Bidirectional Changes in Ethanol Consumption in Rats with Site-Specific Antisense Down-Regulation of 5-Hydroxytryptamine_2A Receptors in Brain

Abstract

The 5-hydroxytryptamine (5-HT)_2A receptor is an important component of the neural substrates underlying ethanol (EtOH) intake and behaviors related to anxiety and stress. Paradoxically, both 5-HT_2A agonists and antagonists have been shown to reduce EtOH intake, however the mechanisms underlying these effects are not understood. This inconsistency could possibly be explained by their chronic down-regulation of the 5-HT_2A receptor. To further address these findings, the present study sought to functionally characterize the role of localized 5-HT_2A receptors in regulating EtOH ingestion by producing central nervous system site-specific receptor down-regulation through infusion of antisense oligonucleotide (ASO). Rats were infused with 5-HT_2Areceptor ASO into the lateral ventricle (i.c.v.), prefrontal cortex (PFC), central amygdaloid nucleus, medial and lateral division (CeA/L), dorsal raphe nucleus (DRN), or hippocampus (HIP) for a period of 26 days. Subjects were tested for EtOH intake and behaviors related to anxiety and stress. ASO administration i.c.v. and into the CeA/L significantly reduced EtOH intake. PFC 5-HT_2A ASO administration increased EtOH intake. Administration of 5-HT_2A ASO into the DRN and HIP had no effect on EtOH intake. Intracerebroventricular ASO administration increased activity in a novel open field and increased anxiety-like behavior in the elevated plus maze. PFC ASO administration produced an anxiogenic effect in the elevated plus maze. Intracerbroventricular, PFC, and CeA/L ASO infusions altered adrenocortical function. These differential behavioral effects specific to the anatomical locations targeted for 5-HT_2A receptor down-regulation may help resolve a long-standing, apparent inconsistency in the role of 5-HT_2Areceptors in EtOH consumption.