Dual sigma receptor/dopamine transporter inhibition and the union of pharmacology and experimental psychology.

Selective standard sigma receptor (σR) antagonists block several behavioral effects of cocaine though they are inactive in altering cocaine self-administration. However, σR antagonists with affinity for the dopamine transporter (DAT) were effective in decreasing maximal cocaine self-administration. Additionally, σR/DAT inhibition affected cocaine or methamphetamine self-administration at doses that had minimal effects on comparable responding maintained by food reinforcement, suggesting that σR/DAT inhibition may serve as a lead for the discovery of stimulant-abuse medications. Further, molecular interactions of σRs and the DAT provide several leads for understanding the mechanisms that may underlie this unique behavioral effect. Despite decreasing stimulant self-administration, dual σR/DAT inhibition only enhanced the discriminative-stimulus effects of cocaine. This outcome would be considered paradoxical if self-administration is based on subjective effects identical to those on which the discrimination is based. Resolving this conundrum of outcomes under 2 procedures, both thought to relate to abuse liability, is suggested by a behavioral analysis of how the drugs function under the 2 procedures. In self-administration procedures, cocaine functions as a reinforcing consequence, whereas in discrimination procedures, cocaine functions as an antecedent stimulus that sets the occasion for responses. Although the subjective nature of that antecedent stimulus is unknown, it is proposed that it contains elements of the experience accompanying cocaine-induced satiety. Evidence supporting σR/DAT inhibition producing an effect related to cocaine-induced satiety is supported by the behavioral economics of cocaine self-administration. Importantly, the potential resolution of this paradox comes from conceptualizing behavioral pharmacology as a union of pharmacology and behavior analysis. SIGNIFICANCE STATEMENT: Sigma receptor (σR) antagonist actions combined with dopamine transport (DAT) inhibition decreased cocaine self-administration, suggesting avenues for stimulant-abuse medications discovery. However, σR/DAT inhibition enhanced the discriminative-stimulus effects of cocaine, an ostensible paradox. Resolving the enigma, it is proposed that the experience of σR/DAT inhibition contains subjective elements of cocaine-induced satiety, and supporting evidence, including the behavioral economics of cocaine self-administration, is outlined. Importantly, the resolution of this paradox comes from conceptualizing behavioral pharmacology as a union of pharmacology and experimental psychology.