Role of ventral medial prefrontal cortex in incubation of cocaine craving
Introduction
Relapse to cocaine use in humans can occur after prolonged abstinence and is often precipitated by exposure to craving-provoking cocaine-associated cues (O'Brien, 2005). In 1986, Gawin and Kleber (1986) hypothesized that cue-induced cocaine craving increases over the first several weeks of abstinence and remains high over extended periods (see (Kosten et al., 2005) for tentative support for this hypothesis in a clinical trial). We and others identified an analogous incubation phenomenon in rats: time-dependent increases in cue-induced cocaine-seeking over the first few months of withdrawal (Grimm et al., 2001, Lu et al., 2004c, Neisewander et al., 2000), a phenomenon we termed incubation of cocaine craving. This incubation was demonstrated in extinction (Hollander and Carelli, 2007, Lee et al., 2006, Lu et al., 2004b, Sorge and Stewart, 2005), cue-induced reinstatement (Grimm et al., 2001, Grimm et al., 2003, Mead et al., 2007), and acquisition of a new response (Di Ciano and Everitt, 2004) procedures. Incubation of reward craving was also demonstrated in rats trained to self-administer heroin (Shalev et al., 2001), methamphetamine (Shepard et al., 2004), alcohol (Bienkowski et al., 2004), sucrose solution (Grimm et al., 2002, Grimm et al., 2005), and food (Youtz, 1938).
We previously explored the role of amygdala extracellular signal-regulated kinases (ERK), a signaling pathway implicated in cocaine's behavioral effects (Girault et al., 2007, Lu et al., 2006) in incubation of cocaine craving (Lu et al., 2005). We found that exposure to cocaine cues in extinction tests increases phosphorylated ERK (p-ERK, a measure of ERK activity) in central amygdala after 30 days but not 1 day of withdrawal from cocaine. After 30 withdrawal days, inhibition of central amygdala p-ERK by U0126 decreased cue-induced cocaine-seeking, while after 1 withdrawal day, stimulation of central amygdala p-ERK by NMDA increased cocaine-seeking, an effect reversed by U0126. These data indicate that in central amygdala, ERK activation rapidly induces changes in synaptic transmission events that acutely control cue-induced cocaine-seeking (Lu et al., 2006).
Here, we assessed whether ERK activity in medial prefrontal cortex (mPFC) plays a role in incubation of cocaine craving. There is evidence from both humans and animal studies that mPFC contributes to cocaine addiction (Jentsch and Taylor, 1999, Kalivas et al., 2005). In both humans (Childress et al., 1999, Maas et al., 1998) and rats (Ciccocioppo et al., 2001, Neisewander et al., 2000), exposure to cocaine cues increases mPFC neuronal activity. In studies using a reinstatement model of drug relapse (Epstein et al., 2006, Stewart and de Wit, 1987, Shaham et al., 2003), acute inactivation of dorsal but not ventral mPFC neurons by tetrodotoxin or GABAa-GABAb receptor agonists (muscimol + baclofen) attenuates cocaine priming-, cocaine cue-, or stress-induced reinstatement of cocaine seeking (Capriles et al., 2003, Fuchs et al., 2005, McFarland and Kalivas, 2001, McLaughlin and See, 2003). Based on these results, and our findings on the role of central amygdala ERK in incubation of cocaine craving (Lu et al., 2005), we hypothesized that dorsal mPFC ERK activity would contribute to this incubation.
However, we found that exposure to cocaine cues in extinction tests increased p-ERK more strongly in ventral than in dorsal mPFC after 30 withdrawal days. Also, acute inhibition of p-ERK by U0126 in dorsal or ventral mPFC had no effect on enhanced responding to cocaine cues after 30 withdrawal days (data not shown) suggesting that acute activation of mPFC ERK does not mediate the incubation of cocaine craving. Therefore, we used local neuronal inactivation (the GABAa + GABAb receptor agonists, muscimol + baclofen) (McFarland and Kalivas, 2001) or activation (the GABAa + GABAb receptor antagonists, bicuculline + saclofen) procedures to further explore mPFC role in incubation of cocaine craving. In these experiments, we continued to use p-ERK as a neuronal activity marker (Thomas and Huganir, 2004) in order to verify the effectiveness (and anatomical specificity) of our pharmacological manipulations that were aimed at inhibiting or activating mPFC neurons. In this regard, results from several studies indicate that ERK activity controls the induction of commonly used neuronal activity markers (e.g. Fos, Zif268) that are induced by cocaine or cocaine cues (Girault et al., 2007, Lu et al., 2006, Mattson et al., 2005, Miller and Marshall, 2005, Valjent et al., 2000).
Section snippets
Subjects and apparatus
Male Long–Evans rats (350–400 g, Charles River) were maintained under a reverse 12-h light–dark cycle. Food and water were available in the rats’ home cage. Procedures followed the guidelines of the “Principles of Laboratory Care” (NIH publication no. 86-23, 1996) and were approved by the local Animal Care Committee. Self-administration chambers were located inside sound-attenuating cabinets and controlled by a Med-Associates system. Each chamber had two levers located 9 cm above the floor.
Results
The rats demonstrated reliable cocaine self-administration and there were no significant differences between rats in Experiments 1–4 (p > 0.05). Mean ± SEM 10-day daily cocaine intake (infusions/6 h) for Experiments 1–4 was 63.7 ± 4.0 (n = 41), 58.0 ± 2.3 (n = 39), 56.2 ± 3.2 (n = 36), and 58.4 ± 2.8 (n = 19), respectively. Eighteen rats were excluded because of misplaced cannulae or suspected neuronal damage near the cannulae; one rat was excluded because of an unusually high number of lever responding on day 1
Discussion
The present results implicate ventral mPFC activity in the incubation of cocaine craving, the progressive increase in cue-induced cocaine-seeking after withdrawal. Exposure to cocaine cues in extinction tests increased ventral mPFC p-ERK immunoreactivity (a neuronal activity marker) after 30 days but not 1 day of withdrawal. Inhibition of ventral mPFC neuronal activity by muscimol + baclofen decreased cue-induced cocaine-seeking after 30 days but not 1 day of withdrawal, while local stimulation of
Concluding remarks
Our data indicate that the ventral but not dorsal mPFC plays a role in the incubation of cocaine craving. The present data are surprising in light of previous studies implicating the dorsal but not ventral mPFC in cue-induced reinstatement of cocaine seeking after extinction of the drug-reinforced responding. Interestingly, recent studies implicate the ventral mPFC in cue-induced relapse to heroin seeking (Rogers et al., 2008, Van den Oever et al., in press), suggesting an important role of
Acknowledgments
Research was supported by the National Institute on Drug Abuse, Intramural Research Program. The authors declare that they do not have any conflicts of interest (financial or otherwise) related to the data presented in this manuscript. We thank Sam Golden for excellent technical support, and Greg Quirk, Devin Mueller, and other members of the Quirk laboratory for their helpful comments on an early version of the manuscript.
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