CRF modulates glutamate transmission in the central amygdala of naïve and ethanol-dependent rats

Abstract

Corticotropin-releasing factor (CRF) signaling in the central nucleus of the amygdala (CeA) is hypothesized to drive the development of alcohol dependence, as it regulates ethanol intake and several anxiogenic behaviors linked to withdrawal. Excitatory glutamatergic neurotransmission contributes to alcohol reinforcement, tolerance and dependence. Therefore, in this study we used in vitro slice electrophysiology to investigate the effects of CRF and its receptor subtype (CRF1 and CRF2) antagonists on both evoked and spontaneous action potential-independent glutamatergic transmission in the CeA of naive and ethanol-dependent Sprague-Dawley rats. We found that CRF (25–200 nM) concentration-dependently diminished evoked compound excitatory postsynaptic potentials (EPSPs), but increased miniature excitatory postsynaptic current (mEPSC) frequencies similarly in CeA neurons of both naïve and ethanol-dependent rats, indicating reduced evoked glutamatergic responses and enhanced vesicular glutamate release, respectively. This CRF-induced vesicular glutamate release was prevented by the CRF1/2 antagonist (Astressin B) and the CRF1 antagonist (R121919), but not by the CRF2 antagonist (Astressin 2B). Similarly, CRF’s effects on evoked glutamatergic responses were completely blocked by CRF1 antagonism, but only slightly decreased in the presence of the CRF2 antagonist. Moreover, CRF1 antagonism reveals a tonic facilitation of vesicular glutamate, whereas the CRF2 antagonism revealed a tonic inhibition of vesicular glutamate release. Collectively our data show that CRF primarily acts at presynaptic CRF1 to produce opposite effects on CeA evoked and spontaneous glutamatergic release and that the CRF system modulates CeA glutamatergic synapses throughout the development of alcohol dependence.

The center of the emotional universe: Alcohol, stress, and CRF1 amygdala circuitry

“…CRF has also been shown to alter excitatory transmission within the CeA. CRF application reduced evoked glutamate responses and enhanced glutamate release in the CeA of Sprague-Dawley rats (Liu et al , 2004; Varodayan et al , 2017) and C57BL/6 mice (Silberman et al , 2013a). In Wistar rats, CRF application had divergent effects on glutamatergic signaling, with a subset of CeA neurons exhibiting enhanced glutamate release following exogenous CRF application and a subset exhibiting reductions in glutamate release (Herman et al , 2016c).…”

“…The CRF1 receptor also plays a role in the effects of acute alcohol on excitatory synaptic transmission in the CeA. Several studies (Herman et al , 2016c; Silberman et al , 2015; Silberman et al , 2013b; Varodayan et al , 2017) have shown that acute alcohol can potentiate spontaneous glutamatergic EPSCs in the CeA. This potentiation was blocked by pretreatment with a CRF1 receptor antagonist, but persisted despite the ablation of CRF-containing neurons in the CeA and whole organism (Silberman et al , 2015).…”

Sexual dimorphism in the neural impact of stress and alcohol

“…Alcohol’s effects on male neurons of the medial CeA have been extensively studied. Alcohol enhances GABAergic inhibitory postsynaptic responses and reduces the magnitude of glutamatergic excitatory postsynaptic potentials and currents (EPSP/Cs) (Roberto et al, 2006; Roberto, Madamba, Moore, Tallent, & Siggins, 2003; Roberto, Madamba, Stouffer, Parsons, & Siggins, 2004), in part via CRF’s actions (Bajo, Cruz, Siggins, Messing, & Roberto, 2008; Herman et al, 2013; Herman et al, 2016; Varodayan et al, 2017). Given the aforementioned sex differences in the effects of stress and alcohol on CeA CRF neurons, associated changes in neuronal activity would be expected to display different patterns in males and females.…”

Basolateral amygdala is required for reconsolidation updating of heroin‐associated memory after prolonged withdrawal

“…We also characterized Fos‐positive neurons after exposure to the UCS in the amygdala by colabeling Fos and glutamatergic marker, CamKinaseII (Figure E,F), as the BLA contains a majority (~80%) of glutamatergic neurons while the CeA contains mainly (~95%) γ‐aminobutyric acid (GABA) neurons . We found that the percentages of neurons that were colabeled for Fos and CaMKII were 80.4 ± 2.3 in the BLA and 3.3 ± 2.7 in the CeA, indicating that exposure to the UCS activates a majority of glutamatergic neurons in the BLA.…”