The serotonin system in the brain plays several important roles in modulating the effects of drugs of abuse. In this proposal we will examine the roles of 5-HT1B and 5-HT6 receptors in the rewarding and motor stimulant effects of cocaine and amphetamine in rats, and correlate these to biochemical adaptations that are associated with the progression of drug addiction. We will focus on a critical neuronal reward circuit using cutting edge techniques with molecular and anatomical precision so that we can discern the role of these receptors in this specific context. It is our hypothesis that, in nucleus accumbens projection neurons, 5-HT1B receptors increase and 5-HT6 receptors decrease the behavioral effects of psychostimulants. This proposal is innovative because it focuses on serotonin receptors that have not received much previous attention in relation to drug addiction. The primary strategy that we will use is viral mediated gene transfer to alter the expression of 5-HT1B and 5-HT6 receptors selectively in medium spiny neurons of the nucleus accumbens shell that project to ventral tegmental area. For 5-HT1B receptors, we will study the effect of altered 5-HT1B receptor expression in the efferents of these neurons on cocaine and amphetamine behaviors. Since cocaine has a large, direct effect on serotonin accumulation and low dose amphetamine affects dopamine predominantly, we will be able to assess the role of 5-HT1B receptors in drug reward in general as opposed to for cocaine in particular. We will also use in situ hybridization histochemistry to study the impact of chronic cocaine administration and drug discontinuation on the expression of these two receptors in medium spiny neurons. For the 5-HT6 receptor, we will combine local injections of highly selective 5-HT6 agonists and antagonists into nucleus accumbens shell with systemic cocaine treatment to evaluate the role of 5-HT6 receptors in these neurons on drug reward mechanisms. We have also developed a 5-HT6 viral vector that will allow us to probe the role of these receptors in accumbens neurons with great precision. The overall goal of this proposal is to extend our molecular and behavioral understandings of how serotonin receptors mediate the addictive properties of cocaine and amphetamine, and to determine if these receptors might serve as novel targets for treating addiction pharmacologically.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
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Frankenheim, Jerry
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University of Washington
Schools of Medicine
United States
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Nair, Sunila G; Furay, Amy R; Liu, Yusha et al. (2013) Differential effect of viral overexpression of nucleus accumbens shell 5-HT1B receptors on stress- and cocaine priming-induced reinstatement of cocaine seeking. Pharmacol Biochem Behav 112:89-95
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Ferguson, Susan M; Sandygren, Nolan A; Neumaier, John F (2009) Pairing mild stress with increased serotonin-1B receptor expression in the nucleus accumbens increases susceptibility to amphetamine. Eur J Neurosci 30:1576-84
Neumaier, John F; McDevitt, Ross A; Polis, Ilham Y et al. (2009) Acquisition of and withdrawal from cocaine self-administration regulates 5-HT mRNA expression in rat striatum. J Neurochem 111:217-27
Mitchell, Ellen S; Neumaier, John F (2008) 5-HT6 receptor antagonist reversal of emotional learning and prepulse inhibition deficits induced by apomorphine or scopolamine. Pharmacol Biochem Behav 88:291-8
Mitchell, Ellen S; Sexton, Timothy; Neumaier, John F (2007) Increased expression of 5-HT6 receptors in the rat dorsomedial striatum impairs instrumental learning. Neuropsychopharmacology 32:1520-30
Barot, Sabiha K; Ferguson, Susan M; Neumaier, John F (2007) 5-HT(1B) receptors in nucleus accumbens efferents enhance both rewarding and aversive effects of cocaine. Eur J Neurosci 25:3125-31
Hoplight, B J; Vincow, E S; Neumaier, J F (2007) Cocaine increases 5-HT1B mRNA in rat nucleus accumbens shell neurons. Neuropharmacology 52:444-9

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