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.

The widespread molecular and physiological consequences of FSH system activation in normal and pathological conditions are becoming better understood. Progress in this area has been achieved by the development of additional investigative and clinical measures to better evaluate specific adverse effects. More research is needed on FSH function in the development of cancer as well as its association with cardiovascular, metabolic, musculoskeletal, and cognitive effects in ADT.

Cocaine users display profound impairments in executive function. Of all the components of executive function, inhibition, or the ability to withhold responding, has been studied the most extensively and may be most impaired. Consistent with these deficits, evidence from imaging studies points to dysregulation in medial and ventromedial prefrontal cortices, areas activated during performance of inhibition tasks. Other aspects of executive function including updating, shifting and decision making are also deficient in cocaine users, and these deficits are paralleled by abnormalities in patterns of prefrontal cortical activation. The extent to which cocaine plays a role in these effects, however, is not certain, and cannot be determined solely on the basis of human studies. Investigations using a non-human primate model of increasing durations of cocaine exposure revealed that initially the effects of cocaine were restricted to ventromedial and orbital prefrontal cortices, but as exposure was extended the intensity and spatial extent of the effects on functional activity also expanded rostrally and laterally. Given the spatial overlap in prefrontal pathology between human and monkey studies, these longitudinal mapping studies in non-human primates provide a unique window of understanding into the dynamic neural changes that are occurring early in human cocaine abuse.

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Although dysregulation within the dopamine (DA) system is a hallmark feature of chronic cocaine exposure, the question of whether these alterations persist into abstinence remains largely unanswered. Nonhuman primates represent an ideal model in which to assess the effects of abstinence on the DA system following chronic cocaine exposure. In this study, male rhesus monkeys self-administered cocaine (0.3 mg/kg per injection, 30 reinforcers per session) under a fixed-interval 3-min schedule for 100 days followed by either 30 or 90 days abstinence. This duration of cocaine self-administration has been previously shown to decrease DA D2-like receptor densities and increase levels of D1-like receptors and DA transporters (DAT). Responding by control monkeys was maintained by food presentation under an identical protocol and the same abstinence periods. [3H]SCH 23390 binding to DA D1 receptors following 30 days of abstinence was significantly higher in all portions of the striatum, compared to control animals, whereas [3H]raclopride binding to DA D2 receptors was not different between groups. [3H]WIN 35 428 binding to DAT was also significantly higher throughout virtually all portions of the dorsal and ventral striatum following 30 days of abstinence. Following 90 days of abstinence, however, levels of DA D1 receptors and DAT were not different from control values. Although these results indicate that there is eventual recovery of the separate elements of the DA system, they also highlight the dynamic nature of these components during the initial phases of abstinence from chronic cocaine self-administration.

Previous studies utilizing a nonhuman primate model have shown that cocaine self-administration in its initial stages is accompanied by alterations in functional activity largely within the prefrontal cortex and ventral striatum. Continued cocaine exposure may considerably change this response. The purpose of the present investigation was to characterize the effects of reinforcing doses of cocaine on cerebral metabolism in a nonhuman primate model of cocaine self-administration, following an extended history of cocaine exposure, using the quantitative 2-[(14)C]deoxyglucose (2-DG) method. Rhesus monkeys were trained to self-administer 0.03 mg/kg/injection (n = 4) or 0.3 mg/kg/injection (n = 4) cocaine and compared to monkeys trained to respond under an identical schedule of food reinforcement (n = 6). Monkeys received 30 reinforcers per session for a total of 100 sessions. Metabolic mapping was conducted at the end of the final session. After this extended history, cocaine self-administration dose-dependently reduced glucose utilization throughout the striatum and prefrontal cortex similarly to the initial stages of self-administration. However, glucose utilization was also decreased in a dose-independent manner in large portions of the temporal lobe including the amygdala, hippocampus and surrounding neocortex. The recruitment of temporal structures indicates that the pattern of changes in functional activity has undergone significant expansion beyond limbic regions into association areas that mediate higher order cognitive and emotional processing. These data strongly contribute to converging evidence from human studies demonstrating structural and functional abnormalities in temporal and prefrontal areas of cocaine abusers, and suggest that substance abusers may undergo progressive cognitive decline with continued exposure to cocaine.

These data demonstrate that cocaine self-administration alters the noradrenergic system of nonhuman primates. Although cocaine affected NET binding sites in the forebrain projections of both the ventral (VNAB) and dorsal (DNAB) noradrenergic bundles, the alteration in the A1 cell group at the early time-point suggests that the VNAB appears to be more sensitive than the DNAB to the effects of cocaine. Given the role of norepinephrine in arousal and attention, as well as mediating responses to stress, long-term exposure to cocaine is likely to result in significant changes in the way in which information is perceived and processed by the central nervous system of long-term cocaine users.

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