GPR30 is a novel, membrane-bound, G-protein coupled estrogen receptor (Filardo et al., 2002; Prossnitz et al., 2008). We hypothesize that GPR30 may mediate effects of estradiol (E2) on basal forebrain cholinergic neurons and cognitive performance. Recently we showed that G-1, a selective GPR30 agonist, enhances the rate of acquisition on a delayed matching-to-position (DMP) T-maze task (Hammond et al., 2009). In the present study, we examined the distribution of GPR30 in the rat forebrain, and the effects of G-1 on potassium-stimulated acetylcholine release in the hippocampus. GPR30-like immunoreactivity was detected in many regions of the forebrain including the hippocampus, frontal cortex, medial septum/diagonal band of Broca, nucleus basalis magnocellularis and striatum. GPR30 mRNA also was detected, with higher levels in the hippocampus and cortex than in the septum and striatum. Co-localization studies revealed that the majority (63-99%) of cholinergic neurons in the forebrain expressed GPR30-like immunoreactivity. A far lower percentage (0.4-42%) of GABAergic (parvalbumin-containing) cells also contained GPR30. Sustained administration of either G-1 or E2 (5 μg/day) to ovariectomized rats produced a nearly 3-fold increase in potassium-stimulated acetylcholine release in the hippocampus relative to vehicle-treated controls. These data demonstrate that GPR30 is expressed by cholinergic neurons in the basal forebrain, and suggest that activation of GPR30 enhances cholinergic function in the hippocampus similar to E2. This may account for the effects of G-1 on DMP acquisition previously reported.
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