Contingency does not contribute to the effects of cocaine self-administration on prodynorphin and proenkephalin gene expression in the rat forebrain.

Neuroadaptations in the brain opioid systems produced by chronic exposure to drugs of abuse may contribute to the drug dependence and addiction. Although regulation of the gene expression of the opioid propeptides proenkephalin (PENK) and prodynorphin (PDYN) by psychostimulants has previously been described, little attention has been paid to dissociating effects of pharmacological actions of the drugs from those produced by motivational processes driving active drug intake in self-administration paradigms. In the present study, effects of response-dependent (contingent) and response-independent (noncontingent) cocaine administration on the PENK and PDYN gene expression in the rat forebrain have been directly compared using the "yoked" self-administration procedure. The i.v. cocaine treatment lasted for 5 weeks, and rats were sacrificed 24 h after the last self-administration session. In situ hybridization analysis revealed that levels of the PDYN mRNA were significantly increased in the caudate/putamen, to the same extent in rats self-administering cocaine as in animals receiving noncontingent injections of the drug at the same frequency and dosage. No changes in the expression of the PDYN gene were detected in the nucleus accumbens or in the central nucleus of amygdala. Levels of the PENK mRNA remained unaltered in all the above-mentioned forebrain regions of rats receiving contingent or noncontingent cocaine injections. The obtained data indicate that up-regulation of the PDYN gene expression in the caudate/putamen results from direct pharmacological actions of cocaine rather than from the motivational and cognitive processes underlying active self-administration of the drug.