By contrast to the effects on intake, the PPAR-γ agonist pioglitazone had no effect on cue-induced reinstatement of alcohol-seeking behavior (73), suggesting that PPAR-γ agonists may function to abate primary responses for drugs and not those conditioned to the environment. As can be seen in Figure 4, reexposure to environmental stimuli induced increases in alcohol-seeking and these increases were similar following administration of pioglitazone. By comparison, as can also be seen in Figure 4, pioglitazone decreased reinstatement induced by yohimbine stress. Yohimbine is an α2 adrenoceptor antagonist that acts as a pharmacologic stressor in animals and in humans. In animals, it potently reinstates alcohol–seeking behavior (76), while in abstinent alcoholics it elicits intense craving that correlates with alcoholism severity (77). Most notably, contrary to pioglitazone, naltrexone reduced reinstatement of drug-seeking triggered by cues but not by yohimbine stress (74). However if the two drugs were combined at relatively low doses, they were able to prevent both forms of relapse (74). This provides further evidence for the potential of this drug combination in the treatment of alcohol addiction. In additional experiments
