Ventral tegmental area 5-HT receptors: mesolimbic dopamine release and behavioural studies

Serotoninergic neurones originating in the dorsal and median raphe nuclei project to mesolimbic structures, including the nucleus accumbens (NAcb) and the ventral tegmental area (VTA), where they may have an important regulatory role. Some evidence from dopamine release, behavioural and binding studies directly implicates involvement of 5-HT3 and 5-HT4 receptors in the NAcb. Other in vivo dopamine release and behavioural experiments in rats have provided evidence for 5-HT3 receptor-mediated enhancement of mesolimbic dopaminergic activity, although the location of the 5-HT3 receptors involved is unknown because the selective 5-HT3 receptor agents used were administered systemically or intracerebroventricularly. This raises the possibility of a VTA site of action; as yet, however, relatively little is specifically known about 5-HT receptors and function in the VTA. Mesolimbic dopamine release in rats, measured in-vivo with microdialysis probes in the NAcb, can be inhibited by tropisetron administered directly into the VTA. In our laboratory, behavioural studies in rats have shown that a sustained hyperlocomotion is produced by 2-methyl-5-HT administered into the VTA via stereotactically implanted guide cannulae. Mesolimbic dopaminergic activation is involved, because pretreatment with the catecholamine synthesis inhibitor alpha-methyl-p-tyrosine abolishes 2-methyl-5-HT-induced hyperlocomotion. The 2-methyl-5-HT hyperlocomotor response is blocked by prior intra-VTA injection of ondansetron but is not affected by methiothepin, and intra-VTA 5-carboxamidotryptamine, alpha-methyl-5-HT or renzapride were without effect, thus a 5-HT3 receptor in the VTA mediates the 2-methyl-5-HT response. These in vivo dopamine release and behavioural studies therefore confirm that 5-HT3 receptors in the VTA can mediate increased locomotor activity, by modulating the firing of mesolimbic dopaminergic cell bodies.