ReviewPrefrontal cortex plasticity mechanisms in drug seeking and relapse
Introduction
Drug addiction is characterized by compulsive drug-taking behavior and high rates of relapse even after many years of abstinence. From a clinical perspective, the enduring vulnerability to relapse is an obvious entry point for effective pharmacotherapeutic intervention (Kalivas and Volkow, 2005, O’Brien, 2003). However, most available treatments are still relatively ineffective, because little information is available on the molecular and cellular underpinnings of relapse. In order to develop pharmaceuticals that reduce relapse susceptibility, it is of crucial importance to gain insight into the neuronal mechanisms underlying the development of a drug addictive state as well as the acute plasticity mechanisms that trigger relapse.
Generally, it is thought that repeated drug intake leads to persistent neuroadaptations that strengthen the desire to obtain the drug and the processing of drug-conditioned stimuli (O’Brien et al., 1986, Robinson and Berridge, 1993, Shaham and Hope, 2005, Thomas et al., 2008). The predominant focus in addiction research has initially been on the role of the mesolimbic dopamine system. The action that most drugs of abuse have in common is to stimulate dopaminergic transmission, either by directly increasing the firing of dopaminergic neurons in the ventral tegmental area (VTA) or by enhancing extracellular dopamine levels in the nucleus accumbens (NA) (Di Chiara and Imperato, 1988, Hyman et al., 2006). This suggests that the mesolimbic dopamine system is a likely substrate for drug-induced neuroadaptations that mediate addiction related behaviors. Indeed, several neuroadaptations have been identified in the NA that provided insight in the effects of acute drug administration and the development of addictive behaviors associated with chronic drug exposure, such as tolerance and dependence (Nestler, 2001, Nestler et al., 2001). For instance, increased expression of cAMP response element binding protein (CREB) in the NA after repeated drug exposure is thought to mediate tolerance and a state of dysphoria during early withdrawal (Barrot et al., 2002, Carlezon et al., 1998). However, the fact that relapse susceptibility persists long after the positive and negative reinforcing effects of the drug have subsided suggests that there might be additional neuronal substrates undergoing long-lasting neuroadaptative changes. During the last decade, cognitive processes that accompany drug self-administration (SA) received more attention, which led to the concept that addiction is a learning and memory disorder that involves mechanisms of neuroplasticity similar to traditional models of learning and memory (Everitt and Wolf, 2002, Hyman, 2005, Jones and Bonci, 2005, Kauer and Malenka, 2007). This view shifted focus to the role of the neocortex and corticofugal glutamate projections in the acquisition of drug SA and the long-lasting propensity to relapse (Kalivas, 2004, Robbins et al., 2008).
Substantial evidence points to the involvement of the mPFC in reinforcement learning and acquisition of drug SA (Tzschentke, 2000). Acquisition of drug SA is associated with altered neuronal activity in the mPFC, as measured by an increase in the expression of Arc (Fumagalli et al., 2009). More specifically, firing of mPFC neurons can be closely time-locked to i.v. injections of cocaine and heroin (Chang et al., 1998) and changes in dopamine levels have been reported in response to food reward (Richardson and Gratton, 1998). In support of a role of dopaminergic transmission, 6-hydroxydopamine lesions of the mPFC enhance cocaine SA by increasing sensitivity to the reinforcing effects of cocaine (Schenk et al., 1991). Moreover, excitotoxic lesions of the mPFC facilitate acquisition of cocaine SA (Weissenborn et al., 1997), which may point to a loss of behavioral inhibition after disruption of mPFC function. Taken together, these studies suggest that the mPFC might be a neuronal substrate for drug-induced neuroadaptations that maintain relapse susceptibility. In support of this, human and animal studies indicate that the mPFC functions as a final relay station in relapse evoked by drugs, stress and drug-conditioned stimuli (Kalivas et al., 2005, Kalivas and Volkow, 2005). Here, we will review the role of the mPFC in relapse to drug seeking in light of novel exciting insights from studies that utilized the rodent drug reinstatement model. Despite recent advances in the understanding of the role of the mPFC in relapse, relatively little is known of the molecular and cellular adaptations that result in altered functioning of mPFC neurons and those maintaining persistent susceptibility to relapse.
Section snippets
Drug craving is associated with altered PFC activity in addicts
It is well established that the PFC is involved in mediating the primary rewarding effects of reinforcing stimuli, including drugs of abuse (Tzschentke, 2000). In addition, human imaging studies have implicated the PFC in feelings of craving and drug seeking elicited by drug-conditioned stimuli during periods of drug abstinence. For instance, a persistent reduction is observed in PFC measures of cellular metabolism and blood flow in psychostimulant and opioid abusers (Botelho et al., 2006,
Preclinical evidence for a role of the mPFC in drug seeking and relapse
Relapse to drug seeking can be modeled successfully in animals. In particular, operant responding for drugs of abuse can be extinguished and subsequently reinstated by acute exposure to the drug itself, stress or conditioned stimuli that were paired with the drug during self-administration (De Vries et al., 2001, Epstein et al., 2006, Shalev et al., 2002). In this model, reinstatement of cocaine- and heroin seeking by all three stimulus modalities can be blocked by reversible pharmacological
Corticostriatal projections
Altered functioning of the mPFC during relapse events reflects maladaptive responding of neurons to information that enters the mPFC and the propagation of information to other brain regions. Studies by Kalivas et al. (2005) strongly support a change in mPFC glutamatergic output to the NA during reinstatement of drug seeking. Anatomically, projections from the mPFC to the NA are organized in a dorsal–ventral pattern, with the dorsal mPFC projecting predominantly to the NA core and the ventral
Long-term drug-induced neuroadaptations in the mPFC-NA pathway
The enduring nature of relapse to drug seeking and the persistent involvement of the mPFC suggest that relapse susceptibility is maintained by long-lived neuroadaptations that alter the responsivity of mPFC neurons to relapse-eliciting stimuli. Unfortunately, persistent drug-induced molecular and cellular changes in the mPFC have not been as well characterized as in the NA, and the majority of studies examined neuroadaptations resulting from cocaine administration only. Moreover, it is not
Acute synaptic plasticity
Apart from long-lasting drug-induced neuroadaptations, relapse is thought to be initiated by acute drug-, stress- or cue-induced changes in synaptic plasticity. In particular, acute changes in glutamatergic transmission in the NA, VTA and amygdala have been implicated in expression of psychomotor sensitization and relapse to drug seeking (Brebner et al., 2005, Jones and Bonci, 2005, Kourrich et al., 2007, Lu et al., 2005), but very little is known about acute mechanisms of synaptic plasticity
Clinical implications and future perspectives
Substantial evidence indicates that glutamatergic output from the dorsal mPFC to the NA core drives reinstatement of drug seeking (Kalivas et al., 2005, LaLumiere and Kalivas, 2008, McFarland et al., 2003). In addition, a growing body of literature suggests that the ventral mPFC suppresses conditioned drug seeking and that reduced functioning of this brain area results in relapse. Hence, whereas the dorsal mPFC output drives relapse, diminished output from the ventral mPFC may contribute to
Acknowledgements
The authors thank Dr. J. Peters for helpful comments on the manuscript. MCVDO is supported by an EMBO Fellowship.
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