Characterization of the neuronal circuits mediating drug reinforcement would be beneficial in understanding the neurobiological basis of abuse disorders. The major goal of this research project is to identify and characterize the brain loci, neurohumor receptors and neuronal circuits that initiate and mediate the reinforcing effects of cocaine. Brain sites where cocaine initiates this activity are under investigation with intracranial self-administration methodologies. The medial prefrontal cortex is one such site while the ventral tegmental area and nucleus accumbens do not support self-administration. During this next grant period the amygdala, sulcal-rhinal cortex, lateral hypothalamus, olfactory tubercle and caudate nucleus-putamen will be assessed for self-administration. Two lever discrimination procedures and intermittent schedules of reinforcement will be used to evaluate the reinforcing effects of the drug whereas pharmacological blockade and neurotoxin lesions of the self- administration site will result in the characterization of the neurotransmitter receptors and neurons responsible for these effects. The ability of amphetamine to initiate reinforcing neuronal activity at these and other brain sites will also be evaluated. Neuronal circuits mediating the reinforcing properties of cocaine will continue to be characterized by measuring the turnover rates of biogenic amine and amino acid neurotransmitters in small brain regions of rats intravenously self-administering the drug and comparing these with littermates receiving either identical yoked infusions of cocaine or the vehicle. Turnover rates of these neurotransmitters will also be determined in discrete brain regions of rats intracranially self-administering cocaine into the medial prefrontal cortex or receiving yoked vehicle injections. Behavioral specificity will be assessed by lesioning the neurons identified to be involved with selective neurotoxins in rats lever pressing on concurrent schedules of food, water and intravenous cocaine presentation. These combined methodologies should continue to characterize the biological mechanisms of the reinforcing effects of cocaine. Such information could be beneficial for the development of therapeutic approaches for the treatment of compulsive cocaine use.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA003628-08
Application #
3208169
Study Section
Special Emphasis Panel (SRCD)
Project Start
1988-01-01
Project End
1992-12-31
Budget Start
1991-01-01
Budget End
1991-12-31
Support Year
8
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Type
Schools of Medicine
DUNS #
041418799
City
Winston-Salem
State
NC
Country
United States
Zip Code
27106
Tannu, N S; Howell, L L; Hemby, S E (2010) Integrative proteomic analysis of the nucleus accumbens in rhesus monkeys following cocaine self-administration. Mol Psychiatry 15:185-203
Hemby, Scott E; Tannu, Nilesh (2009) Modeling substance abuse for applications in proteomics. Methods Mol Biol 566:69-83
Martin, Thomas J; Coller, Michael; Co, Conchita et al. (2008) Micro-opioid receptor alkylation in the ventral pallidum and ventral tegmental area, but not in the nucleus accumbens, attenuates the effects of heroin on cocaine self-administration in rats. Neuropsychopharmacology 33:1171-8
Backes, E N; Hemby, S E (2008) Contribution of ventral tegmental GABA receptors to cocaine self-administration in rats. Neurochem Res 33:459-67
Smith, James E; Vaughn, Tina C; Co, Conchita (2004) Acetylcholine turnover rates in rat brain regions during cocaine self-administration. J Neurochem 88:502-12
Sizemore, Glen M; Co, Conchita; Koves, Timothy R et al. (2004) Time-dependent recovery from the effects of 6-hydroxydopamine lesions of the rat nucleus accumbens on cocaine self-administration and the levels of dopamine in microdialysates. Psychopharmacology (Berl) 171:413-20
Sizemore, Glen M; Davies, Huw M L; Martin, T J et al. (2004) Effects of 2beta-propanoyl-3beta-(4-tolyl)-tropane (PTT) on the self-administration of cocaine, heroin, and cocaine/heroin combinations in rats. Drug Alcohol Depend 73:259-65
Smith, James E; Co, Conchita; Yin, Xinhe et al. (2004) Involvement of cholinergic neuronal systems in intravenous cocaine self-administration. Neurosci Biobehav Rev 27:841-50
Smith, J E; Koves, T R; Co, C (2003) Brain neurotransmitter turnover rates during rat intravenous cocaine self-administration. Neuroscience 117:461-75
Sizemore, G M; Cannon, D G; Smith, J E et al. (2003) The effects of acutely administered cocaine on responding maintained by a progressive-ratio schedule of food presentation. Behav Pharmacol 14:33-40

Showing the most recent 10 out of 38 publications