The effects of cocaine: A shifting target over the course of addiction

Abstract

Repeated exposure to psychostimulant drugs such as cocaine has been shown in numerous studies to produce significant neuroadaptations in both structure and function throughout the brain. Nonhuman primate models provide a way to systematically evaluate these adaptations engendered by cocaine self-administration and simulate the progressive nature of cocaine addiction in humans. Functional activity, measured using the 2-[ 14 C]deoxyglucose method, was evaluated at selected critical time points over the course of chronic cocaine self-administration in rhesus monkeys. The effects of cocaine exposure in the initial stages of self-administration resulted in changes in functional activity in a highly restricted network of interconnected brain regions when compared to activity in food-reinforced controls. This pattern of changes was confined mainly to ventromedial prefrontal cortex and ventral striatum. Following chronic exposure to cocaine self-administration, however, the spatial extent and intensity of significant alterations in functional activity expanded considerably. The shift in topography of these changes was orderly, originating ventromedially in the prefrontal cortical-ventral striatal network and expanding dorsally to encompass the dorsal striatum. A strikingly similar progression occurred within the cortical areas that project to each of these striatal regions. Preliminary studies suggest that this pattern is maintained despite periods of abstinence from cocaine. The shifting patterns of cerebral metabolic function that accompany longer durations of cocaine self-administration may underlie many of the characteristics of chronic drug exposure, and may provide transitional mechanisms to more compulsive cocaine use.

Neuroimaging Evidence of Altered Fronto-Cortical and Striatal Function after Prolonged Cocaine Self-Administration in the Rat

“…Likewise, the reduced bCBV in the nucleus accumbens was not unexpected, given the established interconnection between fronto-cortical activity and ventrostriatal DA cell firing and release (Kalivas et al, 2005;Peoples et al, 2007). In keeping with this, recent PET imaging studies showed lower levels of endogenous DA in cocaine addicts relative to comparison subjects (Martinez et al, 2009) and primate research revealed reduced glucose utilization in the striatal areas upon chronic cocaine use, a feature that became more pronounced with increased cocaine exposure (Porrino et al, 2007).…”

Hierarchical recruitment of phasic dopamine signaling in the striatum during the progression of cocaine use

“…The gradual decline in VMS dopamine signaling is somewhat surprising in the context of models postulating that the amount of dopamine release in response to drug cues, specifically in the nucleus accumbens, increases over repeated drug administration as these cues undergo incentive sensitization (9). In contrast, the emergence of phasic dopamine signaling in the DLS provides further empirical support for current theories postulating the engagement of an increasing number of brain regions with prolonged drug use (10)(11)(12)16).…”

“…Drug selfadministration studies in animals have revealed neuroadaptations in functional markers that progress from the VMS to encompass the DLS over the course of drug use (12). To test whether there are complementary changes in phasic dopamine transmission, we carried out longitudinal subsecond dopamine measurements simultaneously in the VMS and DLS during the establishment of drug taking in rats.…”

“…It has been suggested that each of the stages in the series of transitions from goal-directed to habitual and eventually to compulsive responding for drug is associated with specific brain systems that are recruited progressively (10). Indeed, the DLS comes to exert more dominant control over drug seeking during the course of drug use (21,30) as drug taking becomes maintained by drug-associated stimuli (10,12,16). Although we have demonstrated that phasic dopamine release does indeed develop at a later stage of drug use in the DLS than in the VMS, the training regimen used typically is not sufficient to produce compulsive responding or the significant escalation of drug intake that emerges following extended or long-access training in drug self-administration (31,32).…”

“…However, the progression of drug taking beyond recreational use is thought to reflect the engagement of different psychological processes mediated within several neural loci (10,11), with a particular emphasis on the incorporation of the sensorimotor (dorsolateral) striatum (DLS) in the control of established drugseeking behavior (10,12). Specifically, dopamine transmission in the DLS has been linked to habitual CS-elicited reward seeking (13) and therefore may play an important role in the development of habitual and compulsive seeking of drugs (14)(15)(16).…”