Serotonin is a neurotransmitter in the brain that plays an important role in complex behaviors including addiction. We have previously shown that 5-HT1B receptors alter brain reward mechanisms that play a central role in addiction;these receptors also seem to be involved in the adaptation to stress. Since stress can facilitate drug craving and relapse to drug seeking after abstinence, we will examine the role of this receptor using rodent models of drug addiction. In the initial five years of this grant, we established that the regional expression of 5-HT1B receptors is a critical determinant of their effects on behaviors associated with addiction. An overriding theme in the coming years is to identify the stages at which these receptors play key roles in addiction. We will use strategies that combine molecular and behavioral approaches to investigate the function of 5-HT1B receptors in nucleus accumbens projection neurons, a key component in the brain reward and habit formation systems. We hypothesize that increased 5-HT1B expression is an allostatic adaptation to chronic stress that ameliorates mood disturbance yet facilitates drug addiction.
Aim 1 investigates the temporal association between social defeat stress and 5-HT1B gene expression in dorsal and ventral striatum. We will therefore investigate whether experimentally increased 5-HT1B receptor expression using viral mediated gene transfer reduces the impact of social defeat stress on hedonic state, and whether expression knockdown exacerbates stress-induced changes in the same behavior.
In Aim 2 we will determine whether increased 5-HT1B expression modulates the motivation to self administer cocaine at several key stages, using animal models that capture the developmental progression inherent to addiction. These two Aims constitute a two-pronged strategy investigating the bidirectional relationship between behavioral stress experience and gene expression that impact hedonic state and the propensity to self-administer cocaine.

Public Health Relevance

This research investigates serotonin 5-HT1B receptors involved in regulating behaviors that are relevant to addiction. Increases or decreases in the activity of this receptor strongly impact the drive to self-administer drugs of abuse, including cocaine and alcohol. In this project we will investigate how manipulating this receptor may reduce the compulsive drive to take cocaine and the propensity to relapse after withdrawal from cocaine.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-H (03))
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Frankenheim, Jerry
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University of Washington
Schools of Medicine
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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
Hagan, Catherine E; McDevitt, Ross A; Liu, Yusha et al. (2012) 5-HT(1B) autoreceptor regulation of serotonin transporter activity in synaptosomes. Synapse 66:1024-34
Pentkowski, Nathan S; Cheung, Tim H C; Toy, William A et al. (2012) Protracted withdrawal from cocaine self-administration flips the switch on 5-HT(1B) receptor modulation of cocaine abuse-related behaviors. Biol Psychiatry 72:396-404
Furay, Amy R; McDevitt, Ross A; Miczek, Klaus A et al. (2011) 5-HT1B mRNA expression after chronic social stress. Behav Brain Res 224:350-7
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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