RESUMO
RATIONALE: It has previously been demonstrated that the 5-HT(3) receptors located in the mesolimbic brain areas are able to modulate the dopaminergic effects of various abused drugs, including cocaine (COC). OBJECTIVES: The present experiments investigated the role of 5-HT(3) receptors in the actions of selected monoamine uptake inhibitors. METHODS: The ability of the 5-HT(3) receptor antagonist MDL 72222 (MDL; 0.1 and 1.0 mg/kg) to modify the neurochemical and behavioral changes induced by COC (20 mg/kg), mazindol (MAZ; 10 mg/kg), and methylphenidate (MP; 5.0 or 10, and 20 mg/kg) was assessed with an in vivo microdialysis technique, a conditioned place preference method, and motor activity measurements. RESULTS: MDL robustly attenuated the elevation of extracellular dopamine levels in the nucleus accumbens, acquisition of place preference, and motor activity induced by COC and MAZ, but not those induced by MP, the only drug with no significant effect on 5-HT. In contrast, expression of COC-induced place preference was not attenuated by MDL. CONCLUSIONS: These results show that COC- and MAZ-induced reward-related neurochemical and behavioral effects, preferentially those implicated in development of conditioned reward, are modified by the 5-HT(3) blockade. In contrast to COC and MAZ, the changes induced by MP, which has less effect on the serotonergic system, remain unchanged. Thus it appears that involvement of a serotonergic component in the mechanism of action of a drug could be a prerequisite for effective antagonism by 5-HT(3) receptor blockers.
Assuntos
Comportamento Animal/efeitos dos fármacos , Cocaína/farmacologia , Mazindol/farmacologia , Metilfenidato/farmacologia , Receptores de Serotonina/fisiologia , Antagonistas da Serotonina/farmacologia , Tropanos/farmacologia , Animais , Comportamento Animal/fisiologia , Cocaína/antagonistas & inibidores , Dopamina/biossíntese , Dopamina/metabolismo , Inibidores da Captação de Dopamina/antagonistas & inibidores , Inibidores da Captação de Dopamina/farmacologia , Injeções Subcutâneas , Masculino , Mazindol/antagonistas & inibidores , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ratos , Ratos Wistar , Receptores 5-HT3 de SerotoninaRESUMO
In male Wistar rats trained to eat their normal daily dietary requirement in a restricted 2 h period, dose-dependent decreases in food consumption were produced by fenfluramine, tiflorex, mazindol and amphetamine. The antidepressant drug viloxazine (Vivalan) alone did not alter food intake significantly, nor did the drug prevent the inhibitory effects of either mazindol or amphetamine. However, complete prevention of the inhibitory effect of fenfluramine was achieved with 7.5 mg kg-1 viloxazine, while 40 mg kg-1 viloxazine similarly prevented the anorectic action of tiflorex. An interaction involving 5-hydroxytryptaminergic mechanisms is suggested, and since viloxazine given after fenfluramine or tiflorex produced no reversal of the inhibition of food intake, it is suggested that viloxazine prevents access of the anorectic agents to their site of action. The clinical significance of these interactions is discussed.
Assuntos
Depressores do Apetite/antagonistas & inibidores , Comportamento Alimentar/efeitos dos fármacos , Morfolinas/farmacologia , Viloxazina/farmacologia , Anfetamina/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Fenfluramina/análogos & derivados , Fenfluramina/antagonistas & inibidores , Masculino , Mazindol/antagonistas & inibidores , RatosRESUMO
Iproniazid was found to reduce food consumption in fasting rats. Combined treatment of iproniazid with tryptophan resulted in a significantly greater anorexic action whilst tryptophan alone had no effect on food consumption. Iproniazid treatment was associated with a significant increase in brain 5-hydroxytryptamine (5-HT) concentration but in association with tryptophan higher brain 5-HT concentrations were recorded. The anorexic action of the iproniazid-tryptophan combination was antagonized in a dose-dependent fashion by methysergide. Equivalent levels of anorexia induced by fenfluramine and mazindol were similarly antagonized by methysergide in a dose-related manner. The results suggest a common role of 5-HT in the inhibition of eating behaviour in fasting rats when anorexia is induced by iproniazid, fenfluramine or mazindol, sensitive to a specific 5-HT antagonist.