5-HT3 receptor antagonist MDL 72222 attenuates cocaine- and mazindol-, but not methylphenidate-induced neurochemical and behavioral effects in the rat.

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.