No abstract

Drug craving, the desire to experience the effect(s) of a previously experienced psychoactive substance, has been hypothesized to contribute significantly to continued drug use and relapse after a period of abstinence in humans. In more theoretical terms, drug craving can be conceptualized within the framework of incentive motivational theories of behavior and be defined as the incentive motivation to self-administer a psychoactive substance. The incentive-motivational value of drugs is hypothesized to be determined by a continuous interaction between the hedonic rewarding properties of drugs (incentive) and the motivational state of the organism (organismic state). In drug-dependent individuals, the incentive-motivational value of drugs (i.e., drug craving) is greater compared to non-drug-dependent individuals due to the motivational state (i.e., withdrawal) developed with repeated drug administration. In this conceptual framework, animal models of drug craving would reflect two aspects of the incentive motivation to self-administer a psychoactive substance. One aspect would be the unconditioned incentive (reinforcing) value of the drug itself. The other aspect would be relatively independent of the direct (unconditioned) incentive value of the drug itself and could be reflected in the ability of previously neutral stimuli to acquire conditioned incentive properties that could elicit drug-seeking and drug-taking behavior. Animal models of drug craving that permit the investigation of the behavioral and neurobiological components of these two aspects of drug craving are reviewed and evaluated. The models reviewed are the progressive ratio, choice, extinction, conditioned reinforcement and second-order schedule paradigms. These animal models are evaluated according to two criteria that are established herein as necessary and sufficient criteria for the evaluation of animal models of human psychopathology: reliability and predictive validity. The development of animal models of drug craving will have heuristic value and allow a systematic investigation of the neurobiological mechanisms of craving.

Stress and exposure to drug-related environmental stimuli have been implicated as critical factors in relapse to drug use. What has received little attention, however, is the significance of interactions between these factors for motivating drug-seeking behavior. To address this issue, a reinstatement model of relapse was used. Footshock stress and response-contingent presentation of an ethanol-associated light cue, acting as a conditioned stimulus (CS), effectively reinstated extinguished responding at a previously active, drug-paired lever in male Wistar rats. When response-contingent availability of the ethanol CS was preceded by footshock, additive effects of these stimuli on responding were observed. Both the individual and interactive effects of footshock and the CS were significantly greater in previously ethanol-dependent than in nondependent rats. Responding induced by the ethanol CS was selectively reversed by the nonselective opiate antagonist naltrexone, whereas the effects of footshock were selectively reversed by the corticotropin-releasing factor (CRF) antagonist d-Phe-CRF(12-41). However, both agents only partially reversed the enhanced drug-seeking response produced by the interactive effects of stress and the ethanol CS; full reversal required coadministration of d-Phe-CRF and naltrexone. The results document that stress and drug-related environmental stimuli interact to augment the resumption of drug seeking after extinction and suggest that this effect results from concurrent activation of opioid and CRF transmission.

