DefinePK

Abstract

Pharmaceutical use and abuse are well-known problems worldwide, and dopamine is considered the primary neurochemical substrate for reinforcement, craving, and dependence. This review critically examines the importance of dopamine in the abuse of various drugs. This review begins by describing the neurobiology of the mesolimbic dopamine system, with an emphasis on reward prediction, motivation, and reinforcement learning. There is evidence that the action of psychostimulants, opiates, benzodiazepines, and other prescribed drugs on dopaminergic circuits occurs through direct (increase in extracellular dopamine) or indirect action (regulation of inhibitory and excitatory input to the dopamine neurons). Chronic pharmacological stimulation induces enduring neuroadaptations, such as receptor hyporeactivity, sensitization, and deficits in prefrontal inhibitory control, which contribute to the development of tolerance, craving, and relapse. Interactions between dopamine, glutamate, and GABA neurosystems also promote maladaptive learning and drug-compulsive seeking. In a clinical setting, these mechanisms emphasize the importance of achieving a balance between pain-relieving effects and abuse potential through judicious prescribing, patient monitoring, and regulatory control. Novel strategies, such as partial agonists, biased ligands, functional neuroimaging, and biomarker-based interventions, may be developed to decrease dependence liability while preserving therapeutic effects. By integrating available neurobiological and pharmacological information, this review underscores the critical contribution of dopamine in defining the abuse potential of drugs and the importance of cross-disciplinary approaches between neuroscience, clinical care, and public health policies to minimize misuse while maximizing therapeutic efficacy.