Estrogen differentially modulates the cannabinoid- induced presynaptic inhibition of amino acid neurotransmission in proopiomelanocortin neurons of the arcuate nucleus.
The present study sought to determine whether cannabinoids inhibit glutamatergic and GABAergic synaptic input onto neurons of the hypothalamic arcuate nucleus (ARC), and whether estrogen modulates this process. Whole-cell patch clamp recordings were performed in hypothalamic slices prepared from ovariectomized female guinea pigs. CB1 receptor activation reduced the amplitude of excitatory postsynaptic currents (EPSCs) evoked by electrical stimulation that were sensitive to ionotropic glutamate receptor antagonists. The CB1 receptor antagonist AM251 increased evoked EPSC (eEPSC) amplitude, and reversed the agonist-induced decrease. CB1 receptor activation similarly decreased the amplitude of evoked inhibitory postsynaptic currents (eIPSCs). The cannabinoid-induced reduction in eEPSC and eIPSC amplitude correlated with a decrease in the frequency of miniature EPSCs (mEPSCs) and IPSCs (mIPSCs) that were abolished by ionotropic glutamate and GABA(A) receptor antagonists, respectively. AM251 increased mEPSC frequency, and antagonized the agonist-induced decrease. Compared to neurons obtained from vehicle-treated controls, estradiol benzoate (25 mug; s.c.) given 24 h prior to experimentation increased mEPSC frequency, and markedly decreased the potency of CB1 receptor agonists to decrease mEPSC frequency. Conversely, the steroid potentiated the cannabinoid-induced decrease in mIPSC frequency. These effects were observed in neurons subsequently identified as proopiomelanocortin (POMC) neurons. These data reveal that ARC neurons, including POMC neurons, receive glutamatergic and GABAergic synaptic inputs that are presynaptically inhibited by cannabinoids, and differentially modulated by estrogen. These opposing effects of estrogen on the cannabinoid regulation of amino acid neurotransmission excite POMC neurons, and lend additional insight into the mechanisms underlying estrogen-induced anorexia and negative feedback of the reproductive axis.
Nguyen
Que Huong
QH
Department of Basic Medical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA.
Wagner
Edward J
EJ
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000378:metabolism*; D004558:Electric Stimulation; D004958:Estradiol / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000502:physiology*; D011963:Receptors, GABA-A / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D018709:Statistics, Nonparametric
D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D011963:Receptors, GABA-A; D017470:Receptors, Glutamate; C103505:AM 251; D004958:Estradiol; D011333:Pro-Opiomelanocortin