Dopamine modulation of the basal ganglia differs in males and females and is implicated in numerous neuropsychiatric conditions, including some, like Tourette Syndrome (TS) and attention deficit hyperactivity disorder (ADHD), that have marked sex differences in prevalence. Genetic studies in TS and subsequent work in animals suggest that a loss of histamine may contribute to dysregulation of dopamine. Motivated by this, we characterized the modulation of striatal dopamine by histamine, using microdialysis, targeted pharmacology, and shRNA knockdown of histamine receptors. Intracerebroventricular (ICV) histamine reduced striatal dopamine in male mice, replicating previous work. In contrast, and unexpectedly, ICV histamine increased striatal dopamine in females. ICV or targeted infusion of agonists revealed that the effect in males depends on H2R receptors in the substantia nigra pars compacta (SNc). Knockdown of H2R in SNc GABAergic neurons abrogated the effect, identifying these cells as a key locus of histamine's regulation of dopamine in males. In females, however, H2R had no discernible role
instead, H3R agonists in the striatum increased striatal dopamine. Strikingly, the effect of histamine on dopamine in females was modulated by the estrous cycle, appearing only in estrus/proestrus, when estrogen levels are high. These findings confirm the regulation of striatal dopamine by histamine but identify marked sexual differences in and estrous modulation of this effect. These findings may shed light on the mechanistic underpinnings of sex differences in the striatal circuitry, and in several neuropsychiatric conditions.