Bidirectional changes in ethanol consumption in rats with site-specific antisense down-regulation of 5-hydroxytryptamine2A receptors in brain.
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-HT2A receptor 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-HT2A receptors in EtOH consumption.
Blakley
G G
GG
Division of Neuropharmacology, Center of Alcohol Studies, Rutgers University, Piscataway, New Jersey 08854-8100, USA.
Pohorecky
L A
LA
Benjamin
D
D
D000428:Alcohol Drinking / Q000523:psychology*; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001007:Anxiety / Q000523:psychology; D001345:Autoradiography; D001923:Brain Chemistry / Q000187:drug effects* / Q000235:genetics; D003345:Corticosterone / Q000097:blood; D015536:Down-Regulation / Q000187:drug effects*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D020125:Mutation, Missense / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000235:genetics; D012439:Saccharin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013315:Stress, Psychological / Q000523:psychology; D013649:Taste / Q000187:drug effects; D013997:Time Factors
D000662:Amphetamines; D016376:Oligonucleotides, Antisense; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D012439:Saccharin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D003345:Corticosterone