Bidirectional changes in ethanol consumption in rats with site-specific antisense down-regulation of 5-hydroxytryptamine(2A) receptors in brain

The 5-hydroxytryptamine (5-HT)(2A) receptor is an important component of th e neural substrates underlying ethanol (EtOH) intake and behaviors related to anxiety and stress. Paradoxically, both 5-HT2A agonists and antagonists have been shown to reduce EtOH intake, however the mechanisms underlying th ese effects are not understood. This inconsistency could possibly be explai ned by their chronic down-regulation of the 5-HT2A receptor. To further add ress these findings, the present study sought to functionally characterize the role of localized 5-HT2A receptors in regulating EtOH ingestion by prod ucing central nervous system site-specific receptor down-regulation through infusion of antisense oligonucleotide (ASO). Rats were infused with 5-HT2A receptor ASO into the lateral ventricle (i.c.v.), prefrontal cortex (PFC), central amygdaloid nucleus, medial and lateral division (CeA/L), dorsal ra phe nucleus (DRN), or hippocampus (HIP) for a period of 26 days. Subjects w ere 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-HT2A ASO administration increased EtOH intake. Administration of 5- HT2(A) ASO into the DRN and HIP had no effect on EtOH intake. Intracerebrov entricular ASO administration increased activity in a novel open field and increased anxiety-like behavior in the elevated plus maze. PFC ASO administ ration produced an anxiogenic effect in the elevated plus maze. Intracerbro ventricular, PFC, and CeA/L ASO infusions altered adrenocortical function. These differential behavioral effects specific to the anatomical locations targeted for 5-HT2A receptor down-regulation may help resolve a long-standi ng, apparent inconsistency in the role of 5-HT2A receptors in EtOH consumpt ion.