The article reviews the impact of estradiol on serotonin, dopamine, and glutamate systems in the brain. Estradiol, a potent estrogen, plays a crucial role in modulating neurotransmitter systems, affecting neuronal circuits and brain functions such as learning, memory, and reward. The review examines how estradiol and its receptors regulate these neurotransmitter systems through binding to estrogen receptors (ERα, ERβ, and GPER). Key findings include: 1. **Serotonin System**: - Estradiol increases serotonin synthesis by upregulating TPH2 transcription. - It affects the serotonin reuptake transporter (SERT) and its expression in various brain regions. - Estradiol influences serotonin receptors (5-HT1A and 5-HT2A), with ERβ playing a significant role in TPH2 transcription and 5-HT1A receptor signaling. 2. **Dopamine System**: - Estradiol modulates dopamine (DA) systems, affecting DA synthesis and release. - It influences dopamine transporters (DAT) and DA receptor sensitivity. - Estradiol enhances DA release and metabolism in the nucleus accumbens (NAc) and ventral tegmental area (VTA). 3. **Glutamate System**: - Estradiol enhances glutamate release and synaptic plasticity. - It interacts with ionotropic and metabotropic glutamate receptors (mGluRs). - Estradiol increases NMDA and AMPA receptor binding sites and transmission in the hippocampus. The review highlights the multifaceted effects of estradiol on these neurotransmitter systems and suggests potential therapeutic avenues for treating disorders related to serotonin, dopamine, and glutamate dysfunction. Despite limited human studies, the findings underscore the importance of translational research to bridge the gap between preclinical findings and clinical applications.The article reviews the impact of estradiol on serotonin, dopamine, and glutamate systems in the brain. Estradiol, a potent estrogen, plays a crucial role in modulating neurotransmitter systems, affecting neuronal circuits and brain functions such as learning, memory, and reward. The review examines how estradiol and its receptors regulate these neurotransmitter systems through binding to estrogen receptors (ERα, ERβ, and GPER). Key findings include: 1. **Serotonin System**: - Estradiol increases serotonin synthesis by upregulating TPH2 transcription. - It affects the serotonin reuptake transporter (SERT) and its expression in various brain regions. - Estradiol influences serotonin receptors (5-HT1A and 5-HT2A), with ERβ playing a significant role in TPH2 transcription and 5-HT1A receptor signaling. 2. **Dopamine System**: - Estradiol modulates dopamine (DA) systems, affecting DA synthesis and release. - It influences dopamine transporters (DAT) and DA receptor sensitivity. - Estradiol enhances DA release and metabolism in the nucleus accumbens (NAc) and ventral tegmental area (VTA). 3. **Glutamate System**: - Estradiol enhances glutamate release and synaptic plasticity. - It interacts with ionotropic and metabotropic glutamate receptors (mGluRs). - Estradiol increases NMDA and AMPA receptor binding sites and transmission in the hippocampus. The review highlights the multifaceted effects of estradiol on these neurotransmitter systems and suggests potential therapeutic avenues for treating disorders related to serotonin, dopamine, and glutamate dysfunction. Despite limited human studies, the findings underscore the importance of translational research to bridge the gap between preclinical findings and clinical applications.