Multisystem network model of reward and addiction highlights GLP-1 and other non-dopaminergic pathways.

Addiction to illicit drugs remains a major global health challenge, requiring integrative efforts across neuroscience, psychiatry, and pharmacology. Historically, addiction research has largely focused on dysfunction within dopaminergic circuits, particularly the mesolimbic pathway, as the primary driver of addictive behaviors. However, this dopamine-centric view fails to fully explain the complex and persistent nature of addiction, leaving significant gaps in understanding and treatment efficacy. There is a growing recognition that addiction reflects maladaptive interactions across distributed neuromodulatory and glial networks, necessitating a broader conceptual framework. This review addresses the need to move beyond a singular focus on dopamine to explore the intricate interplay of multiple systems in shaping motivation, reinforcement learning, and affective regulation in addiction.

Researchers conducted a narrative literature review to synthesize converging evidence on multisystem reward regulation and its implications for addiction. The search spanned publications from 1998 to February 2026, utilizing databases including Scopus, PubMed, and Web of Science. Key search terms encompassed "anorexia nervosa addiction," "endocannabinoid system anorexia nervosa," "orexin system anorexia nervosa," and "orexin system addiction," among others, to identify relevant studies. This approach allowed for a comprehensive overview of molecular, circuit, and translational findings supporting a network-based model of reward and addiction, integrating insights from various neuromodulatory systems.