Estradiol modulation of cortical, striatal and raphe nucleus 5-HT1A and 5-HT2A receptors of female hemiparkinsonian monkeys after long-term ovariectomy

Depression is common in Parkinson’s disease and an imbalance in serotonin neurotransmission could be implicated. Estradiol is reported to modulate brain serotonin systems of rodents and monkeys, but this has not been explored in primate models of Parkinson’s disease. Thus, the present study investigated the effect of estradiol on 5-HT1A and 5-HT2A serotonin receptors in the cortex, striatum and raphe nucleus of long-term ovariectomized hemiparkinsonian monkeys. Seven monkeys were ovariectomized and received a month later a unilateral lesion with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Four years after lesion and ovariectomy, three received a month of treatment with 17β-estradiol and four the vehicle. Autoradiography of [3H]8-OH-DPAT specific binding to 5-HT1A receptors showed a decrease in the frontal cortex of monkeys treated with 17β-estradiol in both hemispheres of the brain. [3H]ketanserin specific binding to 5-HT2A receptors was increased in the frontal cortex and the striatum of monkeys treated with 17β-estradiol in both the lesioned and intact sides of the brain. Autoradiography of [35S]GTPγS specific binding stimulated with R-(+)-8-OH-DPAT showed a decrease in the percentage of stimulation in the frontal cortex of monkeys treated with 17β-estradiol in both hemispheres of the brain and in the dorsal raphe nucleus. Treatment with 17β-estradiol was initiated a long time after ovariectomy in monkeys to model post menopausal hormonal conditions and showed that serotonin receptors were still responsive in the brain regions investigated. These results support a role for 17β-estradiol on serotonin activity in Parkinson’s disease and could be useful for treatment of depression associated with this disease.

Research highlights
► We investigated the effect of estradiol on serotonin receptors in hemi-MPTP monkeys.
► 17β-estradiol modified 5-HT receptor specific binding independently of the lesion.
► 5-HT1A receptors decreased in cortex and raphe of 17β-estradiol-treated monkeys.
► Cortical and striatal 5-HT2A receptors increased in 17β-estradiol-treated monkeys.
► Estradiol modulated 5-HT activity in a primate PD model, 4 years after ovariectomy.