Divergent Modulation of Dopaminergic Neurons by Hypocretin/Orexin Receptors 1 and 2 Shapes Dopaminergic Cell Activity and Socioemotional Behavior

Background Many neuropsychiatric disorders involve dysregulation of the dopaminergic (DA) input to the forebrain. DA afferents from the midbrain ventral tegmental area (VTA) are particularly relevant. A key neuromodulatory influence on DAVTA neurons arises from lateral hypothalamic area hypocretin/orexin (OX) neurons. Despite being a major input, the differential actions of OX peptides A and B on their receptors (OX1R and OX2R) in DA neurons are poorly understood. Methods Using genetically engineered mice whose DA cells selectively lack OX input via Hcrtr1 (DA Ox1R-KO ) or Hcrtr2 (DA Ox2R-KO ), we assessed DAVTA neuron intrinsic excitability ex vivo and evaluated behavioral phenotypes across socioemotional and cognitive domains. Results We discovered previously unrecognized effects of OX peptides on DAVTA cell response. While OXA enhanced DAVTA neuron firing via OX1Rs, OXB diminished firing via OX2Rs. Behaviorally, DA OX1R loss generated anxiety-like responding and context-dependent hyperactivity, while DA OX2R loss decreased sociability and compromised aversion-driven learning. Loss of either OX1Rs or OX2Rs in DA cells elicited impulsivity and compulsivity-like behavioral patterns. Conclusions We evidenced distinct functions of OX1R versus OX2R signaling in modulating the intrinsic excitability of DAVTA neurons and influencing DA-related behaviors. Our data implicate OX→DA signaling pathways in neuropsychiatric endophenotypes relevant to obsessive-compulsive, attention-deficit/hyperactivity, and autism spectrum disorders and inform therapeutic strategies targeting OX receptors.