Elevated expression of 5-HT1B receptors in nucleus accumbens efferents sensitizes animals to cocaine.

Although the effects of psychostimulants on brain dopamine systems are well recognized, the direct actions of cocaine on serotonin systems also appear to be important to its addictive properties. For example, serotonin actions at 5-HT1B receptors in the ventral tegmental area (VTA) modulate cocaine-induced dopamine release in the nucleus accumbens (NAcc) and alter the rewarding and stimulant properties of cocaine. However, the mechanisms of these effects have been unclear, because several neuron types in VTA express 5-HT1B receptors. One possibility is that 5-HT1B receptors on the terminals of GABAergic projections from NAcc to VTA inhibit local GABA release, thereby disinhibiting VTA neurons. We tested this hypothesis directly by using viral-mediated gene transfer to overexpress 5-HT1B receptors in NAcc projections to VTA. A viral vector containing either epitope hemagglutinin-tagged 5-HT1B and green fluorescent protein (HA1B-GFP) cassettes or green fluorescent protein cassette alone (GFP-only) was injected into the NAcc shell, which sends projections to the VTA. HA1B-GFP injection induced elevated expression of 5-HT1B receptors in neuronal fibers in VTA and increased cocaine-induced locomotor hyperactivity without affecting baseline locomotion. Overexpression of 5-HT1B receptors also shifted the dose-response curve for cocaine-conditioned place preference to the left, indicating alterations in the rewarding effects of cocaine. Thus, increased expression of 5-HT1B receptors in NAcc efferents, probably in the terminals of medium spiny neurons projecting to the VTA, may contribute to psychomotor sensitization and offer an important target for regulating the addictive effects of cocaine.