This project employed pharmacogenetic and neurochemical techniques to evaluate the contribution of genetic and environmental factors to individual differences in response to the chronic administration of drugs of abuse and to drugs proposed for the treatment of drug abuse. We are continuing to examine genetic differences in response to the convulsant and epileptogenic effects of cocaine. Having previously identified genetically distinct strains of mice that differ quantitatively and qualitatively in their response to chronic cocaine, as well as carbamazepine (CBZ), opiates and benzodiazepines, we are now using these models to study the mechanisms underlying the effects of the long-term administration of these drugs. To this end, we have examined neurochemical systems thought to be affected by these drugs. We have examined changes in GABAergic function following chronic treatment with benzodiazepine agonists and inverse agonists, naltrexone or cocaine and observed that there are genotypic differences in the homeostatic regulation of GABAergic function following chronic drug treatment. Characterization of receptor binding parameters for subtypes of opioid receptors in a number of inbred strains has revealed a strong genetic correlation between the number of mu and delta receptors in mouse brain. Studies of the effects of CBZ on cocaine seizures revealed that the efficacy of CBZ for inhibiting cocaine seizures increased with decreasing plasma and brain levels of CBZ suggesting that chronic carbamazepine induces the cytochrome P450-mediated metabolism of cocaine. We also conducted classical Mendelian cross analyses to examine genetic and environmental influences on morphine analgesia and found that genetic and environmental variables were acting to modulate genetic control of the analgesic response to morphine.
