The present study demonstrates that extended access to cocaine self-administration induces an escalated pattern of cocaine intake associated with an impairment of working memory and a decrease in the density of dmPFC neurons that lasts for months after cocaine cessation. LgA and ShA rats exhibited a high percentage of correct responses in the delayed nonmatching-to-sample task under low cognitive demand (delay <10 s). LgA and ShA rats refrained from visiting the previously reinforced arm and chose the opposite arm to obtain a reward, demonstrating apparently intact executive control function. However, increasing the working memory load (ie close to the capacity limit of working memory), by increasing the delay from 10 to 70 and 130 s, revealed a robust working memory deficit in LgA rats. Furthermore, the magnitude of escalation of cocaine intake was negatively correlated with working memory performance in ShA and LgA rats with the 70 and 130 s delays, but not with the 10 s delay or with baseline performance during training, demonstrating that the relationship between escalation of cocaine intake and behavioral performance in this task was restricted to working memory performance under high cognitive demand.
Moreover, when tested under a low-incentive condition (ie using novelty instead of highly palatable food as a reinforcer), no difference was observed between LgA, ShA, and naive rats, suggesting that high incentive and high cognitive demand are required to reveal working memory impairments in LgA rats. Also, the working memory impairments observed in LgA rats cannot be explained by use of a different navigational strategy used to solve the task (egocentric vs allocentric). Behavioral performance after rotation of the T-maze demonstrated that all three groups used an allocentric strategy to solve the task. Thus, extended access to cocaine self-administration induced long-lasting impairments of working memory under high cognitive demand and high-incentive conditions that can be predicted by the increase in cocaine intake.
The cognitive dysfunctions observed in LgA rats under a high, but not low, incentive condition, and in humans with cocaine addiction (Hester and Garavan, 2004
), may result from an imbalance between a hypoactive cognitive system that controls decision-making under a high cognitive demand situation and an overactive incentive salience system (Bechara, 2005
). The working memory impairment in this task also may be explained by an increase of perseveration or compulsion, a prominent feature of prefrontal cortex lesions (Brush et al, 1961
; Mishkin, 1964
; Pribram, 1961
The density of neurons and oligodendrocytes in the dmPFC was positively correlated with working memory performance. The lower the density of neurons or oligodendrocytes in the dmPFC, the more severe the working memory impairment. Working memory also was correlated with the density of oligodendrocytes in the OFC, suggesting that OFC alteration after escalated drug intake may play a role in working memory deficits. However, no correlation was found between working memory performance and neuronal density in the OFC, suggesting that OFC neurons may be less vulnerable to the deleterious effects of chronic cocaine exposure than dmPFC neurons. Finally, it is unlikely that the decrease of neurons and oligodendrocytes in the prefrontal cortex resulted from a global decrease of prefrontal cortex volume. The density of astrocytes in the dmPFC and OFC was similar in the three groups and was not correlated with working memory performance.
The correlations between working memory and density of neurons and oligodendrocytes in the dmPFC confirm reports showing that lesions of the dmPFC affect performance in the delayed nonmatching-to-sample task, particularly when longer delays are used to increase working memory load (Aggleton et al, 1995
; Walton et al, 2003
). The role of the OFC in the delayed nonmatching-to-sample task has been less studied and definitive conclusions cannot be drawn, but our results show that the density of oligodendrocytes in the OFC was correlated with working memory performance, suggesting that the OFC also may be involved in this task.
Considering that cocaine withdrawal is associated with low dopaminergic tone in the dmPFC (Sorg et al, 1997
; Williams and Steketee, 2005
), and that low dopaminergic tone in the dmPFC induces working memory impairments in this task (Mizoguchi et al, 2000
; Simon et al, 1980
), it is likely that the working memory impairments observed in LgA rats resulted from both decreased dopaminergic tone and a decreased number of neurons/oligodendrocytes in the dmPFC. Similar neural changes may be responsible for the cognitive impairments observed in humans with drug addiction (Goldstein and Volkow, 2002
; Pfefferbaum et al, 1998
; Bechara, 2005
; Franklin et al, 2002
; Jentsch and Taylor, 1999
; Rogers and Robbins, 2001
There is accumulating evidence that repeated passive exposure to psychostimulants leads to deficits in tasks that depend on intact prefrontal cortex function (Fletcher et al, 2005
; Roesch et al, 2007
; Schoenbaum et al, 2004
; Schoenbaum and Setlow, 2005
). Moreover, withdrawal from repeated passive cocaine or amphetamine treatments also decreases firing rate and bursting activity of dmPFC neurons (Nogueira et al, 2006
; Homayoun and Moghaddam, 2007
) and abolishes dopamine D2
receptor-mediated regulation of dmPFC excitability (Nogueira et al, 2006
) and membrane bistability of dmPFC neurons (Trantham et al, 2002
). These reports suggest that chronic cocaine self-administration, even with limited access, may impair behavioral performance in prefrontal cortex-dependent tasks. Surprisingly, we did not find any working memory impairments in ShA rats, suggesting that the prefrontal cortex dysfunctions observed in previous studies after passive administration of cocaine may not adequately model the neuroadaptations occurring during chronic self-administration, and that alterations of prefrontal cortex function after cocaine use are not inevitable but may be observed only when subjects exhibit the increased drug intake associated with extended access.
Cognitive dysfunctions observed in humans with drug addiction may also result from preexisting abnormalities of the prefrontal cortex. Indeed, extended access to cocaine self-administration in rats does not induce long-lasting impairments of cognitive function known to depend on the prefrontal cortex, such as response inhibition and sustained attention (Dalley et al, 2005
), whereas trait impulsivity precedes the onset of drug use and facilitates the progression to drug addiction (Dalley et al, 2007
). However, our results demonstrate that independent of any premorbid condition (because rats were randomly assigned to the three groups), extended access to cocaine self-administration by itself may cause severe working memory impairments associated with prefrontal cortex damage, suggesting that a significant contribution to prefrontal cortex dysfunction also may be a consequence of chronic drug use.
In summary, this study demonstrates that extended access to cocaine self-administration induced an escalated pattern of cocaine intake associated with long-lasting damage to the prefrontal cortex. Considering the role of the prefrontal cortex in goal-directed behavior, particularly with regard to mediating delays in reinforcement, prefrontal cortex dysfunction may decrease the ability to self-regulate (reflecting a loss of control), thus contributing to the compulsive nature of the addiction process, and reflect-—and possibly be responsible for—the transition from drug use to drug dependence.