5th Edition of Addiction World Conference 2026

Abstract

Background: Cocaine blocks monoamine reuptake by inhibiting dopamine (DAT), serotonin (SERT), and norepinephrine (NET) transporters. Although cocaine’s rewarding and reinforcing effects have traditionally been attributed to DAT inhibition, accumulating evidence suggests this dopamine-centric model may be incomplete.

Objectives: This review aimed to evaluate experimental support for and limitations of the DAT hypothesis, examine evidence for multi-transporter mechanisms underlying cocaine reward and reinforcement, and identify key conceptual gaps relevant to therapeutic development.

Methods: Preclinical and translational studies examining cocaine reward and reinforcement were reviewed, with emphasis on monoamine transporter knockout and knock-in models, pharmacological inhibition studies, and behavioral paradigms including conditioned place preference and drug self-administration. Evidence was synthesized to distinguish between the sufficiency and necessity of DAT inhibition.

Results: While DAT inhibition can be sufficient to produce cocaine reward in some paradigms, it is not necessary. Animals lacking functional DAT retain cocaine-conditioned place preference and self-administration, and selective DAT inhibitors fail to reproduce cocaine’s reinforcing profile. Transporter knockout studies support a multi-transporter framework in which serotonergic and noradrenergic systems contribute through compensatory or redundant mechanisms. Combined disruption of dopamine and serotonin transport abolishes cocaine reward, highlighting functional redundancy. Emerging evidence also implicates non-canonical modulatory pathways.

Conclusions: Cocaine reward and reinforcement arise from a distributed, multi-target neurobiological mechanism rather than DAT inhibition alone. This reframing has important implications for pharmacotherapy development, suggesting that single-target approaches may be insufficient. Addressing existing gaps through reinforcement-focused paradigms and circuit-level analyses may facilitate more effective treatments for cocaine use disorder.