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Review
. 2007 Nov 15;31(8):1593-600.
doi: 10.1016/j.pnpbp.2007.08.040. Epub 2007 Sep 4.

The effects of cocaine: a shifting _target over the course of addiction

Linda J Porrino  1 , Hilary R Smith, Michael A Nader, Thomas J R Beveridge
Affiliations
Review

The effects of cocaine: a shifting _target over the course of addiction

Linda J Porrino et al. Prog Neuropsychopharmacol Biol Psychiatry. .

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-[14C]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.

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Figures

Figure 1
Figure 1
Areas of cerebral metabolic response produced by self-administered cocaine in the prefrontal cortex of rhesus monkey. Shown are representative autoradiograms of 2-[14C]deoxyglucose uptake in coronal sections through rostral to caudal levels of prefrontal cortex (+ 15.30, + 9.5 and + 4.5 from bregma; Paxinos et al., 2000). Top panel shows the effects of initial (5 days) cocaine self-administration, bottom panel shows the effects of chronic (100 days) cocaine self-administration. Blue coloring superimposed upon the grayscale autoradiograms represents the location of significant decreases in rates of glucose utilization (note that effects were bilateral, however in the interest of simplicity the effects are depicted on one hemisphere). Numbered labels are from Brodmann’s definitions of cortical areas.
Figure 2
Figure 2
Areas of cerebral metabolic response produced by self-administered cocaine in the striatum of rhesus monkey. Shown are representative autoradiograms of 2-[14C]deoxyglucose uptake in coronal sections of rostral and caudal pre-commissural and post-commissural striatum (+ 4.50, - 0.45 and - 9.0 from bregma respectively; Paxinos et al., 2000). Top panel are effects of initial (5 days) cocaine self-administration, bottom panel are effects of chronic (100 days) cocaine self-administration. The vertical line represents the level of the anterior commissure. Blue coloring superimposed upon the grayscale autoradiograms represents the location of significant decreases in rates of glucose utilization (note that effects were bilateral, however in the interest of simplicity the effects are depicted on one hemisphere). Caud, caudate; Put, putamen; NAc, rostral nucleus accumbens; NAcC, nucleus accumbens core; NAcS, nucleus accumbens shell.
Figure 3
Figure 3
The effects of cocaine self-administration on rates of local cerebral glucose utilization across the anterior-posterior extent of the dorsal (upper panel) and ventral (lower panel) striatum of rhesus monkey. Rates of glucose utilization of monkeys in the initial (5 day), chronic (100 day) and abstinent (100 day self-administration with 30 days abstinence) stages of self-administration are compared with rates of glucose utilization of control monkeys in which responding was maintained by food under identical schedules of reinforcement. The vertical line in each panel represents the level of the anterior commissure.
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