Enhanced Vulnerability to Cocaine Self-Administration Is Associated with Elevated Impulse Activity of Midbrain Dopamine Neurons

Abstract

Individual differences in responding to a novel environment predict behavioral and neurochemical responses to psychostimulant drugs. Rats with a high locomotor response to a novel environment (HRs) exhibit enhanced self-administration (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 differences in vulnerability to drug addiction might be related to differences in dopamine (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 g/kg per infusion), whereas 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 experiment, we used extracellular single-unit recordings and found that HRs exhibit higher basal firing rates and bursting activity of DA neurons in the ventral tegmental area and, to a lesser extent, in the substantia nigra pars compacta. The greater activity of midbrain DA cells in HRs was accompanied by reduced sensitivity to the inhibitory effects of a DA D2-class receptor agonist, indicating possible subsensitivity of impulse-regulating DA autoreceptors. These results demonstrate that differences in the basal activity of DA neurons may be critically involved in determining individual vulnerability to drugs of abuse. Key words: cocaine self-administration; dopamine; electrophysiology; ventral tegmental area; substantia nigra; individual vulnerability; drug addictionThere is considerable individual variation in sensitivity to the reinforcing effects of addictive drugs in both humans and animals (de Wit et al., 1986;O'Brien et al., 1986). For example, the amount and pattern of drug intake vary across individuals; whereas some subjects more easily acquire drug self-administration (SA) and develop drug addiction, others are more resistant. Elucidating the mechanisms responsible for these differences in drug sensitivity may provide important information for understanding determinants of drug addiction.In both humans and animals, the individual propensity to develop drug intake can be predicted by drug-independent behavior, such as the level of motor activity during a stressful situation. In humans, children with heightened motor activity during concentration tasks have greater addiction liability compared with children with lower motor activities (Moss et al., 1992). In rats, high levels of locomotor activity in a novel environment predict greater probability to acquire and maintain psychostimulant SA (Piazza et al., 1989;Deroche et al., 1995;Grimm and See, 1997;Pierre and Vezina, 1997). Locomotor response to a novel context also predicts other behavioral responses to psychostimulants. For example, high responders (HRs) show more locomotor activation in response to p...

Amphetamine-Induced Increases in Extracellular Dopamine, Drug Wanting, and Novelty Seeking A PET/[11C]Raclopride Study in Healthy Men

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Voluntary Nicotine Consumption TriggersIn VivoPotentiation of Cortical Excitatory Drives to Midbrain Dopaminergic Neurons

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