Several distinct lines of research have implicated the brain serotonin system in the consumption of ethanol (ET). Research with both human and experimental subjects indicates that low serotonergic function is associated with increased consumption of ET. However, there are inconsistencies in the literature; an increase in 5-HT function (e.g., reuptake inhibitors and releasers, 5-HT-1A agonists) decreases ingestion of ET, but 5-HT-2A/2C antagonists also decrease the ingestion of ET. Our understanding of the role of 5-HT receptors in ET preference has been impeded because of a lack of selective drugs. In the proposed experiments, receptor synthesis will be specifically attenuated using antisense oligonucleotides. Sequences complementary to mRNA coding for the 5-HT-1A, 5-HT-2A and 5-HT-2C receptor subtypes will be injected into specific brain areas. Antisense technology allows the molecular specificity necessary to determine the role of 5-HT receptor subtypes in the control of ET ingestion. Based on previous pharmacological studies, it is proposed that 5-HT-2A and 5-HT-2C receptors exert tonic positive control over ethanol preference, and 5- HT1A receptors exert tonic negative control. Following depletion using antisense sequences, the role of 5-HT-1A, 5-HT-2A and 5-HT-2C receptors in ET ingestion will be determined using a two bottle (ET versus water) preference test with 24 hour access. Using male rats, oligonucleotides in antisense and control sequences will be infused continuously into the ventral tegmental area (VTA), dorsal raphe (DRN), nucleus accumbens (NAc) and prefrontal cortex (PFC) using osmotic minipumps. The extent and specificity of receptor changes produced by each oligonucleotide sequence will be determined using saturation binding and quantitative receptor autoradiography; functional tests will also be performed. Experiment 1 will test the ability of an antisense sequence to attenuate 5-HT- 1A receptor expression in cultured neural cells. Experiment 2 will ascertain the pharmacological and regional specificity of the antisense oligonucleotides, and quantify the extent of 5-HT-1A, 5-HT-2A and 5-HT-2C receptor loss as a result of antisense or control sequence infusion in rats. Experiment 3 will characterize the functional consequences of selective downregulation of 5-HT receptor subtypes, and behavioral and physiological measurements will be performed to characterize the role of the three receptors in the acute response to ET. Experiments 4-6 will characterize the role of 5- HT-1A, 5-HT-2A and 5-HT-2C receptors located in the DRN, VTA, NAc, and PFC in ET preference. Experiment 7 will establish a positive control for the antisense knockout experiments using mianserin, a potent downregulator of 5- HT-2A and 5-HT-2C receptors; mianserin (30 ug/day ICV via minipump) or its vehicle will be administered during ET preference testing. These experiments will specifically determine the role of 5-HT receptor subtypes in the control of ET ingestion, and thus provide a rational basis for clinical trials, and lead to improved therapy of abusive alcohol consumption and related problems.
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