¹Queen's University, School of Medicine, Kingston, Canada

Background: Cocaine blocks monoamine reuptake by inhibiting the dopamine (DAT), serotonin (SERT), and norepinephrine (NET) transporters. For decades, cocaine’s rewarding and reinforcing effects have been primarily attributed to DAT inhibition and increased dopaminergic neurotransmission within mesolimbocorticolimbic pathways (the “DAT hypothesis”). While this framework has guided much of addiction neuropharmacology, accumulating evidence suggests that DAT blockade alone may be insufficient to fully explain cocaine reward and reinforcement.

Aims & Objectives: This narrative review aims to
(1) evaluate experimental support for and limitations of the DAT hypothesis,
(2) examine evidence for multi-transporter and redundant monoaminergic mechanisms underlying cocaine reward and reinforcement, and
(3) identify key methodological and conceptual gaps that limit current understanding and therapeutic translation.

Method: Preclinical and translational studies investigating cocaine reward and reinforcement were reviewed, with emphasis on monoamine transporter knockout and knock-in models, pharmacological inhibition studies, conditioned place preference (CPP), and drug self-administration paradigms. Particular attention was given to evidence distinguishing sufficiency versus necessity of DAT inhibition. Monoamine transporter terminology follows Neuroscience-based Nomenclature (NbN).

Results: While DAT inhibition appears sufficient to produce cocaine reward under certain conditions, substantial evidence indicates it is not necessary. Homozygous DAT knockout mice retain cocaine CPP and self-administration, challenging the exclusivity of the DAT hypothesis. Additional findings demonstrate that selective DAT inhibitors fail to reproduce cocaine’s reinforcing profile, further questioning DAT blockade alone as a complete mechanism. Evidence from transporter knockout models supports a multi-transporter framework in which SERT and NET contribute to cocaine’s rewarding effects, potentially through compensatory or redundant mechanisms. Notably, combined reductions in DAT and SERT function abolish cocaine CPP, suggesting functional redundancy between these systems. Dopaminergic signaling remains central; however, its modulation may occur indirectly through serotonergic and noradrenergic pathways. Emerging data also implicate non-canonical targets, including intracellular sigma-1 receptors and Toll-like receptor 4, as modulators of cocaine reward and reinforcement.

Discussion & Conclusions: Cocaine’s rewarding and reinforcing effects cannot be fully explained by DAT inhibition alone. Instead, evidence supports a diffuse, multi-target mechanism involving DAT, SERT, NET, and additional modulatory pathways. Important knowledge gaps remain, including limitations of CPP as a proxy for reinforcement, route-dependent differences in cocaine reward mechanisms, and incomplete understanding of relevant neural circuitry. Addressing these gaps—particularly through self-administration paradigms and circuit-level analyses—may facilitate development of more effective pharmacotherapies for cocaine use disorder.