Recent studies suggest the participation of cholinergic neurons in the brain processes underlying reinforcement. The involvement of cholinergic neurons in cocaine self-administration has been recently demonstrated in studies using muscarinic and nicotinic agonists and antagonists, microdialysis, assessment of choline acetyltransferase activity and acetylcholine (ACh) turnover rates. The present experiment was initiated to identify subsets of cholinergic neurons involved in the brain processes that underlie cocaine self-administration by lesioning discrete populations with a selective neurotoxin. Rats were trained to self-administer cocaine and the cholinergic neurotoxin 192-IgG-saporin or vehicle was then bilaterally administered into the posterior nucleus accumbens (NAcc)-ventral pallidum (VP). The 192-IgG-saporin induced lesions resulted in a pattern of drug-intake consistent with either a shift in the dose intake relationship to the left or downward compared to sham-treated controls. A second experiment used a self-administration threshold procedure that demonstrated this lesion shifted the dose intake relationship to the left compared to the sham-vehicle treated rats. The magnitude and extent of the lesion was assessed by measuring the expression of p75 (the target for 192-IgG-saporin) and choline acetyltransferase (ChAT) in the NAcc, VP, caudate nucleus-putamen (CP) and vertical limb of the medial septal nucleus-diagonal band (MS-DB) of these rats using real time reverse transcriptase-polymerase chain reaction. Significant reductions in gene expression for p75 (a selective marker for basal forebrain cholinergic neurons) and ChAT were seen in the MS-DB and VP while only small decreases were seen in the NAcc and CP of the 192-IgG-saporin treated rats. These data indicate that the overall influence of cholinergic neurons in the MS-DB and VP are inhibitory to the processes underlying cocaine self-administration and suggest that agonists directed toward subclasses of cholinergic receptors may have efficacy as pharmacotherapeutic adjuncts for the treatment of cocaine abuse.