The purpose of the current research has been to develop a series of complementary projects using a behavior genetics approach to investigate pharmacological and behavioral factors important in drug abuse. Genetic factors involved in the acute, chronic and reinforcing effects of opioids have been investigated. This effort provides data important for testing pharmacological mechanisms thought to be important in the drug effect. For example, large differences in the potency versus efficacy of morphine-induced analgesia were found to vary independently as a function of genotype. In vivo methods for determining agonist effective receptor reserve, agonist affinity and stimulus-response relationships indicate that receptor reserve and modulation of mu-opioid effects by delta- mechanisms are responsible, in part, for genetic differences in potency and therapeutic efficacy, respectively. In addition, innate nociception as determined by stimulus-effect curves significantly influences the potency of opioid-induced analgesia. The results of these types of studies demonstrate genotype and the use of classic receptor theory to be mutually beneficial for investigating pharmacological constructs important in the behavioral effects of a drug and will be applied to more complex measures of drug effect such as drug-reinforced behavior. To this end, genetic and environmental aspects of vulnerability to drug self-administration behavior have been determined in four inbred rat strains. Genetic factors that influence vulnerability are moderately related to innate locomotor behavior and significantly influenced by environmental events in a genotype-dependent manner. Additionally, genetic variations in extinction patterns enable further investigation of multiple aspects of the addiction process. Environmental conditioning studies demonstrate genotype to be an important factor in conditioned drug-like effects and may play a role in drug-seeking behavior. Genotype by environment interactions thought to be important in the complex behavioral effects of a drug have been investigated in tolerance and sensitization paradigms and are designed to complement self- administration studies using unique inbred mouse strains.
