Important questions, then, are how functional activity within the prefrontal cortex has changed over the course of cocaine exposure, and how such changes might account for the cognitive impairments associated with cocaine use in human substance-abusing populations.
To address this question, we have used the 2-[14C]deoxyglucose method to map the changes in cerebral metabolism after increasing durations of cocaine exposure. By assessing these changes in metabolism following the final infusion of cocaine at the end of a self-administration session, we are effectively measuring the response of the brain to a cocaine challenge in animals with different drug histories. Using this approach, we have been able to characterize alterations in the pattern and intensity of the changes in functional activity in the prefrontal cortex after increasing the durations of cocaine self-administration experience: (i) initial exposure, designed to model the initial phases of drug exposure, when cocaine use is still considered casual or recreational (5 days of cocaine self-administration), (ii) chronic exposure, designed to model the effects of repeated cocaine self-administration (3.3 months of self-administration), and (iii) prolonged exposure, designed to more closely model investigations of human addicts in which the minimum inclusion criterion is typically at least 1 year of heavy use, and actual duration of use is frequently much longer (1.2 years of cocaine self-administration). We have recently undertaken a detailed re-analysis of the effects of cocaine on functional activity in the prefrontal cortex in order to map more carefully the topography of the initial effects and any potential shifts in this topography with continued exposure.
In the initial stages of drug exposure, cocaine produced a highly restricted pattern of changes in functional activity throughout the brain. Within the prefrontal cortex, significant decreases in cerebral metabolism were focused along the more caudal sectors of the medial wall in the gyrus rectus (area 14), cingulate areas 24 and 25 and caudal portions of area 32 (a
(ii)(iii)). These regions that have been shown to be involved in visceromotor functioning, providing cortical influence over autonomic and endocrine function (Price 1999
). Decreases were also found in anterior insula cortex (area Ia), areas believed to be responsible for associations between taste and smell, specifically linking olfactory and gustatory cues to reward (Rolls 1996
). These decreases were accompanied by increases in dorsomedial and dorsolateral portions of the prefrontal cortex (areas 45, 46 and 9). In primates as in humans, these regions are essential for working memory function (Baddeley 1986
; Fuster 1997
). These effects may result from a continuing representation of the drug-associated environment that persists beyond the end of the session. This continued activation at a time when access to cocaine has ceased may constitute the basis for the formation of memories for cues that can elicit cravings, even in abstinence. Thus, it appears that even in the initial stages of drug experience, cocaine may influence higher order processing of converging sensory and visceral information, as well as the formation of associations between various stimuli with the presence of reward.
After chronic self-administration, however, adaptations to repeated cocaine exposure became evident. In these studies, monkeys had total intakes of over 900
of cocaine over more than a three-month period. In contrast to the rather restricted pattern of changes in cerebral metabolism in the initial stages of exposure, the pattern after repeated exposure shifted to encompass larger expanses of the prefrontal cortex. In addition, the magnitude of the changes was more intense than in the earlier stages of cocaine experience. Although there was considerable overlap when comparing the initial and chronic stages along the medial wall of the prefrontal cortex (areas 14, 24, 25 and 32), the decreases extended further rostrally into more anterior portions of the cingulate cortex (b
(i)). Furthermore, functional activity was altered in areas not seen previously, in the orbitofrontal cortex (area 13), as well as in the caudal portions of area 12 (b
(ii)(iii)). These are areas that are critical for the processing of reward value and salience (Schultz et al. 2000
; Tremblay & Schultz 2000
). Another important difference at this time point was the absence of any increases in cerebral metabolism. In fact, metabolism was decreased in some portions of the dorsal prefrontal regions, suggesting that significant adaptations may be occurring within the dorsolateral prefrontal cortex as a result of the more chronic drug exposure.
Studies of the changes in functional activity associated with cocaine self-administration exposure have recently been extended to include protracted periods of cocaine exposure. The goal of these studies was to include durations of exposure more consistent with most investigations of human addicts where subjects report extended periods of heavy use. In these studies, animals self-administered high doses of cocaine for a minimum of 300 sessions, receiving on average 2700
cocaine total intake. Although these data are still preliminary, glucose metabolism in the prolonged cocaine exposure group was significantly decreased in the medial and orbital regions of the prefrontal cortex, in a pattern very similar to that observed following chronic cocaine exposure (c
(ii)(iii)). The overlap in terms of spatial extent between the two groups was striking. The only difference was an extension of functional changes into more rostral ventromedial and orbital cortices (areas 10, 11 and 12 (c
(i))). Furthermore, there was very little change in the magnitude of the effects despite the much longer cocaine histories.