Effects of 5-HT3 receptor-selective agents on locomotor activity in rats following injection into the nucleus accumbens and the ventral tegmental area

Abstract

5-Hydroxytryptamine (5-HT) is involved in the modulation of dopaminergic activity in the mesolimbic system, but its sites of action and the receptors involved are not well understood. Locomotor activity responses in rats were monitored in Animex automated activity boxes following injection of 5-HT3 receptor-selective agents directly into two mesolimbic nuclei, the nucleus accumbens and the ventral tegmental area, via stereotactically implanted injection guide cannulae. Neither spontaneous nor dexamphetamine-stimulated locomotor activity was changed by bilateral intra-nucleus accumbens injection of the selective agonist 2-methyl-5-HT or the selective antagonists ondansetron or granisetron. In contrast, intra-ventral tegmental area injection of 2-methyl-5-HT produced significant long-lasting (approximately 240 min) increases in locomotor activity; intra-ventral tegmental area injection of ondansetron elicited an initial inhibition of spontaneous and dexamphetamine-stimulated locomotor activity (for the 0-30 min period), but granisetron had no effect. The hyperlocomotor response to intra-ventral tegmental area 2-methyl-5-HT was abolished by pretreatment with the catecholamine synthesis inhibitor alpha-methyl-p-tyrosine, or by pretreatment with ondansetron. Methiothepin pretreatment had no effect on the hyperlocomotor response to 2-methyl-5-HT, although methiothepin itself produced an initial increase in spontaneous locomotor activity (for the 60-120 min period). Intra-ventral tegmental area injection of 5-carboxamidotryptamine, alpha-methyl-5-HT or renzapride produced no changes in spontaneous locomotor activity. In some of the ventral tegmental area experiments, other behaviours were also monitored. 2-Methyl-5-HT produced forward locomotion, rearing, and increased wakefulness, but did not appreciably alter circling, grooming or sniffing. Ondansetron alone had no effect on any of these behaviours, but it opposed the 2-methyl-5-HT-induced changes. Methiothepin alone increased forward locomotion and wakefulness but did not alter the other behaviours; it had no effect on the responses to 2-methyl-5-HT. These observations show that 5-HT3 receptors may mediate increased locomotor activity by modulating firing of mesolimbic dopaminergic cell bodies in the ventral tegmental area rather than terminals in the nucleus accumbens.