In contrast to the limited effects of initial cocaine self-administration, following 100 days of chronic cocaine self-administration, the topography and intensity of significant reductions in functional activity expanded considerably. Instead of the highly restricted pattern of functional brain changes observed early in the course of drug exposure, after continued exposure to self-administration over several months cocaine produced widespread alterations in functional activity. This expansion of effects included structures not previously impacted by cocaine including the amygdala, hippocampus, temporal and parietal cortex, as well as areas previously affected by cocaine at the earlier time point, including the striatum and prefrontal cortex (Porrino et al., 2004
; Beveridge et al., 2006
In the case of the prefrontal cortex, there was considerable overlap in the patterns of changes in functional activity when comparing the initial and chronic stages of cocaine self-administration. This was particularly evident along regions of the medial wall of the prefrontal cortex (areas 24, 14, 32 and 25). Although the spatial extent of the changes in these regions was similar, the longer histories of cocaine exposure resulted in effects of greater magnitude. Furthermore, the response to cocaine broadened across the orbital surface to include not only area 13, which had been impacted by 5 days of self-administration, but also area 11 and some of area 12. This shift can be seen in by comparing the upper panel which depicts the changes in cerebral metabolism in the initial phases of self-administration to the lower panel which depicts the changes after longer exposure periods. Finally, with more prolonged cocaine self-administration experience the reductions tended to spread more rostrally to encompass area 10 of the frontal pole. It appears, then, that the effects of cocaine in prefrontal cortex may continue to grow in both magnitude and spatial extent with repeated exposure, suggesting a larger influence of cocaine in areas mediating the processing of reward-related and emotional stimuli, as well as an expansion into areas involved in higher order cognitive processing.
A similar picture emerged in the striatum. Rates of metabolism in the ventral striatum core and shell were significantly decreased at all pre-commissural levels following chronic exposure. This can be seen in the lower panel of . However, in the dorsal striatum, the pattern of changes in functional activity was considerably different. In contrast to the initial phases of self-administration, where reductions in cerebral metabolism were confined to the more ventromedial portions of the caudate and putamen just rostral to the anterior commissure (see ), with extended experience cerebral metabolism was reduced throughout both caudate and putamen rostral to the anterior commissure even in their most anterior aspects. In addition, the decreases extended into the post-commissural striatum ( and upper panel). Clearly then, the impact of cocaine on rates of cerebral metabolism in the striatum expand dramatically with increased exposure to cocaine. This suggests that the impact of cocaine impinges progressively into areas of the striatum involved in the processing of cognitive and sensorimotor information as cocaine use continues.
This shift in the pattern of alterations in glucose utilization as a result of chronic exposure is also consistent with reports of adaptations in dopamine and opioid systems. Prolonged self-administration results in an upregulation in these monkeys of dopamine transporter binding sites (Letchworth et al., 2001
) and preprodynorphin mRNA (Fagergren et al., 2003
), as well as downregulation of D2
receptors (Moore et al., 1998
; Nader et al., 2002
). The pattern of these adaptations followed an identical progression from ventral to dorsal striatum, as well as an expansion to more rostral and caudal portions of the striatum with increasing durations of cocaine self-administration history. Again, taken together, it is clear that adaptations associated with cocaine exposure continue to expand over time and are likely to involve more and more of the behavioral repertoire.
Recently, hypotheses concerning the development of addiction have centered on the progressively habitual or compulsive nature of drug use, with the concept that control over drug use evolves from action to habit (Berke and Hyman, 2000
; Everitt and Wolf, 2002
). More specifically, it is thought that a shift in control from ventral to dorsal striatal domains is in part responsible for the progression from voluntary drug use to more habitual and compulsive use (Everitt and Robbins, 2005
). Our data concerning the expanding effects of cocaine with progressively longer durations of self-administration experience provide a neurobiological framework for these behavioral and cognitive concepts. In particular the expansion of cocaine’s effects in the functional domains of the striatum moving from primarily motivational, ventral limbic areas to more dorsal habit-related regions perhaps provides an anatomical basis for the behavioral shift that may occur in human addicts.