failure of ADCI to induce hyperlocomotion and stereotypy suggests that anticataleptic doses of ADCI may be devoid of the psychotomimetic actions commonly associated with non-competitive blockade of NMDA receptor function.
Assuntos
Comportamento Animal/efeitos dos fármacos , Dextrorfano/farmacologia , Maleato de Dizocilpina/análogos & derivados , Dopamina/metabolismo , Atividade Motora/efeitos dos fármacos , Prosencéfalo/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Benzazepinas/farmacologia , Maleato de Dizocilpina/farmacologia , Masculino , Prosencéfalo/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
The role of the entopeduncular nucleus (EP) and the subthalamic nucleus (STN) in mediating dopamine receptor antagonist-induced catalepsy in the rat was investigated. Five days after bilateral lesions of EP and STN respectively with the excitotoxin quinolinic acid (15, 30 nmol/0.5 microliter/side and 24 nmol/0.5 microliter/side, respectively) rats were injected intraperitoneally with the dopamine D1 receptor antagonist SCH 23390 (0.5 mg/kg) or the dopamine D2 receptor antagonist haloperidol (0.5 mg/kg). Complete EP lesions prevented both SCH 23390- and haloperidol-induced catalepsy. STN lesions exerted pronounced anticataleptic effects in case of haloperidol-induced catalepsy, but less pronounced in case of SCH 233390-induced catalepsy. Further characterization of these anticataleptic effects in an open field demonstrated, that neither EP- nor STN lesions reversed bradykinesia, which occurred after selective dopamine receptor blockade. In conclusion, both EP and STN participate in the mediation of catalepsy induced by dopamine D1- and dopamine D2 receptor antagonists. Thereby these nuclei preferentially mediate rigidity and akinesia, but to a lesser extent bradykinesia.
Assuntos
Antagonistas de Dopamina/farmacologia , Globo Pálido/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Receptores Dopaminérgicos/efeitos dos fármacos , Substância Negra/efeitos dos fármacos , Núcleos Talâmicos/efeitos dos fármacos , Animais , Benzazepinas/farmacologia , Mapeamento Encefálico , Corpo Estriado , Globo Pálido/fisiologia , Haloperidol/farmacologia , Masculino , Atividade Motora/fisiologia , Destreza Motora/efeitos dos fármacos , Destreza Motora/fisiologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores Dopaminérgicos/fisiologia , Substância Negra/fisiologia , Núcleos Talâmicos/fisiologiaRESUMO
The AMPA antagonists NBQX (2.5, 5, 10 mg/kg) and GYKI 52466 (4.8, 8 mg/kg) were investigated in haloperidol (0.5 mg/kg)-induced catalepsy in the rat. The effects of AMPA antagonists administered either alone or in combination with the noncompetitive NMDA antagonist dizocilpine (0.02 mg/kg), with the dopamine D-2 agonist quinpirole (1 mg/kg) or with L-DOPA (50, 100 mg/kg plus benserazide) were tested. NBQX or GYKI 52466 did not exert anticataleptic effects, neither alone nor in combination with dizocilpine, quinpirole or L-DOPA. Thus, in the rat inhibition of AMPA receptors with NBQX or GYKI 52466 does not have effects predictive for an antiparkinsonian potential.
Assuntos
Ansiolíticos , Antipsicóticos , Benzodiazepinas/farmacologia , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Quinoxalinas/farmacologia , Receptores de AMPA/antagonistas & inibidores , Animais , Maleato de Dizocilpina/farmacologia , Interações Medicamentosas , Ergolinas/farmacologia , Haloperidol , Levodopa/farmacologia , Masculino , Projetos Piloto , Quimpirol , Ratos , Ratos Sprague-DawleyRESUMO
The effects of competitive (CGP 37849 and CGP 39551) and non-competitive (dizocilpine) N-methyl-D-aspartate (NMDA) antagonists were tested in three animal models (catalepsy, sniffing, locomotion) and, in addition, the modulation of these effects by an agonist of the strychnine-insensitive glycine binding site was investigated. Both competitive and non-competitive NMDA antagonists reduced neuroleptic-induced catalepsy. Weak sniffing was induced by the competitive antagonist but strong sniffing by the non-competitive NMDA antagonist. Due to muscle relaxation the competitive antagonist reduced locomotion, in contrast to stimulation of locomotor activity induced by the non-competitive NMDA antagonist. The glycine agonist (D-cycloserine) potentiated the effects of the non-competitive but antagonized those of the competitive NMDA antagonist.
Assuntos
Comportamento Animal/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Sítios de Ligação/efeitos dos fármacos , Catalepsia/induzido quimicamente , Catalepsia/fisiopatologia , Ciclosserina/farmacologia , Maleato de Dizocilpina/farmacologia , Haloperidol/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/efeitos dos fármacosRESUMO
The anticataleptic effects of non-competitive and competitive NMDA antagonists as well as those of an agonist at the allosteric glycine binding site of the NMDA receptor were tested in the catalepsy model. Some of these drugs were further tested in a reaction time task demanding rapid locomotor initiation. The results show that the non-competitive NMDA antagonists dizocilpine and memantine as well as the competitive antagonists CGP 39551, CGP 37849 and CPPene antagonized dopamine D2 receptor mediated catalepsy induced by haloperidol. D-cycloserine, a partial glycine agonist per se had no effects, but it enhanced the anticataleptic effects of dizocilpine when coadministered. However, the effects of CGP 37849 were abolished. Dopamine D1 receptor mediated catalepsy induced by SCH 23390 was antagonized by dizocilpine, memantine, CPPene, but not by CGP 37849. In the reaction time task dizocilpine, memantine and CGP 37849 were tested for their anti-akinetic and anti-bradykinetic potencies. All these compounds improved haloperidolinduced slowing of reaction time. However, they acted differentially on haloperidol-induced slowing of movement execution and decreased initial acceleration. Thus, antagonists at the NMDA receptor may have a therapeutic potential in the treatment of Parkinson's disease. Their potency can be manipulated specifically at the glycine binding site.