RESUMO
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.
Assuntos
Núcleo Arqueado do Hipotálamo/metabolismo , Estradiol/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Inibição Neural/fisiologia , Neurônios/metabolismo , Receptor CB1 de Canabinoide/fisiologia , Animais , Núcleo Arqueado do Hipotálamo/citologia , Estimulação Elétrica , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Feminino , Cobaias , Técnicas In Vitro , Inibição Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Piperidinas/farmacologia , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Pró-Opiomelanocortina/metabolismo , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Receptores de Glutamato/metabolismo , Estatísticas não ParamétricasRESUMO
Treatment of molybdenum Fischer carbene complexes with 6-methylene-7-octen-1-yne derivatives at 40 degrees C generates substituted tricyclo[4.3.1.0(1,6)]deca-2,4-dienes in good yield. Pentacarbonyl(butylmethoxycarbene)molybdenum(0) afforded the highest cyclization yields (54%), while the analogous chromium carbene complex gave no reaction. The range of dienyne substrates that participate in this reaction is explored and its mechanism is analyzed and discussed.
