RSA 2006 Abstracts

The Scripps Research Institute, La Jolla

CRF AND ETHANOL POSTSYNAPTICALLY ALTER NMDA RECEPTOR MEDIATED SYNAPTIC TRANSMISSION IN THE MOUSE CENTRAL AMYGDALA: Z. Nie; M. Roberto; G. R. Siggins. Department of Molecular and Integrative Neurosciences and Alcohol Research Center, The Scripps Research Institute, La Jolla, CA 92037.
           
            The neuropeptide corticotrophin releasing factor (CRF) is a 41 amino acid peptide involved in the responses to stress. Glutamate is the major excitatory neurotransmitter in the CNS, and NMDA type of glutamate receptor involved in stress and drug and alcohol dependent. We recently reported that both CRF and ethanol augment GABAergic transmission in the mouse CeA via actvation of CRF1 receptors (Nie et al., SCIENCE 303:1512, 2004). To assess whether CRF could also affect glutamatergic transmission in CeA, we used whole-cell patch-clamp in mouse CeA slices, evoked pharmacological isolated NMDA receptor-mediated EPSCs (NMDA-EPSCs) by local stimulation and recorded spontaneous miniature NMDA-EPSCs (mEPSCs; in 1 µM TTX to block Na+ channels). We found that 200 nM CRF enhanced the amplitude of evoked NMDA-EPSCs in 33% (4 of 12 cells) of recorded neurons from CeA slices. CRF enhanced the amplitude, but not the frequency of mEPSCs, suggesting a postsynaptic CRF action. CRF had no effect on either series resistance or holding currents in any recorded cell. Ethanol (44 mM) decreased NMDA-EPSCs (in 80% of cells), and decreased both the amplitude and frequency of mEPSCs in mice CeA neurons. These data suggest that there may be some reciprocal postsynaptic interaction between CRF and ethanol on NMDA receptors. Supported by NIAAA grant U01-AA13498 and U01-AA013517 (part of the Integrative Neuroscience Initiative on Alcoholism), and by AA06420 and DA03665.

CHRONIC ETHANOL EXPOSURE ELICITS MULTIPLE SITES OF NEUROADAPTATION IN SYNAPSES OF THE CENTRAL AMYGDALA: G. R. Siggins; Z. Nie; M. Roberto. Molecular and Integrative Neuroscience Department and Alcohol Research Center, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla CA, 92014.

            The central amygdala (CeA) is considered a major component of the extended amygdala, and as such is likely to be involved in alcohol dependence and stress-related excessive drinking. Several CeA neurotransmitters such as GABA and glutamate, and neuropeptides such as opioids and corticotropin releasing factor (CRF), also figure prominently in these behaviors. Therefore, over the last 5 years our laboratory has used electrophysiological and neurochemical methods to probe the cellular and synaptic mechanisms underlying these behaviors. We recently reported that acute ethanol enhanced GABAergic transmission in the rat CeA slice, in large part by increasing vesicular GABA release presynaptically (Roberto et al. PNAS 100: 2053, 2003). In the mouse CeA this effect appears to be mediated by activation of presynaptic CRFR1 receptors (Nie et al., Science, 303: 1512, 2004). Our more recent studies have shown that chronic ethanol exposure in rats causes neuroadaptations of glutamatergic and GABAergic synapses in CeA at both pre- and postsynaptic levels. Thus, we found persistent changes in baseline presynaptic glutamate release and postsynaptic NMDA receptor expression and function in CeA neurons of ethanol-dependent rats (Roberto et al., J. Neurosci., 24: 10159, 2004; Roberto et al., Neuropsychopharmacol., online July 27, 2005). Further, chronic ethanol exposure increased baseline vesicular GABA release, as evidenced by studies of evoked and spontaneous miniature IPSCs and in vivo CeA microdialysis (Roberto et al., J. Neurosci. 24: 1594, 2004). Our most recent studies suggest that this neuroadaptation of GABAergic transmission is likely to occur at presynaptic terminals and may involve persistently increased sensitivity or upregulation of CRFR1 receptors. Supported by grants from NIAAA (U01 AA013517 - INIA Project, U01 AA013498 - INIA Project and P60 AA-006420).

 

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