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The objective of this article is to review data from studies that used a reinstatement model in rats to elucidate the neural mechanisms underlying relapse to heroin and cocaine seeking induced by exposure to the self-administered drug (drug priming), conditioned drug cues, and stressors. These factors were reported to contribute to relapse to drug use in humans following prolonged abstinence periods. In the reinstatement model, the ability of acute exposure to drug or nondrug stimuli to reinstate drug seeking is determined following training for drug self-administration and subsequent extinction of the drug-reinforced behavior. We will review studies in which pharmacological agents were injected systemically or intracranially to block (or mimic) reinstatement by drug priming, drug cues, and stressors. We also will review studies in which brain lesions, in vivo microdialysis and electrochemistry, and gene expression methods were used to map brain sites involved in relapse to drug seeking. Subsequently, we will discuss theoretical issues related to the processes underlying relapse to drugs and address methodological issues in studies on reinstatement of drug seeking. Finally, the implications of the findings from the studies reviewed for addiction theories and treatment will be discussed. The main conclusion of this review is that the neuronal mechanisms involved in relapse to heroin and cocaine seeking induced by drug priming, drug cues, and stressors are to a large degree dissociable. The data reviewed also suggest that the neuronal events mediating drug-induced reinstatement are to some degree dissociable from those mediating drug reinforcement.

Using a rat model of drug craving, we found that the responsiveness to cocaine cues progressively increases or incubates over the first 60 d of cocaine withdrawal. Here we studied whether alterations in brain-derived neurotrophic factor (BDNF) protein levels within the mesolimbic dopamine system are associated with this incubation phenomenon. BDNF is involved in synaptic plasticity and was found to enhance responding for cues associated with natural rewards. Rats were trained to press a lever to receive intravenous cocaine or oral sucrose for 6 hr/d for 10 d; each earned reward was paired with a tone-light cue. Resumption of lever-pressing behavior was then assessed on days 1, 30, or 90 of reward withdrawal. First, resistance to extinction was assessed during 6 hr in which lever presses were not reinforced and the cue was absent. Second, cue-induced reinstatement was assessed after extinction during 1 hr in which responding led to cue presentations. Other rats were killed without testing on days 1, 30, and 90 of reward withdrawal, and BDNF and nerve growth factor (NGF) protein levels were measured in the ventral tegmental area (VTA), accumbens, and amygdala. Lever pressing during extinction and cue-induced reinstatement tests of cocaine craving progressively increased after cocaine withdrawal. Time-dependent changes also were observed during the tests for sucrose craving, with maximal responding on day 30. BDNF, but not NGF, levels in the VTA, accumbens, and amygdala progressively increased after cocaine, but not sucrose, withdrawal. Time-dependent increases in BDNF levels may lead to synaptic modifications that underlie enhanced responsiveness to cocaine cues after prolonged withdrawal periods.

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The neural substrates underlying relapse to drug-seeking behavior after chronic drug abuse may differ from those underlying immediate drug-taking behavior. In a model of relapse to drug-seeking behavior following chronic cocaine self-administration and prolonged extinction, we have previously shown that rats will significantly reinstate lever responding for either primary reward (cocaine) or secondary reward (tone + light stimulus previously paired with cocaine). In the present study, we utilized reversible inactivation of discrete brain nuclei with tetrodotoxin (TTX) in order to examine the neural substrates mediating primary and secondary cocaine reward in rats allowed two weeks of cocaine self-administration. After one week of daily extinction sessions, bilateral inactivation of the basolateral amygdala resulted in significant attenuation of lever pressing for a cocaine-conditioned reward (tone + light). Following three more days of extinction, bilateral TTX inactivation of the basolateral amygdala had no effect on the reinstatement of cocaine self-administration. In contrast, TTX inactivation of the nucleus accumbens produced the exact opposite effects, with significant blockade of primary reward (cocaine alone), but not secondary reward (tone + light). Thus, cocaine-conditioned reward is neuroanatomically dissociated from primary cocaine reward.

Results indicate that the withdrawal period is a critical modulator of drug seeking provoked by re-exposure to cocaine cues, but not cocaine itself. Results also indicate that while the incubation of responsiveness to cocaine cues is a long lasting phenomenon, it is not permanent.

These results suggest that conditioned reinstatement of drug-seeking behavior is dependent on amygdalar D1 receptors.

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