Incentive motivation, craving, and relapse
Conditioning of the rewarding effects of ethanol and other drugs of abuse with discrete stimuli is a major factor in abuse potential. Drug-related stimuli evoke drug desire that can lead to resumption of addictive behavior in abstinent individuals (O'Brien et al., 1998). Such stimuli may also elicit automatic responses that lead to drug-seeking and relapse without distinct feelings of craving. Thus, learned responses to drug-related stimuli may be a critical element in the chronic relapsing nature of ethanol and other drug addiction.
In animals, ethanol-associated contextual stimuli (Katner and Weiss, 1999; Ciccocioppo et al., 2001) consistently elicit recovery of responding at a previously ethanol-paired lever after extinction in the absence of further drug availability. Research using reinstatement procedures points to both DA and opioid systems in the motivating effects of ethanol-associated environmental stimuli. In rats, exposure to environments associated with ethanol availability increase extracellular NAc DA levels (Weiss et al., 1993; Gonzales and Weiss, 1998), and alcohol-associated stimuli activate the ventral striatum in abstinent alcoholics (Braus et al., 2001), suggesting that mesolimbic DA transmission may have an important function in mediating behavior that brings the animal into contact with reinforcers. Such a role of DA may be relevant for the initiation of ethanol-seeking by alcohol cues and, by extension, ethanol craving and relapse. Indeed, appetitively motivated behavior preceding delivery of an ethanol solution is more sensitive to reversal by DA D2 receptor antagonists than behavior maintained by ethanol itself (Czachowski et al., 2001). Similarly, the conditioned reinforcing effects of a discrete stimulus previously paired with ethanol-reinforced responses are reversed by the DA receptor antagonist haloperidol (Wilson et al., 2000). A role of DA in relapse associated with exposure to alcohol cues has also been proposed. In rats tested for the response-reinstating effects of an alcohol-associated contextual stimulus after extinction of alcohol-reinforced behavior, blockade of either DA D1 or D2 receptors dose-dependently increases latency to initiate responding and reduces the number of responses at a previously active lever (Liu and Weiss, 2002). These effects of DA receptor blockade mesh well with an emerging view that the function of midbrain DA neurons is to convert motivational signals that predict reward into behavior directed at obtaining the predicted rewarding stimulus (Schultz et al., 1997).
The effects of ethanol-associated contextual stimuli in animal models of relapse are also sensitive to pharmacological manipulation of opioid receptors. The nonselective opioid receptor antagonist naltrexone, as well as MOR- and DOR-selective antagonists, reverses ethanol-seeking induced by ethanol-associated contextual stimuli (Katner et al., 1999; Ciccocioppo et al., 2002). Clearly, opioid receptors participate in ethanol-seeking motivated by drug cues. The fact that the MOR antagonist naloxonazine, but not the DOR antagonist naltrindole, produced nonselective behavioral suppression in these tasks suggests that DORs may be a target for treatment of alcohol craving and relapse (Ciccocioppo et al., 2002). These findings also have a bearing on the extinction hypothesis (Sinclair, 1990), which proposes that the anti-relapse actions of naltrexone are dependent on an associative component whereby subjects learn across repeated trials that ethanol is no longer reinforcing after opioid receptor antagonist administration. There is strong recent support for this hypothesis that has led to the suggestion that longer clinical use of naltrexone may be beneficial in reducing the number of relapse episodes (Stromberg et al., 1998). However, the "intrinsic" anti-relapse efficacy of opioid receptor antagonists in preventing ethanol-seeking after a single administration may also contribute to their clinical effectiveness.
Although the neurobiological basis of the ability of cues to produce reinstatement of drinking or drug seeking has been studied primarily in animal models, there are several recent reports of the neural correlates of craving for alcohol produced by olfactory and visual cues (Braus et al., 2001; Mann et al., 2001; Schneider et al., 2001). The results of these studies, however, have been somewhat variable. In one study (Schneider et al., 2001), the presentation of an alcohol olfactory stimulus to newly detoxified alcoholics produced activation within both the amygdala and cerebellum that was reversed by pharmacological and cognitive therapy. In contrast, a preliminary report assessing the effects of combined visual and olfactory stimuli to elicit craving in alcoholics identified cortical and thalamic loci (Mann et al., 2001), whereas a third study (Braus et al., 2001) reported effects in the ventral putamen. There is some similarity to the patterns of activation reported in cocaine users when exposed to various drug-related cues (Grant et al., 1996; Childress et al., 1999), but sample sizes and the kinds of paradigms used to elicit craving in alcoholics need to be expanded before we will obtain a consistent pattern of the substrates underlying cue-elicited ethanol craving.