Previous research has implicated the mesotelencephalic dopaminergic system as the primary substrate mediating the reinforcing effects of many abused drugs. However, endogenous opioid peptides have also been implicated in this phenomenon. The presence of enkephalins in the nucleus accumbens-pallidal projection, and the demonstrated importance of this pathway in reinforcement, provides an anatomical basis for such a hypothesis. Previously, using microdialysis linked to a solid-phase radioimmunoassay, we demonstrated that opiate administration elevates extracellular concentrations of enkephalins in the pallidum. The first part of the current proposal will examine further the mechanisms underlying this effect. Repeated intermittent administration of opiate and psychostimulant drugs induces a state of behavioral sensitization believed to be largely dependent on a sensitized mesotelencephalic dopamine system. This phenomenon has been implicated in the attribution of 'incentive salience' to environmental cues associated with drug administration. However, not all the evidence is in favor of such a hypothesis and the possible role of other neurotransmitters/neuromodulators in this process needs to be investigated. Our preliminary data suggest that heroin-induced pallidal enkephalin release may exhibit acute sensitization. We will therefore examine if repeated intermittent administration of heroin induces sensitization to the enkephalin-releasing effect of this drug. We will determine for how long such sensitization persists and whether its expression is dependent on conditioned environmental cues. The final part of the proposal will combine microdialysis with a modified conditioned place-preference paradigm to examine if environmental cues themselves elicit a pallidal enkephalin release response in animals conditioned to associate such cues with heroin administration. These studies will provide valuable information concerning the mechanisms underlying heroin addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA009359-08
Application #
6603956
Study Section
Special Emphasis Panel (ZRG1-IFCN-1 (01))
Program Officer
Lin, Yu
Project Start
1995-08-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2005-06-30
Support Year
8
Fiscal Year
2003
Total Cost
$220,769
Indirect Cost
Name
University of California Los Angeles
Department
Type
Other Domestic Higher Education
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Wassum, Kate M; Greenfield, Venuz Y; Linker, Kay E et al. (2016) Inflated reward value in early opiate withdrawal. Addict Biol 21:221-33
Ostlund, Sean B; LeBlanc, Kimberly H; Kosheleff, Alisa R et al. (2014) Phasic mesolimbic dopamine signaling encodes the facilitation of incentive motivation produced by repeated cocaine exposure. Neuropsychopharmacology 39:2441-9
Ostlund, Sean B; Kosheleff, Alisa R; Maidment, Nigel T (2014) Differential effects of systemic cholinergic receptor blockade on Pavlovian incentive motivation and goal-directed action selection. Neuropsychopharmacology 39:1490-7
LeBlanc, Kimberly H; Maidment, Nigel T; Ostlund, Sean B (2014) Impact of repeated intravenous cocaine administration on incentive motivation depends on mode of drug delivery. Addict Biol 19:965-71
Ostlund, Sean B; Kosheleff, Alisa; Maidment, Nigel T et al. (2013) Decreased consumption of sweet fluids in ? opioid receptor knockout mice: a microstructural analysis of licking behavior. Psychopharmacology (Berl) 229:105-13
Wassum, Kate M; Ostlund, Sean B; Loewinger, Gabriel C et al. (2013) Phasic mesolimbic dopamine release tracks reward seeking during expression of pavlovian-to-instrumental transfer. Biol Psychiatry 73:747-55
LeBlanc, Kimberly H; Maidment, Nigel T; Ostlund, Sean B (2013) Repeated cocaine exposure facilitates the expression of incentive motivation and induces habitual control in rats. PLoS One 8:e61355
Ostlund, Sean B; Maidment, Nigel T (2012) Dopamine receptor blockade attenuates the general incentive motivational effects of noncontingently delivered rewards and reward-paired cues without affecting their ability to bias action selection. Neuropsychopharmacology 37:508-19
LeBlanc, Kimberly H; Ostlund, Sean B; Maidment, Nigel T (2012) Pavlovian-to-instrumental transfer in cocaine seeking rats. Behav Neurosci 126:681-9
Ostlund, Sean B; Kosheleff, Alisa R; Maidment, Nigel T (2012) Relative response cost determines the sensitivity of instrumental reward seeking to dopamine receptor blockade. Neuropsychopharmacology 37:2653-60

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