Incubation of cocaine craving after withdrawal: a review of preclinical data

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Abstract

Using a rat model of drug craving and relapse, we recently found that cocaine seeking induced by re-exposure to drug-associated cues progressively increases over the first 2 months after withdrawal from cocaine self-administration, suggesting that drug craving incubates over time [Nature 412 (2001) 141]. Here, we summarize data from studies that further characterized this incubation phenomenon and briefly discuss its implications for drug addiction. The main findings of our ongoing research are:

  • 1.

    Incubation of cocaine craving is long-lasting, but not permanent: cocaine seeking induced by exposure to cocaine cues remains elevated for up to 3 months of withdrawal, but decreases after 6 months.

  • 2.

    Incubation of reward craving is not drug specific: sucrose seeking induced by re-exposure to the reward cues also increases after withdrawal, but for a time period that is shorter than that of cocaine.

  • 3.

    Incubation of cocaine craving is not evident after acute re-exposure to cocaine itself: cocaine seeking induced by cocaine priming injections remains essentially unchanged over the first 6 months of withdrawal.

  • 4.

    Incubation of cocaine craving after withdrawal is associated with increases in the levels of brain-derived neurotrophic factor (BDNF) in mesolimbic dopamine areas.

Introduction

Relapse to cocaine use is the major clinical problem in the treatment of cocaine addiction (Mendelson and Mello, 1996, O’Brien, 1997). This relapse can occur after prolonged withdrawal periods and is often precipitated by re-exposure to cues previously associated with cocaine use that provoke craving, a poorly understood subjective state that precedes and accompanies cocaine seeking (O’Brien et al., 1992). In an attempt to account for this persistent relapse, Gawin and Kleber (1986) suggested that craving induced by cocaine cues progressively increases over the first several weeks of withdrawal and remains high over extended drug-free periods. However, empirical data demonstrating time-dependent increases of cocaine craving and relapse in humans do not exist.

Until recently, the impact of the drug withdrawal period on drug seeking induced by cocaine cues was not systematically examined in preclinical models of drug relapse and craving (Shalev et al., 2002, Shaham et al., 2003). In an initial study in rats, Tran-Nguyen et al. (1998) reported that extinction responding, a behavior induced by re-exposure to the reward-associated cues (Catania, 1992), is somewhat (non-significantly) elevated after 1 month or 1 week than after 1 day of withdrawal from cocaine. In a subsequent study, Neisewander et al. (2000) found that extinction responding is significantly higher after 3 weeks than after 1 day of withdrawal from cocaine. In a study from our laboratory with heroin-trained rats, Shalev et al. (2001) found that extinction responding follows an inverted U-shaped curve, with higher responding after 6, 12 or 25 days than after 1 or 66 days of withdrawal from heroin. Shalev et al. also found that the effect of intermittent footshock stress on reinstatement of heroin seeking (Shaham and Stewart, 1995, Shaham et al., 2000) followed a similar inverted U-shaped curve after withdrawal.

Based on these previous findings, we assessed drug seeking induced by re-exposure to cocaine cues after withdrawal from cocaine in two ways (Grimm et al., 2001). First, we determined non-reinforced lever pressing in extinction tests in the presence of a houselight and other contextual cues that had indicated drug availability during training, but in the absence of a discrete tone–light cue that had been paired with the drug injections during training. Second, we determined cue-induced reinstatement of cocaine seeking (See, 2002) in a test wherein lever presses led to contingent presentations of the tone–light cue, which served as a conditioned reinforcer during testing (Robbins, 1975). We found profound time-dependent increases of lever responding induced by re-exposure to the cocaine cues in the two tests, with significantly higher responding after 1–2 months than after 1–7 days of withdrawal from cocaine (Grimm et al., 2001) (Fig. 1). Based on these data, we concluded that craving (a motivational state elicited by exposure to drug-associated cues that often precedes and accompanies drug seeking) incubates after withdrawal from cocaine self-administration.

Here, we summarize data from ongoing studies in rats that further characterize this novel incubation phenomenon at the behavioral, neuroanatomical, and molecular levels. We also discuss the potential implications of this phenomenon for drug addiction and treatment. In the studies described below we assessed:

  • 1.

    Drug seeking induced by re-exposure to cocaine cues over withdrawal periods of up to 6 months after drug self-administration.

  • 2.

    The generality of the incubation phenomenon to another psychostimulant (methamphetamine) and a non-drug (sucrose) reinforcer.

  • 3.

    Whether cocaine seeking induced by re-exposure to cocaine itself, as measured in a test for drug priming-induced reinstatement (de Wit and Stewart, 1981, Stewart, 2000), follows the time course of cocaine seeking induced by re-exposure to cocaine cues after withdrawal.

  • 4.

    The time course of protein expression and activity of candidate molecular neuroadaptations (Nestler, 2001, Wolf, 2003, Kalivas, 2004) within components of the mesolimbic dopamine reward system (Wise, 2002) over the first 3 months of withdrawal from cocaine. These include enzyme activities of cAMP-dependent protein kinase (PKA) and adenylate cyclase (AC), and protein expression of cyclin-dependent kinase 5 (cdk5), tyrosine hydroxylase (TH), dopamine transporter (DAT), glutamate receptor subunits (GluR1, GluR2, and NMDAR1), and brain-derived neurotrophic factor (BDNF).

Section snippets

Overview

In our studies, rats were trained for 10 days to self-administer intravenous cocaine (0.5–1.0 mg/kg/infusion) or 10% oral sucrose (0.2–0.4 ml/reward delivery) under a fixed-ratio-1 schedule of reinforcement (40 s timeout); each reward delivery was paired with a 5 s compound tone–light cue. For most studies, the training sessions were for 6 h/day. During training, responding on one (active) lever led to reward delivery, while pressing on a second (inactive) lever was not reinforced. During the

Molecular and neuroanatomical studies

The main question from the above behavioral studies is concerned with the neuronal mechanisms underlying the incubation of cocaine craving after withdrawal. Below, we describe our initial studies aimed at identifying molecular alterations associated with this incubation. These studies were inspired by the “neuroadaptation hypothesis” that argues that cocaine exposure causes long-lasting molecular alterations within the mesocorticolimbic dopamine reward system, which underlie cocaine addiction

Discussion

The main finding from our studies is that incubation of reward craving after withdrawal is a general phenomenon that is not specific for drugs as reinforcers. Another main finding is that the incubation of cocaine craving after withdrawal is not manifested after re-exposure to the drug itself: cocaine priming-induced reinstatement of lever responding remains essentially unchanged over extended withdrawal periods of up to 6 months. Our molecular and neuroanatomical studies revealed long-lasting

Acknowledgments

We thank Drs. Roy Wise, Jane Stewart and David Epstein for helpful comments and discussions, and Shirley Liu, Kelly Badger, Jack Dempsey and Polly Robarts for technical assistance in collecting some of the data presented in this paper.

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