Summary: New mouse research shows that histamine changes dopamine levels in the striatum differently in males and females: lowering dopamine in males while increasing it in females. In females, this effect depends on the stage of the estrous cycle. The study also identifies distinct cellular pathways mediating these effects, suggesting that sex-specific regulation of histamine receptors could inform better treatments for disorders linked to dopamine dysfunction, such as Tourette syndrome (TS), schizophrenia, and attention-deficit/hyperactivity disorder (ADHD).
Researchers examined how histamine interacts with dopamine in the basal ganglia, a brain network central to movement, motivation, and numerous neuropsychiatric conditions. Using targeted pharmacology, microdialysis, and genetic knockdown techniques in mice, the team mapped how different histamine receptors and specific neural populations contribute to sex-specific modulation of striatal dopamine.
Key findings
- Opposite effects by sex: Central histamine administration reduced striatal dopamine in male mice but increased it in female mice.
- Estrous modulation: The dopamine-increasing response in females appeared only during estrus/proestrus, when estrogen levels are elevated.
- Different receptor pathways: In males, the effect depends on H2 receptors (H2R) acting in the substantia nigra pars compacta (SNc) and involves GABAergic neurons; in females, H3 receptors (H3R) in the striatum mediate the dopamine increase.
- Therapeutic implication: These sex-specific mechanisms indicate that targeted modulation of histamine receptors by sex could correct dopamine imbalances in TS, ADHD, and schizophrenia more effectively than one-size-fits-all approaches.
The work, published in the Journal of Neuroscience by Meghan Van Zandt, Christopher Pittenger, and colleagues, builds on genetic and animal studies that have linked histamine signaling to dopamine dysregulation in conditions such as TS. Prior evidence suggested that histamine loss could contribute to abnormal dopamine signaling; this study clarifies how histamine acts differently in male and female brains and pinpoints receptor- and cell-type-specific mechanisms.
Methodologically, the team used intracerebroventricular (ICV) infusion of histamine to reproduce previously observed decreases in male striatal dopamine while revealing an unexpected increase in females. Pharmacological experiments delivered receptor-specific agonists either centrally or into specific regions to identify which histamine receptors were responsible. In males, H2R activity in the SNc was required for the dopamine decrease; knocking down H2R selectively in SNc GABAergic neurons removed the effect, implicating those GABA neurons as a crucial locus of histamine action. In contrast, female responses did not rely on H2R in the SNc; instead, H3R activation within the striatum raised dopamine levels.
A striking aspect of the female response is its dependence on hormonal state. The study observed the histamine-induced dopamine increase only during estrus and proestrus, phases of the estrous cycle associated with higher estrogen. This points to an interaction between sex hormones and histamine-dopamine signaling pathways that could underlie sex differences in disease prevalence and symptom expression.
From a clinical perspective, these findings highlight the value of considering sex as a biological variable in studies of neurotransmitter systems and in the development of pharmacological treatments. If similar sex-specific histamine–dopamine interactions occur in humans, drugs that selectively target H2R or H3R, or that modulate their activity depending on sex and hormonal state, could offer more precise ways to rebalance dopamine signaling in disorders marked by its dysregulation.
About this dopamine and sex differences research news
Author: SfN Media
Source: SfN
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Original Research: Closed access. “Sex Differences in Histamine Regulation of Striatal Dopamine” by Meghan Van Zandt et al., Journal of Neuroscience. DOI: 10.1523/JNEUROSCI.2182-24.2025
Abstract (summary)
Dopamine modulation of the basal ganglia varies between males and females and is implicated in several neuropsychiatric disorders that show sex-biased prevalence, including Tourette Syndrome and ADHD. Motivated by genetic evidence implicating histamine in dopamine dysregulation, the authors characterized how histamine modulates striatal dopamine using microdialysis, targeted pharmacology, and shRNA knockdown of specific histamine receptors. Central histamine reduced striatal dopamine in male mice but increased it in females. In males, H2 receptors in the SNc and SNc GABAergic neurons were central to the effect. In females, H3 receptor activation in the striatum increased dopamine, and the female effect was present only during estrus/proestrus. These results confirm histamine’s regulation of striatal dopamine and reveal pronounced sexual dimorphism and estrous modulation, with potential relevance for understanding sex differences in striatal circuitry and related neuropsychiatric conditions.