Role of dopamine in behavioral effects of serotonin microinjected into rat striatum.

Bilateral local microinfusion of serotonin (5-hydroxytryptamine; 5-HT) into the ventrolateral striatum (VLS) of the rat forebrain induces quantifiable stereotyped orofacial behaviors. The role of presynaptic dopamine (DA) and structural requirements of indoles for expression of this behavioral effect and for inhibition of neuronal transport of [3H]DA were examined. Bilateral local injection of 6-OHDA (8 micrograms/side) into VLS depleted DA and markedly diminished the behavioral effects of 5-HT. Intracerebral pretreatment with the potent DA transport inhibitors GBR-12909 (6 micrograms/side) or nomifensine (4 micrograms/side) also markedly decreased behavioral responses to 5-HT. A series of indoles and tyramine were examined for ability to induce stereotypy following infusion into the VLS. Of compounds tested, only p-tyramine, 5-HT, tryptamine and L-5-hydroxytryptophan (5-HTP) elicited strong orofacial behaviors; indoles lacking a free amino group or containing other substituents were virtually inactive in vivo, and the effect of 5-HTP was prevented by systemic pretreatment with the decarboxylase inhibitor NSD-1015, indicating its required conversion to 5-HT. Uptake of [3H]DA (0.1 microM) into rat striatal synaptosomes was inhibited in a concentration-dependent manner in the following apparent rank-order: p-tyramine, N-methyl-5-HT, tryptamine, 5-HT, N-methyltryptamine (IC50 = 44-718 nM), other indoles (IC50 = 10-100 microM). These results support the conclusion that oral stereotypy induced by microinjection of 5-HT or other aromatic amines into rat VLS is mediated by local release of endogenous DA. These results extend previous findings indicating that this effect of 5-HT was not blocked by 5-HT receptor antagonists, and suggest mediation by a neuronal transport process involved in the uptake or storage of DA.