The potential neuroadaptations to cocaine self-administration (SA) were evaluated using quantitative in situ hybridisation histochemistry. Levels of mRNAs of the monoamine transporters, i.e. the primary molecular targets of cocaine, and the striatal neuropeptides substance P and enkephalin, which predominantly exist in different populations of dopaminoceptive striatal neurons, were quantified in rats which had reached different stages of acquisition of cocaine SA. Thus, animals were killed 1 h after completing a self-administration session (i) early in or after acquisition of cocaine SA (ii) after various regimes of chronic cocaine SA, and (iii) a 10-day period of withdrawal from chronic cocaine intake. Control mRNA levels of all molecules under study were those quantified in animals receiving i.v. saline yoked to rats self-administering cocaine (1.5 or 0.75 mg/kg per infusion, depending on the experiment). Monoamine transporter expression was differentially altered by cocaine; dopamine transporter mRNA levels in the ventral tegmental area, but not in the substantia nigra, were increased following withdrawal from cocaine, suggesting a role for the upregulated mesolimbic dopamine transporter in the mechanisms underlying relapse to cocaine taking. By contrast, serotonin transporter mRNA in the dorsal raphé and noradrenaline transporter mRNA in the locus coeruleus remained unaltered under all experimental conditions. In addition, the expression of the striatal neuropeptides was also differentially altered; substance P mRNA levels were transiently increased in the shell of the nucleus accumbens by prolonged cocaine self-administration, but enkephalin mRNA levels in the dorsal and ventral striatum remained unaltered under all conditions.