Modulation of aggression by neuropeptide Y: receptor pharmacology, neural circuitry, and psychiatric relevance

Neuropeptides. 2026 May 17;118:102620. doi: 10.1016/j.npep.2026.102620. Online ahead of print.

ABSTRACT

Violence and aggression arise from dynamic interactions among genetic liability, neurobiological regulation, and environmental stressors, mediated by a distributed “core aggression circuit” encompassing the prefrontal cortex, amygdala, hypothalamus, and brainstem. Neuropeptide Y (NPY), a highly conserved 36-amino acid neuromodulator, has emerged as a key stress-buffering and emotion-regulatory agent with relevance to impulsive and reactive aggression. This review synthesizes translational evidence linking NPY biology to aggression and violence by integrating molecular mechanisms, receptor pharmacology, neural circuitry, and clinical phenotypes across psychiatric disorders. Evidence from animal models, neuroimaging, cerebrospinal fluid and plasma studies, and genetic investigations indicates that reduced central NPY signaling is generally associated with heightened stress sensitivity and impulsivity, well recognized risk factors for aggression, and, in paradigms using direct aggression measures, with aggressive behavior itself, whereas preserved or elevated NPY supports resilience. Mechanistically, postsynaptic Y1 receptor signaling dampens excitability in corticolimbic and amygdala-hypothalamic pathways and restrains stress-driven autonomic/endocrine escalation via modulation of hypothalamic corticotropin-releasing hormone and hypothalamic-pituitary-adrenal-axis activity. In contrast, presynaptic Y2 receptor limits NPY availability and, when overactivated, may promote vulnerability to anxiety and emotional dysregulation. Genetic variants and disorder-linked alterations further support clinical relevance, with indirect implications for intermittent explosive disorder, borderline personality disorder, oppositional defiant disorder, and disruptive mood dysregulation disorder. Despite inconsistent study designs and limited aggression-specific clinical data, NPY represents a candidate biomarker and potential therapeutic target for stress-related conditions involving aggression, though most therapeutic findings remain preclinical or disorder-general, underscoring the need for aggression-focused clinical trials, dimensional refinement of anger/aggression constructs, and cautious translational framing.

PMID:42166979 | DOI:10.1016/j.npep.2026.102620