ObjectiveNarcolepsy type 1 (NT1) is assumed to be caused solely by a lack of hypocretin (orexin) neurotransmission. Recently, however, we found an 88% reduction in corticotropin‐releasing hormone (CRH)‐positive neurons in the paraventricular nucleus (PVN). We assessed the remaining CRH neurons in NT1 to determine whether they co‐express vasopressin (AVP) to reflect upregulation. We also systematically assessed other wake‐systems, since current NT1 treatments target histamine, dopamine, and norepinephrine pathways.MethodsIn postmortem tissue of people with NT1 and matched controls, we immunohistochemically stained and quantified neuronal populations expressing: CRH and AVP in the PVN, and CRH in the Barrington nucleus; the key neuronal histamine‐synthesizing enzyme, histidine decarboxylase (HDC) in the hypothalamic tuberomammillary nucleus (TMN); the rate‐limited‐synthesizing enzyme, tyrosine hydroxylase (TH), for dopamine in the mid‐brain and for norepinephrine in the locus coeruleus (LC).ResultsIn NT1, there was: a 234% increase in the percentage of CRH cells co‐expressing AVP, while there was an unchanged integrated optical density of CRH staining in the Barrington nucleus; a 36% increased number of histamine neurons expressing HDC, while the number of typical human TMN neuronal profiles was unchanged; a tendency toward an increased density of TH‐positive neurons in the substantia nigra compacta; while the density of TH‐positive LC neurons was unchanged.InterpretationOur findings suggest an upregulation of activity by histamine neurons and remaining CRH neurons in NT1. This may explain earlier reports of normal basal plasma cortisol levels but lower levels after dexamethasone suppression. Alternatively, CRH neurons co‐expressing AVP neurons are less vulnerable. ANN NEUROL 2023;94:762–771