Methamphetamine-induced sensitization includes a functional upregulation of ventral pallidal 5-HT2A/2C receptors

Methamphetamine (METH) causes the release of serotonin (5-HT), but little is known about how repeated exposure to METH modifies serotonergic receptor function, especially in the ventral pallidum (VP), a brain region highly innervated by serotonin inputs. The current study was designed to ascertain if ventral pallidal neurons are functionally upregulated 3 days after a behaviorally sensitizing treatment regimen of METH, and whether these effects could be revealed by activating the 5-HT2A/2C receptors. Rats treated with METH (2.5 kg/mg/day) for 5 days, responded with enhanced stereotypic behaviors. Electrophysiological evaluations of the VP conducted in anesthetized rats 3 days following this sensitizing treatment regimen of METH revealed that spiking rate increases induced by intravenous METH were augmented above that seen in rats with a history of saline treatments. The efficacy of the 5-HT2A/2C agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) to augment ventral pallidal cell firing also was enhanced in METH-sensitized rats. These data reveal that METH-induced behavioral sensitization renders the VP more responsive to METH and is associated with a functional upregulation of 5-HT2 receptors.