The substantial health risk posed by the compulsive use of cocaine has prompted a serious research effort to identify the neurobiological substrates that underlie the development of addiction to this drug. Despite substantial progress, an understanding of the neurochemical systems that mediate the motivational aspects of drug seeking and craving remains incomplete. To expand this understanding, this proposal will examine the involvement of four discrete cholinergic systems in the development of compulsive cocaine intake and cocaine-seeking behaviors in rats. Experiments will focus on nicotinic acetylcholine (ACh) receptor activation in the development and expression of addictive behavior. The first specific aim is to identify the impact of escalating cocaine self-administration on the release of ACh in amygdaloid complex (AmC), ventral tegmental area (VTA), nucleus accumbens (NAc) and prefrontal cortex (PFC). Rats will be trained to press a lever to self-administer cocaine through indwelling jugular catheters. Availability of cocaine will be increased from 1 to 6 hr per day (which has been shown to escalate daily cocaine intake) and microdialysis will measure ACh release before and after escalated cocaine intake. A second experiment will examine the impact of intracerebral microinjections of nicotine or the nicotinic antagonist mecamylamine on the escalation of cocaine intake.
The second aim of this proposal is to determine if nicotine injections in VTA, NAc, PFC or AmC will prime non-reinforced lever-press behavior in cocaine addicted rats. Prior to testing, rats will receive systemic injections of nicotine or saline before self-administering cocaine for 2 weeks. On test days, rats will be given intracerebral nicotine and non-reinforced responding will be measured as an index of cocaine craving.
The third aim of this research is to determine the role of AmC, VTA, NAc and PFC ACh systems in the ability of drug-associated stimuli to control non-reinforced responding. ACh will be measured during the presentation of cocaine-associated cues along with responding elicited by a cocaine-conditioned stimulus after microinjection of nicotinic drugs into AmC, VTA, NAc and PFC. Injections of nicotinic antagonists in these four areas are expected to reduce lever-press behavior in response to presentation of second-order stimuli. It is hoped that the results of these studies will further our understanding of the involvement of central cholinergic mechanisms in cocaine-reinforced behavior and drug craving and the brain site-specific influence of nicotine on cocaine addiction and relapse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA014639-04
Application #
6784514
Study Section
Special Emphasis Panel (ZDA1-MXG-S (01))
Program Officer
Lynch, Minda
Project Start
2001-09-30
Project End
2006-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
4
Fiscal Year
2004
Total Cost
$226,500
Indirect Cost
Name
Oregon Health and Science University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Mark, Gregory P; Shabani, Shkelzen; Dobbs, Lauren K et al. (2011) Cholinergic modulation of mesolimbic dopamine function and reward. Physiol Behav 104:76-81
Shabani, S; Foster, R; Gubner, N et al. (2010) Muscarinic type 2 receptors in the lateral dorsal tegmental area modulate cocaine and food seeking behavior in rats. Neuroscience 170:559-69
Ford, Matthew M; Fretwell, Andrea M; Nickel, Jeffrey D et al. (2009) The influence of mecamylamine on ethanol and sucrose self-administration. Neuropharmacology 57:250-8
Beckstead, Michael J; Gantz, Stephanie C; Ford, Christopher P et al. (2009) CRF enhancement of GIRK channel-mediated transmission in dopamine neurons. Neuropsychopharmacology 34:1926-35
Dobbs, L K; Mark, G P (2008) Comparison of systemic and local methamphetamine treatment on acetylcholine and dopamine levels in the ventral tegmental area in the mouse. Neuroscience 156:700-11
Finn, Deborah A; Mark, Gregory P; Fretwell, Andrea M et al. (2008) Reinstatement of ethanol and sucrose seeking by the neurosteroid allopregnanolone in C57BL/6 mice. Psychopharmacology (Berl) 201:423-33
Jaworski, Jason N; Hansen, Stephen T; Kuhar, Michael J et al. (2008) Injection of CART (cocaine- and amphetamine-regulated transcript) peptide into the nucleus accumbens reduces cocaine self-administration in rats. Behav Brain Res 191:266-71
Ford, Matthew M; Fretwell, Andrea M; Mark, Gregory P et al. (2007) Influence of reinforcement schedule on ethanol consumption patterns in non-food restricted male C57BL/6J mice. Alcohol 41:21-9
Hansen, Stephen T; Mark, Gregory P (2007) The nicotinic acetylcholine receptor antagonist mecamylamine prevents escalation of cocaine self-administration in rats with extended daily access. Psychopharmacology (Berl) 194:53-61
Roseberry, Aaron G; Painter, Tammie; Mark, Gregory P et al. (2007) Decreased vesicular somatodendritic dopamine stores in leptin-deficient mice. J Neurosci 27:7021-7

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