Chronic alcohol disrupts hypothalamic responses to stress by modifying CRF and NMDA receptor function

The chronic inability of alcoholics to effectively cope with relapse-inducing stressors has been linked to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and corticotropin-releasing factor (CRF) signaling. However, the cellular mechanisms responsible for this dysregulation are yet to be identified. After exposure of male Sprague Dawley rats to chronic intermittent ethanol (CIE; 5-6 g/kg orally for 35 doses over 50 days) or water, followed by 40-60 days of protracted withdrawal, we investigated CIE effects on glutamatergic synaptic transmission, stress-induced plasticity, CRF- and ethanol-induced NMDAR inhibition using electrophysiological recordings in parvocellular neurosecretory cells (PNCs) of the paraventricular nucleus. We also assessed CIE effects on hypothalamic mRNA expression of CRF-related genes using real-time polymerase chain reaction, and on HPA axis function by measuring stress-induced increases in plasma adrenocorticotropic hormone, corticosterone, and self-grooming. In control rats, ethanol-mediated inhibition of NMDARs was prevented by CRF1 receptor (CRFR1) blockade with antalarmin, while CRF/CRFR1-mediated NMDAR blockade was prevented by intracellularly-applied inhibitor of phosphatases PP1/PP2A, okadaic acid, but not the selective striatal-enriched tyrosine protein phosphatase inhibitor, TC-2153. CIE exposure increased GluN2B subunit-dependent NMDAR function of PNCs. This was associated with the loss of both ethanol- and CRF-mediated NMDAR inhibition, and loss of stress-induced short-term potentiation of glutamatergic synaptic inputs, which could be reversed by intracellular blockade of NMDARs with MK801. CIE exposure also blunted the hormonal and self-grooming behavioral responses to repeated restraint stress. These findings suggest a cellular mechanism whereby chronic alcohol dysregulates the hormonal and behavioral responses to repetitive stressors by increasing NMDAR function and decreasing CRFR1 function.