Pathways to relapse: factors controlling the reinitiation of drug seeking after abstinence.

Although considerable knowledge has accumulated over the past 50 years concerning the systems of the brain that support the reinforcing effects of drug of abuse, this knowledge has not been easily translated into effective treatment. The primary problem for treatment of drug abuse remains the reinitiation of drug craving and seeking after abstinence (relapse). It is not understood why, for example, when drugs are unavailable for long periods of time or when users are successful in curbing their own drug use for extended periods, individuals remain vulnerable to relapse. Studies carried out in rats over the last several years have demonstrated clearly that reinitiation of drug seeking can be induced by re-exposure to cues previously associated with drug exposure, by re-exposure to the drug, itself, and by acute exposure to certain stressors. Thus, when rats are trained to self-administer drugs such as cocaine or heroin, and are then subjected to a period of extinction training, the presentation of cues that have been explicitly paired with drug delivery, an experimenter delivered injection of the drug, or acute exposure to footshock stress all result in an increase in pressing on lever previously associated with drug delivery; the amount of responding during the period of extinction and during the test for relapse can be considered to reflect the magnitude of drug seeking or the level of motivation to obtain the drug. Studies carried out in a number of laboratories have provided evidence that the brain systems mediating the effects of conditioned stimuli, priming injections of drugs and stress on the reinitiation of drug seeking are to some degree dissociable (Erb, Shaham, & Stewart, 2001b; McFarland & Kalivas, 2001; Shaham, Erb, & Stewart, 2000a; Shalev, Grimm, & Shaham, 2002; Stewart, 2000). Nonetheless, new evidence is beginning to emerge suggesting that the motivation underlying drug seeking induced by all of these manipulations is influenced by two factors, the duration and intensity of pre-exposure to a drug, and the time since withdrawal of the drug. In this paper I will discuss how these two factors could act to increase the motivation to take drugs that is observed in the experienced drug user even after long periods of abstinence. Before doing this, however, I will review the evidence showing that repeated exposure to some drugs of abuse does induce changes in the circuitry relevant for reinstatement of drug seeking and will discuss possible mechanisms for the induction of these changes. I will then review evidence showing that pre-exposure to stimulant and opioid drugs affects both appetitive and aversive motivational processes.