The long-term goal of this research is a better understanding of neurobehavioral factors determining the addictive liabilities of drugs (stimulants and opiates). A major focus is the determination of neuroanatomical site(s) and mode(s) of drug action(s) with particular reference to differential involvement of the two sides of the brain. The methodology uses rats and involves relating a behavioral index (rotation or circling behavior) of asymmetry motor activity and brain chemistry. Neurochemical effect of drugs and neurochemical correlates of behavior are determined by using in vivo microdialysis to obtain prefusates of discrete brain regions; extracellular levels of biogenic amines (dopamine, norepinephrine, serotonin) and their metabolites are then measured by HPLC. Specific experimental problems include the following: (1) Mechanisms that characterize and differentiate drug classes (i.e., opiates vs. stimulants) as well as different drugs of the same class (e.g., cocaine vs. d- amphetamine) will continue to be investigated with respect to their bilateral effects on dopamine release in several brain regions; the effects of repeated drug administration, with respect to mechanisms of sensitization and tolerance, will also be studied. (2) Relationship of individual differences in brain lateralization to behavioral differences in sensitivity to opiates (e.g., morphine, meperidine) and stimulants (e.g., d-amphetamine, cocaine) will be further characterized; the hypothesis that changes in drug responsiveness will occur as a result of altering temporal relationship between drug self-administration and dopamine release in brain will be directly analyzed using in vivo microdialysis; an important goal will be to distinguish which neurochemical events precede or elicit drug seeking behavior and which neurochemical events are the result or consequence of drug intake. These studies should provide basic information on mechanisms of drug actions as well as an animal model for understanding interindividual differences in drug preferences and patterns of abuse among humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA003817-08
Application #
2116837
Study Section
Special Emphasis Panel (SRCD (31))
Program Officer
Acri, Jane
Project Start
1984-07-01
Project End
1994-09-29
Budget Start
1992-04-01
Budget End
1994-09-29
Support Year
8
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Albany Medical College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Albany
State
NY
Country
United States
Zip Code
12208
Shoblock, James R; Maisonneuve, Isabelle M; Glick, Stanley D (2004) Differential interactions of desipramine with amphetamine and methamphetamine: evidence that amphetamine releases dopamine from noradrenergic neurons in the medial prefrontal cortex. Neurochem Res 29:1437-42
Pace, Christopher J; Glick, Stanley D; Maisonneuve, Isabelle M et al. (2004) Novel iboga alkaloid congeners block nicotinic receptors and reduce drug self-administration. Eur J Pharmacol 492:159-67
Kuehne, Martin E; He, Liwen; Jokiel, Patrick A et al. (2003) Synthesis and biological evaluation of 18-methoxycoronaridine congeners. Potential antiaddiction agents. J Med Chem 46:2716-30
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Steinmiller, Caren L; Maisonneuve, Isabelle M; Glick, Stanley D (2003) Effects of dextromethorphan on dopamine release in the nucleus accumbens: Interactions with morphine. Pharmacol Biochem Behav 74:803-10
Shoblock, James R; Sullivan, Eric B; Maisonneuve, Isabelle M et al. (2003) Neurochemical and behavioral differences between d-methamphetamine and d-amphetamine in rats. Psychopharmacology (Berl) 165:359-69
Shoblock, James R; Maisonneuve, Isabelle M; Glick, Stanley D (2003) Differences between d-methamphetamine and d-amphetamine in rats: working memory, tolerance, and extinction. Psychopharmacology (Berl) 170:150-6
Zhang, Wenjiang; Ramamoorthy, Yamini; Tyndale, Rachel F et al. (2003) Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes p450 in vitro. Drug Metab Dispos 31:768-72
Glick, Stanley D; Maisonneuve, Isabelle M; Kitchen, Barbara A et al. (2002) Antagonism of alpha 3 beta 4 nicotinic receptors as a strategy to reduce opioid and stimulant self-administration. Eur J Pharmacol 438:99-105
Zhang, Wenjiang; Ramamoorthy, Yamini; Tyndale, Rachel F et al. (2002) Metabolism of 18-methoxycoronaridine, an ibogaine analog, to 18-hydroxycoronaridine by genetically variable CYP2C19. Drug Metab Dispos 30:663-9

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