GLP-1 and beyond: Metabolic modulation in neuropsychiatric disease

Glucagon-like peptide‑1 (GLP‑1) receptor agonists (semaglutide, liraglutide) and the incretin co‑ and tri‑agonists tirzepatide (GLP‑1/GIP) and retatrutide (GLP‑1/GIP/glucagon) are among the fastest-growing therapeutic classes in medicine. While developed for type 2 diabetes and obesity, these agents exert significant central effects by engaging neural systems that regulate motivation, reward processing, and affective state, positioning metabolic signaling as a mechanistic driver of neuropsychiatric symptom domains.
GLP‑1 signaling operates across a distributed gut–brain axis, with receptors in the nucleus of the solitary tract, area postrema, hypothalamus, lateral septum, central amygdala, bed nucleus of the stria terminalis, and ventral tegmental area, as well as on vagal afferents. Through these pathways, GLP‑1 modulates dopaminergic transmission, effort allocation, reinforcement learning, and goal-directed behavior, in concert with a broader hormonal network (e.g., ghrelin, leptin, insulin, amylin, oxytocin).
GLP‑1 signaling also interacts with neuroinflammatory processes, synaptic plasticity, microbiome-derived signals, and sex-dependent mechanisms, factors likely to shape individual variability in behavioral and clinical outcomes.
The basic neurobiology of GLP‑1 in healthy reward circuits is increasingly well characterized; how these systems behave in disease, and how they should be targeted, is not yet clear.
Key questions remain about how sustained GLP‑1 activation reshapes craving, hedonic tone, and mood in vulnerable populations, and how it interacts with psychotropic medications. Preclinical and clinical observations point to blunted reward processing, with implications for both therapeutic benefit (e.g., reduced craving and intake in substance use disorders (SUDs) and alcohol use disorder (AUD)), and adverse effects (e.g., anhedonia, affective flattening).

This Research Topic focuses on metabolic modulation of reward and affective function in neuropsychiatric disease, highlighting GLP‑1 and similar brain–body mechanisms that shape craving, relapse vulnerability, anhedonia, and stress-linked motivational states. It brings together preclinical, experimental, neuroimaging, translational, and clinical contributions, provided manuscripts maintain a clear behavioral neuroscience emphasis and a direct link to neuropsychiatric disease, studies without explicit linkage to neuropsychiatric mechanisms will be considered out of scope.

Topics of interest include:

• Addiction and relapse: GLP‑1 and incretin modulation of craving, reinforcement learning, and habit versus goal-directed control in SUDs and AUD.

• Stress * reward and HPA–metabolic crosstalk: hindbrain (NTS), amygdalar, and BNST contributions to incretin and hormonal regulation of disease-relevant behavior.

• Anti-craving benefit versus anhedonic liability: vulnerability factors and moderators (stress history, comorbidity, sex, prior psychiatric diagnosis) that shape individual outcomes.

• Behavioral endocrinology beyond GLP‑1: ghrelin, leptin, insulin, amylin, and oxytocin in reward, stress, and motivated behavior under pathological conditions.

• Dual and triple incretin agonists (GLP‑1/GIP, GLP‑1/GIP/glucagon): distinct motivational and affective profiles.

• Clinical, translational, and neuroimaging studies of GLP‑1 therapies in SUDs, mood and anxiety disorders, and serious mental illness.

• Interactions with psychotropic medications (antipsychotics, antidepressants, mood stabilizers) on behavior, affect, and reward function.

Out of scope: studies focused primarily on weight loss, glycemic control, or peripheral metabolic endpoints, and descriptive metabolic physiology in healthy conditions without explicit linkage to neuropsychiatric mechanisms.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
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Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Systematic Review

Keywords: GLP-1, GIP, motivation, reward, dopaminergic tranmission, effort allocation, reinforcement learning, goal-directed network, craving, hedonic tonic, mood, SUDs, alcohol use disorder, anhedonia, relapse vulnerability, stress, translational, neuropsychiatric, ghrelin, leptin, insulin, amylin, oxytocin, anxiety disorder

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.