Central and peripheral interactions between endocannabinoids and steroids, and implications for drug dependence.

Endocannabinoids are biologically active amides, esters and ether of long chain polyunsaturated fatty acids. They interact with several neurotransmitters in the central nervous system (CNS), and with various signaling molecules (including cytokines) in the periphery. Critical interactions have emerged also with steroids, another group of well-known bioactive lipids, both centrally and peripherally. Here, I briefly review the targets of the combined action of endocannabinoids and steroids, and the available evidence concerning the direct regulation by the latter compounds of the proteins of the endocannabinoid system (ES). In addition, I discuss recent examples of endocannabinoids and steroids working together in the central nervous system and in the periphery, which allowed to disclose some molecular details of the interactions between these two groups of lipids. Taken together, available data suggest that steroids can modulate the endocannabinoid tone, through genomic or nongenomic regulation, and that endocannabinoids can complement the biological activity of steroids. In this line, the issues concerning the tissue- and species-specificity of the endocannabinoid-steroid interface, and the possibility that also endocannabinoids may modulate steroid metabolism, are addressed. Finally, I present the hypothesis that retrograde endocannabinoid signaling, by reducing striatal glutamate release, may be part of the molecular events responsible for the influence of steroids on drug abuse.