The conditioning of the pharmacological actions of cocaine with environmental stimuli is thought to be a critical factor in the longterm addictive potential of this drug. Cocaine-related stimuli may increase the likelihood of relapse by evoking drug craving, and brain-imaging studies have identified the amygdala and nucleus accumbens (NAcc) as putative neuroanatomical substrates for these effects of cocaine cues. To study the significance of environmental stimuli in the recovery of extinguished cocaine-seeking behavior, male Wistar rats were trained to associate discriminative stimuli (S⌬s) with response-contingent availability of intravenous cocaine vs. saline. The rats then were subjected to repeated extinction sessions during which cocaine, saline, and the respective S⌬s were withheld until the animals reached an extinction criterion of <4 responses over three consecutive sessions. Subsequent re-exposure to the cocaine S⌬, but not the nonreward S⌬, produced strong recovery of responding at the previously active lever in the absence of any further drug availability. The efficacy and behavioral selectivity of the cocaine S⌬ remained unaltered throughout an 8-day test period. Exposure to the cocaine S⌬ significantly increased dopamine efflux in the NAcc and amygdala as measured by intracranial microdialysis in a separate group of rats. Dopamine levels remained unaltered in the presence of the nonreward S⌬. The results demonstrate that cocaine-predictive stimuli elicit robust and persistent cocaine-seeking behavior, and that this effect may involve activation of dopamine transmission in the NAcc and amygdala.T he classical conditioning of the pharmacological actions of cocaine with environmental stimuli is thought to have an important role in the long-term addictive potential of this drug. Environmental cues repeatedly associated with the subjective effects of cocaine can elicit drug craving (1-6) and possibly, automatic behavioral responses (7,8) that may lead to relapse in recovering cocaine addicts. Whereas the role of drug-related stimuli in motivating the resumption of drug use is not fully understood, such learned responses may be among the most important factors responsible for the high rates of relapse associated with cocaine and other drug addiction (9).Consistent with the well-established conditioned reactivity to cocaine cues in humans, classically conditioned behavioral responses to cocaine can be readily elicited in animals (10-14). However, it has been more difficult to demonstrate motivating effects of stimuli conditioned to cocaine in animal models of relapse. Stimuli paired contiguously with cocaine infusions in self-administering rats can reinstate responding following extinction (15-17), but these stimuli often produce only weak and transient effects (16,17), or fail to elicit cocaine-seeking behavior (18,19). The lack of robust and enduring behavioral effects of cocaine cues in many ''reinstatement'' studies appears inconsistent with the presumed strength and persistence of the motivating effe...

The conditioning of cocaine's subjective actions with environmental stimuli may be a critical factor in long-lasting relapse risk associated with cocaine addiction. To study the significance of learning factors in persistent addictive behavior as well as the neurobiological basis of this phenomenon, rats were trained to associate discriminative stimuli (S D ) with the availability of i.v. cocaine vs. nonrewarding saline solution, and then placed on extinction conditions during which the i.v. solutions and S D s were withheld. The effects of reexposure to the S D on the recovery of responding at the previously cocaine-paired lever and on Fos protein expression then were determined in two groups. One group was tested immediately after extinction, whereas rats in the second group were confined to their home cages for an additional 4 months before testing. In both groups, the cocaine S D , but not the non-reward S D , elicited strong recovery of responding and increased Fos immunoreactivity in the basolateral amygdala and medial prefrontal cortex (areas Cg1͞Cg3). The response reinstatement and Fos expression induced by the cocaine S D were both reversed by selective dopamine D1 receptor antagonists. The undiminished efficacy of the cocaine S D to elicit drug-seeking behavior after 4 months of abstinence parallels the long-lasting nature of conditioned cue reactivity and cue-induced cocaine craving in humans, and confirms a significant role of learning factors in the long-lasting addictive potential of cocaine. Moreover, the results implicate D 1-dependent neural mechanisms within the medial prefrontal cortex and basolateral amygdala as substrates for cocaine-seeking behavior elicited by cocaine-predictive environmental stimuli. T he conditioning of cocaine's pharmacological actions with discrete environmental stimuli has been implicated as a major factor in the abuse potential of this drug (1). Both retrospective (2) and controlled laboratory studies (3)(4)(5) show that such stimuli can evoke drug desire that may lead to the resumption of drug use in abstinent individuals. Drug-related stimuli may also elicit automatic responses that lead to drug-seeking behavior and relapse without the intervention of distinct feelings of craving (6, 7). Learned responses to drug-related stimuli, therefore, represent a possibly critical element contributing to the chronic relapsing nature of cocaine and other drug addiction (8, 9).Consistent with a role of learning factors in the initiation of drug-seeking behavior, cocaine-related stimuli can elicit strong recovery of responding at a lever previously associated with i.v. cocaine infusions in animal models of relapse (10, 11). However, little information is available about the perseverance of the motivating actions of such stimuli over prolonged periods of abstinence and the neurobiological substrates mediating these effects. In humans, relapse risk is typically greatest during the first 6 months of abstinence but may persist for substantially longer periods of time (1,8,12). Bette...