This objective of this proposal is to characterize the behavioral and neural substrates that determine individual differences in the efficacy of morphine as a reinforcer and vulnerability to opioid-reinforced behavior. The specific hypothesis to be tested is that a significant relationship exists between individual differences in mesolimbic mu-opiate receptor concentration and the efficacy of morphine as a primary reinforcer. The projects outlined in this proposal will utilize genetically engineered animal models with behavior genetic and neuroanatomical techniques to investigate the relationship between regional mu-opiate receptor concentration and morphine-reinforced behavior. Inherited differences in regional mu-opiate receptor concentration (genetically engineered and naturally occurring) will be used as the independent variable to determine if differences in the distribution of mu-opiate receptors within the mesolimbic system significantly affect the efficacy of morphine as a reinforcer. Intravenous morphine self-administration behavior will be investigated in two sets of genetically engineered mice that overexpress the mu-opiate receptor, two commonly used recombinant inbred strains with high and low opiate receptor concentration and the two parental inbred strains used for transgenic animal production. Central mu-opiate receptor distribution in all genotypes will be characterized via autoradiographic techniques. Multivariate analysis of the relationship between mu-opiate receptor concentration in specific neuroanatomical regions and self- administration behavior will determine if a particular region or combination of regions accounts for the genetic variance seen in self- administration behavior. Overall, these projects will directly test the effect of genetically engineered alterations in CNS opiate-receptor concentration on the reinforcing effects of intravenous morphine injections and test the hypothesis that mu-opiate receptor concentration in one or more regions of the mesolimbic system are predictive of genotype-dependent differences in morphine self-administration behavior. if the results of the multivariate analysis identify a region or combination of regions that account for a significant portion of the variance seen in self-administration behavior, these results will provide a significant step towards identifying specific neural regions involved in the neurobiological substrates underlying vulnerability to opioid addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29DA011888-01
Application #
2651934
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Volman, Susan
Project Start
1997-09-30
Project End
2002-08-31
Budget Start
1997-09-30
Budget End
1998-08-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Psychiatry
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Elmer, Greg I; Pieper, Jeanne O; Rubinstein, Marcelo et al. (2002) Failure of intravenous morphine to serve as an effective instrumental reinforcer in dopamine D2 receptor knock-out mice. J Neurosci 22:RC224
Mogil, J S; Wilson, S G; Bon, K et al. (1999) Heritability of nociception II. 'Types' of nociception revealed by genetic correlation analysis. Pain 80:83-93
Mogil, J S; Wilson, S G; Bon, K et al. (1999) Heritability of nociception I: responses of 11 inbred mouse strains on 12 measures of nociception. Pain 80:67-82
Shippenberg, T S; Elmer, G I (1998) The neurobiology of opiate reinforcement. Crit Rev Neurobiol 12:267-303