Estrogen Differentially Modulates the Cannabinoid- Induced Presynaptic Inhibition of Amino Acid Neurotransmission in Proopiomelanocortin Neurons of the Arcuate Nucleus

Nov 16, 2006Neuroendocrinology

Estrogen changes how cannabinoids reduce chemical signals in appetite-control neurons

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Abstract

CB1 receptor activation reduced the amplitude of excitatory postsynaptic currents by 50% in hypothalamic neurons.

Cannabinoids inhibit both excitatory and inhibitory synaptic input onto neurons in the hypothalamic arcuate nucleus.
Activation of CB1 receptors leads to a decrease in the frequency of miniature excitatory and inhibitory postsynaptic currents.
The CB1 receptor antagonist AM251 increases the amplitude of excitatory postsynaptic currents and reverses the effects of cannabinoids.
Estrogen treatment increased the frequency of miniature excitatory postsynaptic currents and reduced the potency of cannabinoids in decreasing this frequency.
Estrogen differentially influences cannabinoid effects on excitatory and inhibitory synaptic inputs, potentially impacting neuronal excitability.

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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.

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Estrogen Differentially Modulates the Cannabinoid- Induced Presynaptic Inhibition of Amino Acid Neurotransmission in Proopiomelanocortin Neurons of the Arcuate Nucleus

Abstract

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