To examine neuronal activation associated with incentive motivation for cocaine, cocaine-seeking behavior (operant responding without cocaine reinforcement) and Fos expression were examined in rats exposed to saline and cocaine priming injections and/or a self-administration environment. Rats were first trained to self-administer cocaine or received yoked saline administration (“control”). They then received 21 daily exposures to either the self-administration environment (“extinction”) or a different environment (“no extinction”) without cocaine available. Extinction training, used to decrease incentive motivation for cocaine elicited by the self-administration environment, decreased cocaine-seeking behavior elicited by both the environment and the cocaine priming injection. Exposure to the self-administration environment enhanced Fos expression in the no extinction group relative to control and extinction groups in the anterior cingulate, basolateral amygdala, hippocampal CA1 region, dentate gyrus, nucleus accumbens shell and core, and central gray area, regardless of whether or not priming injections were given. The priming injections enhanced Fos expression in the ventral tegmental area, caudate putamen, substantia nigra pars reticulata, entorhinal cortex, central amygdala, lateral amygdala, arcuate nucleus, and central gray area, regardless of group. Thus, these changes likely reflect an unconditioned effect from either cocaine or injection stress. The priming injections also enhanced Fos expression in the anterior cingulate, but only in cocaine-experienced groups, suggesting that this enhancement reflects an experience-dependent motivational effect of the priming injections. The results suggest that different neural circuits may be involved in the incentive motivational effects of cocaine-paired environmental stimuli versus priming injections and that the anterior cingulate may be part of a common pathway for both.

The interaction of drugs with biologic targets is a critical area of research, particularly for the development of medications to treat substance use disorders. In addition to understanding these drug-target interactions, however, there is a need to understand more fully the psychosocial influences that moderate these interactions. The first section of this review introduces some examples from human behavioral pharmacology that illustrate the clinical importance of this research. The second section covers preclinical evidence to characterize some of the key individual differences that alter drug sensitivity and abuse vulnerability, related primarily to differences in response to novelty and impulsivity. Evidence is presented to indicate that critical neuropharmacological mechanisms associated with these individual differences involve integrated neurocircuits underlying stress, reward, and behavioral inhibitory processes. The third section covers social influences on drug abuse vulnerability, including effects experienced during infancy, adolescence, and young adulthood, such as maternal separation, housing conditions, and social interactions (defeat, play, and social rank). Some of the same neurocircuits involved in individual differences also are altered by social influences, although the precise neurochemical and cellular mechanisms involved remain to be elucidated fully. Finally, some speculation is offered about the implications of this research for the prevention and treatment of substance abuse.

Previous research suggests that cocaine dysregulates dopamine D₃ receptors. The present study examined the time course of changes in dopamine D₃ receptor binding after terminating a cocaine self-administration regimen. [¹²⁵I]-7-hydroxy-2-[N-propyl-N-(3′-iodo-2′-propenyl)-amino]-tetralin was used to label dopamine D₃ receptors in rats that had undergone testing for cocaine-seeking behavior reinstated by a cocaine priming injection (15 mg/kg, i.p.; the behavior results have been previously published), and were killed 24 h after the test at time points that were either 2, 8, or 31–32 days after their last cocaine self-administration session. The results indicated a time-dependent increase in D₃ receptor binding relative to controls that received saline yoked to the delivery of cocaine in an experimental animal. Specifically, there was no significant change in D₃ receptor binding in cocaine-experienced rats killed at the 2- or 8-day time points relative to controls, but there was an increase in D₃ receptor binding in the nucleus accumbens core and ventral caudate-putamen in rats killed at the 31- to 32-day time point. In a subsequent experiment, we replicated the increase in D₃ receptor binding in rats that underwent a less extensive self-administration regimen, then were tested for cocaine-primed reinstatement of cocaine-seeking behavior, and then were killed 24 h later at a time point of 22 days after their last self-administration session. Furthermore, the increase in binding was attenuated by repeated 7-hydroxy-N,N-di-n-propyl-2-aminotetralin administration (1 mg/kg/day, s.c. for 14 days), a regimen that also reduces cocaine-seeking behavior in animals when tested in a nondrug state. Collectively, the findings suggest that regulatory responses of D₃ receptors may be functionally related to changes in propensity for cocaine-seeking behavior.