Antagonism of 5-hydroxytryptamine₄ receptors attenuates hyperactivity induced by cocaine: Putative role for 5-hydroxytryptamine₄ receptors in the nucleus accumbens shell

The localization of 5-hydroxytryptamine₄ (5-HT₄) receptors suggests their role in the regulation of dopamine (DA) neurotransmission, a speculation that has been supported by neurochemical studies. Mesolimbic DA systems play a prominent role in mediating the behavioral effects of the abused psychostimulant cocaine, and the intent of the present study was to assess the role of 5-HT₄ receptors in the control of spontaneous and cocaine-induced activity. Systemic administration of the 5-HT₄ receptor partial agonist 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-butyl-4- piperidinyl]1-propanone hydrochloride (RS 67333; 0.0001-1 mg/kg) or the 5- HT₄ receptor antagonist 4-amino-5-chloro-2-methoxy-benzoic acid- (diethylamino)ethyl ester hydrochloride (SDZ 205,557; 0.0001-1 mg/kg) did not significantly alter spontaneous activity, whereas SDZ 205,557 significantly attenuated cocaine-induced horizontal activity and rearing. To test the hypothesis that cocaine-elicited behaviors were modulated by 5-HT₄ receptors in the nucleus accumbens (NAc) shell, two separate groups of male rats were implanted with bilateral cannulas aimed at the NAc shell. Intra-NAc shell microinjections of either RS 67333 (1 or 3 μg/0.2 μl/side) or SDZ 205,557 (1-5 μg/0.2 μl/side) did not alter spontaneous activity observed after a systemic saline injection but did significantly attenuate the hyperactivity induced by systemic cocaine injection (10 mg/kg). These results support an involvement of 5-HT₄ receptors, particularly those in the NAc shell, in the locomotor stimulatory effects of cocaine. Furthermore, these data suggest that 5-HT₄ receptors may regulate behavioral processes dependent on mesolimbic DA pathways and may provide a novel target for the development of medications useful in the treatment of both drug dependence and psychiatric disorders.