The effect of a 5-HT3 receptor antagonist, ondansetron, on brain stimulation reward, and its interaction with direct and indirect stimulants of central dopaminergic transmission.

5-HT3 receptors are abundant in central dopamine (DA) terminal areas. They do not affect basal DA turnover but appear to modulate DA release by e.g. morphine and nicotine. The interpretation of these findings is uncertain, and it is unclear whether 5-HT3 receptors also influence the activity of compounds such as amphetamine and cocaine, which act more directly on the DA synapse. Variable-interval (VI), threshold-current hypothalamic self-stimulation can provide a continuous index of central dopaminergic activity, but is relatively insensitive to changes in 5-HT and thus offers a means of investigating this question. In the present study, a selective 5-HT3 receptor antagonist, ondansetron (GR 38032F) (1.0 to 1000 micrograms/kg sc), had no effect on VI self-stimulation, nor did a 100 micrograms/kg dose affect facilitation of responding by d-amphetamine (500 micrograms/kg ip). Ondansetron (100 micrograms/kg) reduced the initial depression of self-stimulation by high-dose nicotine (400 micrograms/kg), but not the ensuing facilitation. Similar results were obtained in rats "sensitized" to nicotine by prior chronic exposure. These results support the proposal that 5-HT3 receptors, normally quiescent under basal conditions, mediate the excitatory effect of compounds acting upstream from the DA neuron, such as nicotine, but do not affect the dopaminergic synapse directly.