Cannabinoids play a major role in the regulation of homeostasis, mainly those governed by the hypothalamus such as reproduction and stress responses. The present study investigated the effects of cannabinoids on glutamatergic synaptic input onto pro-opiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) as well as estrogen's influences on this process. Whole-cell patch clamp recordings using biocytin-filled electrodes were used to detect evoked and miniature excitatory postsynaptic currents (EPSCs) in slices through the ARC of ovariectomized female guinea pigs. Bath application of the CB1 receptor agonist WIN 55,212-2 (1-3 μM) to vehicle-treated controls in the presence of the GABAA receptor antagonist SR 95531 (10 μM) revealed a reduction in EPSC amplitude evoked by electrical stimulation that were sensitive to the ionotropic glutamate receptor antagonists CGS 19755 (10 μM) and NBQX (3 μM). Pretreatment with the CB1 receptor antagonist AM251 (1 μM) blocked this action. The reduction in evoked EPSC amplitude correlated with a decrease in the frequency but not the amplitude of miniature EPSCs recorded in the presence of the voltage-gated Na+ channel blocker tetrodotoxin (TTX; 500 nM) and SR 95531 (10 μM) that were completely abolished by CGS 19755 (10 μM) and NBQX (3 μM). This effect also was antagonized by AM251 (1 μM). Estradiol benzoate (EB) administered 24 hr prior to experimentation induced a pronounced rightward shift in the dose-response for WIN 55,212-2 to decrease mEPSC frequency. The cannabinoid-induced decrease in mEPSC frequency, and the corresponding modulatory influence of EB, was observed in ARC neurons subsequently identified as glutamate-, α-MSH-, or CART-containing cells via immunohistofluorescence. Collectively, these findings indicate that cannabinoids presynaptically inhibit glutamatergic synaptic input onto ARC neurons, including glutamatergic and POMC neurons, and that estrogen attenuates this effect by markedly reducing agonist potency. Results from this study provide great insights into the mechanisms by which cannabinoids and estrogen interact to regulate hypothalamic control of homeostasis.
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