The primary mission of the Behavioral Pharmacology Unit is to assess the behavioral effects of pharmacological agents, designed by the LMC and other sources, for their efficacies to modify the abuse potential of cocaine. The usual means by which this mission is accomplished is the direct assessment of these agents on drug -seeking behavior of monkeys. A) The primary current effort of the lab is to characterize the effects of GBR 12909HCl and GBR 12935HCl, using cocaine self-administration in monkeys. GBR12909 and GBR12935 decrease cocaine-seeking behavior (up to 100%) at doses that have little or no effect on food-seeking behavior. These effects are further explored by 1) altering the maintenance dose of cocaine while assessing the effects of GBR 12909,2) comparing these effects to other related agents having high affinity for the DA re-uptake site, including LR-1111,DM-69,DM-58, and DM-77, and 3) comparing these effects to other non-chemically related agents having affinity for the DA re-uptake site, including pemoline, buproprion and mazindol. The results show that drug-seeking behavior can be selectively attenuated by high-affinity dopamine reuptake inhibitors, suggesting that such agents may be useful in treating cocaine abuse. However, the results also suggest that other factors (e.g. lipophilicity, bioavailability, etc.) may be important in determining the behavioral effects of these agents. B) A second line of studies furthers the association between stress and drug abuse using genetic rodent models. For example, different rat strains can exhibit large differences in hypothalamic pituitary-adrenal activity that have been used to determine the role of the neuroendocrine system in susceptibility to autoimmune disease, drug abuse and other behavioral end points. To further characterize potential behavioral correlates of these differences, the amplitude of the acoustic (ASR) and tactile (TSR) startle response and the corticosterone response to acoustic startle stimuli were compared between two histocompatible strains, Lewis (LEW/N) and Fischer (F344/N) rats, as well as outbred Harlan Sprague-Dawley (SD) rats. These finding suggested an inverse relationship between the amplitude of the ASR and hypothalamic-pituitary- adrenal activation across strains. This relationship was further supported by high negative correlation between corticosterone level and ASR amplitude within the F344/N group.
