Enhanced vulnerability to cocaine self-administration is associated with elevated impulse activity of midbrain dopamine neurons

Individual differences in responding to a novel environment predict behavio ral and neurochemical responses to psychostimulant drugs. Rats with a high locomotor response to a novel environment (HRs) exhibit enhanced self-admin istration (SA) behavior, sensitization, and basal or drug-induced dopamine release in the nucleus accumbens compared with rats with a low response to the novel context (LRs). In this study, we determined whether such differen ces in vulnerability to drug addiction might be related to differences in d opamine (DA) neuron activity. Rats were divided into HRs and LRs according to their response to a novel environment and then tested for acquisition of cocaine SA. HRs rapidly acquired cocaine SA (175 mug/kg per infusion), whe reas LRs did not. Differences in cocaine SA were not caused by differences in exploratory behavior or sampling because these behaviors did not differ in HRs and LRs self-administering a saline solution. In a separate experime nt, we used extracellular single-unit recordings and found that HRs exhibit higher basal firing rates and bursting activity of DA neurons in the ventr al tegmental area and, to a lesser extent, in the substantia nigra pars com pacta. The greater activity of midbrain DA cells in HRs was accompanied by reduced sensitivity to the inhibitory effects of a DA D2-class receptor ago nist, indicating possible subsensitivity of impulse-regulating DA autorecep tors. These results demonstrate that differences in the basal activity of D A neurons may be critically involved in determining individual vulnerabilit y to drugs of abuse.