The substantial health risk posed by chronic cocaine use has prompted a serious research effort to identify the neurobiological substrates that underlie the motivational aspects of drug seeking and drug relapse. Research in this area has concentrated on the nucleus accumbens (NAc) which is considered to be an integral component in the link between motivation and action. The NAc receives afferents from several neurotransmitter systems (e.g. dopamine, serotonin, glutamate) and each of these has been implicated in drug reinforcement. Despite this substantial progress, our understanding of the neurochemical mechanisms involved in the motivational aspects of drug seeking remains incomplete. The NAc is known to contain cholinergic interneurons whose activity may have important motivational consequences. The first specific aim of this research is to identify the impact of cocaine self-administration on acetylcholine (ACh) release within the NAc and, as a motoric control, the dorso-lateral striatum. Sprague-Dawley rats will be implanted with intravenous catheters and trained to lever-press for infusions of cocaine. Microdialysis will be used to measure ACh at four time points: 1) during initial exposure to cocaine, 2) after 2 weeks of daily self-administration, 3) after 10 days of withdrawal and finally 4) during reinstated self-administration.
The second aim of these experiments is to determine the responsiveness of ACh interneurons within the NAc to GABAergic and dopaminergic drugs following 2 weeks of cocaine self-administration and after ten days of withdrawal. Microdialysis probes will be used to administer drugs into the NAc while ACh release is measured.
The third aim of this research is to characterize the extent to which ACh modulates cocaine self-administration. Rats will be trained to lever-press for intravenous infusions of cocaine on a progressive ratio schedule of reinforcement. Micro-infusions of ACh agonists and antagonists will be delivered bilaterally into the NAc prior to drug availability. Responding on drug-active and inactive levers will be measured for five hours following infusions. Selective increases in responding on the drug-active lever should indicate an increase in the motivation to obtain cocaine while decreases in responding would signal a suppression. It is hoped that these results will further our understanding of the involvement of cholinergic mechanisms in drug-seeking and potentially to the development of clinically efficacious treatments for drug craving and relapse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DA011203-04
Application #
6362831
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Aigner, Thomas G
Project Start
1998-05-01
Project End
2003-02-28
Budget Start
2001-03-15
Budget End
2002-02-28
Support Year
4
Fiscal Year
2001
Total Cost
$105,210
Indirect Cost
Name
Oregon Health and Science University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
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
Mark, Gregory P; Kinney, Anthony E; Grubb, Michele C et al. (2006) Injection of oxotremorine in nucleus accumbens shell reduces cocaine but not food self-administration in rats. Brain Res 1123:51-9
Song, Pingfang; Sekhon, Harmanjatinder S; Jia, Yibing et al. (2003) Acetylcholine is synthesized by and acts as an autocrine growth factor for small cell lung carcinoma. Cancer Res 63:214-21
Song, P; Sekhon, H S; Proskocil, B et al. (2003) Synthesis of acetylcholine by lung cancer. Life Sci 72:2159-68
Sinnott, Rachna S; Mark, Gregory P; Finn, Deborah A (2002) Reinforcing effects of the neurosteroid allopregnanolone in rats. Pharmacol Biochem Behav 72:923-9
Grubb, Michele C; Welch, James R; Finn, Deborah A et al. (2002) Cocaine self-administration alters the locomotor response to microinjection of bicuculline into the ventral tegmental area of rats. Brain Res 952:44-51
Mark, Gregory P; Finn, Deborah A (2002) The relationship between hippocampal acetylcholine release and cholinergic convulsant sensitivity in withdrawal seizure-prone and withdrawal seizure-resistant selected mouse lines. Alcohol Clin Exp Res 26:1141-52
Bechtholt, Anita J; Mark, Gregory P (2002) Enhancement of cocaine-seeking behavior by repeated nicotine exposure in rats. Psychopharmacology (Berl) 162:178-85
Ryabinin, A E; Wang, Y M; Bachtell, R K et al. (2000) Cocaine- and alcohol-mediated expression of inducible transcription factors is blocked by pentobarbital anesthesia. Brain Res 877:251-61
Mark, G P; Hajnal, A; Kinney, A E et al. (1999) Self-administration of cocaine increases the release of acetylcholine to a greater extent than response-independent cocaine in the nucleus accumbens of rats. Psychopharmacology (Berl) 143:47-53