Sexual dimorphism in histamine regulation of striatal dopamine

Many neuropsychiatric disorders show sex differences in prevalence and presentation. For example, Tourette's Syndrome (TS) is diagnosed 3-5 times more often in males. Dopamine modulation of the basal ganglia is implicated in numerous neuropsychiatric conditions, including TS. Motivated by an unexpected genetic finding in a family with TS, we previously characterized the modulation of striatal dopamine by histamine.

These findings confirm the regulation of striatal dopamine by histamine but identify marked sexual dimorphism in and estrous modulation of this effect. These findings may shed light on the mechanistic underpinnings of other sex differences in the striatal circuitry, perhaps including the marked sex differences seen in TS and related neuropsychiatric conditions.

We used microdialysis to analyze striatal dopamine response to the targeted infusion of histamine and histamine agonists. siRNA knockdown of histamine receptors was used to identify the cellular mediators of observed effects.

Intracerebroventricular histamine reduced striatal dopamine in male mice, replicating previous work. Unexpectedly, histamine increased striatal dopamine in females. Targeted infusion of selected 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, in contrast, H2R had no 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 in estrus/proestrus but not in metestrus/diestrus. Conclusions: These findings confirm the regulation of striatal dopamine by histamine but identify marked sexual dimorphism in and estrous modulation of this effect. These findings may shed light on the mechanistic underpinnings of other sex differences in the striatal circuitry, perhaps including the marked sex differences seen in TS and related neuropsychiatric conditions.