Neural Circuits Associated with 5-HT_1B Receptor Agonist Inhibition of Methamphetamine Seeking in the Conditioned Place Preference Model

Abstract

5-HT1B receptors (5-HT1BRs) modulate psychostimulant reward and incentive motivation in rodents. Here we investigated the effects of the 5-HT1BR agonist CP94253 (10 mg/kg, IP) on the acquisition and expression of methamphetamine (Meth) conditioned place preference (CPP) in C57BL/6 male mice. We subsequently examined the potential brain regions involved in CP94253 effects using FOS as a marker of neural activity. In the acquisition experiment, mice received the agonist 30 min before each of the Meth injections given during conditioning. In the expression experiment, mice that had acquired Meth-CPP were given either saline or CP94253 and were tested for CPP 30 min later. We found that CP94253 attenuated the expression of Meth-CPP, but had no effect on acquisition. Mice expressing Meth-CPP had elevated numbers of FOS+ cells in the ventral tegmental area (VTA) and basolateral amygdala (BlA) and reduced FOS+ cells in the central amygdala (CeA) compared to saline controls. CP94253 given before the expression test, but not acutely in drug-naive mice, enhanced FOS+ cells in the VTA, the nucleus accumbens (NAc) shell and core, and the dorsomedial striatum and reversed the Meth-conditioned changes in FOS in the BlA and CeA. Approximately 50–70% of FOS+ cells in the NAc and VTA were GABAergic regardless of group. By contrast, we did not observe FOS-labeling in dopamine neurons in the VTA. The findings suggest that CP94253 attenuates the motivational effects of the Meth-associated environment and highlight the amygdala, VTA, NAc, and dorsomedial striatum as potential regions involved in this effect.