In both the human clinical situation, and animal models of drug abuse, there are substantial differences between individuals in the amounts of drugs consumed. In an attempt to understand the neurobiology of drug abuse, and relapse following abstention, biochemical correlates of vulnerability to amphetamine self-administration in the rat will be studied. These studies will expand upon recent findings which demonstrate that certain behavioral measures (novelty-and amphetamine-induced locomotion) predict the amount of amphetamine self-administered by animals. Because of the role of the mesoaccumbens dopamine system in supporting both self-administration and amphetamine-induced locomotion, these studies will primarily focus on this system. This proposal is based on the hypothesis that the individual differences between animals which render some more vulnerable to drug self-administration are reflected in measurable biochemical differences. Measurable indices of both pre-and postsynaptic dopaminergic transmission in the nucleus accumbens will be examined. There are four basic aims of this proposal. The first will be to determine to what degree differences in presynaptic dopamine function correlate with differences in novelty-and amphetamine-induced locomotion. Specific experiments will examine amphetamine-induced dopamine release in vivo following local perfusion through a microdialysis probe: 2) amphetamine-induced dopamine release in vitro; 3) whole tissue measures of dopamine and metabolite under basal conditions; 4) dopamine uptake site density. The second specific aim examines mechanisms post-synaptic to dopaminergic actions in the nucleus accumbens for correlation with behavioral predictors: 1) dopamine receptor binding in the accumbens and striatum, 2) dopamine receptor mediated changes in cyclic AMP using accumbens and striatal tissue in vitro, and 3) gamma-aminobutyric acid receptor binding in the ventral pallidum. The third specific aim will determine the correlation between behavioral predictors and the following measures which attempt to determine the """"""""degree of behavioral sensitization"""""""" in individual animals: 1) systemic amphetamine-induced dopamine release in vivo, measured by microdialysis in awake rats: 2) morphine-induced locomotion and dopamine release in vivo; 3) stress (novelty) induced increases in extracellular dopamine in the prefrontal cortex and nucleus accumbens. G-protein levels will be determined for correlation with novelty-induced locomotion, novelty-and amphetamine- induced increases in extracellular dopamine, and the effects of pertussis toxin treatment in the ventral tegmental area will be studied. The fourth specific aim will determine if selected parameters (assessed post-mortem) which were shown to correlate with novelty-induced locomotion also correlate with amount of amphetamine self-administered previously in an operant chamber. These studies may substantially enhance our knowledge of the possible biochemical bases of drug abuse and addiction, and therefore increase the prospects for rational therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DA008073-02
Application #
3461381
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1992-09-25
Project End
1997-08-31
Budget Start
1993-09-25
Budget End
1994-08-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Bradberry, Charles W (2011) Cortical and sub-cortical effects in primate models of cocaine use: implications for addiction and the increased risk of psychiatric illness. Neurotox Res 19:235-42
Bradberry, Charles W (2002) Dose-dependent effect of ethanol on extracellular dopamine in mesolimbic striatum of awake rhesus monkeys: comparison with cocaine across individuals. Psychopharmacology (Berl) 165:67-76
Bradberry, Charles W (2002) Dynamics of extracellular dopamine in the acute and chronic actions of cocaine. Neuroscientist 8:315-22
Bradberry, C W (2000) Acute and chronic dopamine dynamics in a nonhuman primate model of recreational cocaine use. J Neurosci 20:7109-15
Bradberry, C W; Barrett-Larimore, R L; Jatlow, P et al. (2000) Impact of self-administered cocaine and cocaine cues on extracellular dopamine in mesolimbic and sensorimotor striatum in rhesus monkeys. J Neurosci 20:3874-83
Bradberry, C W; Lee, T; Jatlow, P (1999) Rapid induction of behavioral and neurochemical tolerance to cocaethylene, a model compound for agonist therapy of cocaine dependence. Psychopharmacology (Berl) 146:87-92
Gruen, R J; Stoker, S; Friedhoff, A J et al. (1999) Effects of repeated amphetamine treatment on regional GABAA receptor binding. Brain Res 825:180-2
Cunningham, K A; Bradberry, C W; Chang, A S et al. (1996) The role of serotonin in the actions of psychostimulants: molecular and pharmacological analyses. Behav Brain Res 73:93-102
Gruen, R J; Wenberg, K; Selim, M et al. (1996) Novelty-associated locomotion: correlation with cortical and sub-cortical GABAA receptor binding. Eur J Pharmacol 309:115-20
Selim, M; Bradberry, C W (1996) Effect of ethanol on extracellular 5-HT and glutamate in the nucleus accumbens and prefrontal cortex: comparison between the Lewis and Fischer 344 rat strains. Brain Res 716:157-64

Showing the most recent 10 out of 15 publications