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-HT2A 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-HT2A receptor. To further address these findings, the present study sought to functionally characterize the role of localized 5-HT2A 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-HT2Areceptor 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-HT2A ASO administration increased EtOH intake. Administration of 5-HT2A 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-HT2A receptor down-regulation may help resolve a long-standing, apparent inconsistency in the role of 5-HT2Areceptors in EtOH consumption.
Footnotes
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This research was supported in part by funds from the National Institute of Alcoholism and Alcohol Abuse, Grant 1RO1AA10124. Portions of this research were presented at the 1997 and 1998 Annual Meetings of the Society for Neuroscience and at the Annual Meeting of the Research Society for Alcohol, 1997 and 1998.
- Abbreviations:
- 5-HT
- serotonin, 5-hydroxytryptamine
- EtOH
- ethanol
- DOI
- dihydroxyiodoaminopropane
- CNS
- central nervous system
- PFC
- prefrontal cortex
- CeA/L
- central amygdaloid nucleus, medial and lateral division
- DRN
- dorsal raphe nucleus
- HIP
- hippocampus
- ASO
- antisense oligonucleotide
- MSO
- missense oligonucleotide
- EPM
- elevated plus maze
- LSD
- d-lysergic acid diethylamide
- MANOVA
- multivariate analysis of variance
- Received February 23, 2001.
- Accepted June 1, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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