Acute and long-term effects of 17β-estradiol on Gi/o coupled neurotransmitter receptor function in the female rat brain as assessed by agonist-stimulated [S]GTPγS binding

Estrogens exert effects on mood, mental state, memory and other central nervous system (CNS) functions by modulating neurotransmitter receptor systems in the brain. Studies were designed to investigate the effect of 17β-estradiol (E₂) on agonist-stimulated [³⁵S]GTPγS binding in membranes to assess the first step in the intracellular signal transduction cascade in a functional assay following: (1) an acute, one-time bolus subcutaneous injection, or (2) 14-day continuous exposure by a slow-release pellet implanted subcutaneously. In rats treated with E₂ acutely, the maximal response produced by activation of serotonin_1A (5-HT_1A) receptors was decreased 25% in the hippocampus, cortex, and amygdala. Similarly, acute E₂ administration desensitized 5-HT_1B and GABA_B receptors in hypothalamus and cerebellum, respectively, and cannabinoid receptors in hippocampus and cortex. Although the maximal responses were decreased, acute E₂ treatment did not alter the EC₅₀ of any of the aforementioned receptors. The incubation of membranes prepared from the cortex of ovariectomized (OVX) rats with E₂ (1 μM) in vitro did not alter 5-HT_1A or cannabinoid receptor-mediated [³⁵S]GTPγS binding. By contrast to acute treatment in vivo, 14-day E₂ administration to OVX rats did not alter the maximal responses produced by activation of 5-HT_1A, 5-HT_1B, GABA_B, or cannabinoid receptors in any of the brain regions examined. Thus, it is concluded that acute E₂ administration in vivo modulates multiple G_i/o coupled receptors in various regions of the female rat brain. Because these effects are observed only in vivo, it is concluded that cytosolic, nuclear and/or extraneuronal factors are required.