Chronic Cocaine Administration Switches Corticotropin-Releasing Factor2Receptor-Mediated Depression to Facilitation of Glutamatergic Transmission in the Lateral Septum

Abstract

Corticotropin-releasing factor (CRF) and urocortin (Ucn I) are endogenous members among a family of CRF-related peptides that activate two different and synaptically localized G-protein-coupled receptors, CRF₁and CRF₂. These peptides and their receptors have been implicated in stress responses and stress with cocaine abuse.In this study, we observed significant alterations in excitatory transmission and CRF-related peptide regulation of excitatory transmission in the lateral septum mediolateral nucleus (LSMLN) after chronic cocaine administration. In brain slice recordings from the LSMLN of control (saline-treated) rats, glutamatergic synaptic transmission was facilitated by activation of CRF₁receptors with CRF but was depressed after activation of CRF₂receptors with Ucn I. After acute withdrawal from a chronic cocaine administration regimen, CRF₁activation remained facilitatory, but CRF₂activation facilitated rather than depressed LSMLN EPSCs. These alterations in CRF₂effects occurred through both presynaptic and postsynaptic mechanisms. In saline-treated rats, CRF₁and CRF₂coupled predominantly to protein kinase A signaling pathways, whereas after cocaine withdrawal, protein kinase C activity was more prominent and likely contributed to the CRF₂-mediated presynaptic facilitation. Neither CRF nor Ucn I altered monosynaptic GABA_A-mediated IPSCs before or after chronic cocaine administration, suggesting that loss of GABA_A-mediated inhibition could not account for the facilitation. This switch in polarity of Ucn I-mediated neuromodulation, from a negative to positive regulation of excitatory glutamatergic transmission after chronic cocaine administration, could generate an imbalance in the brain reward circuitry associated with the LSMLN.