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RSA 2004 Abstracts
The Scripps Research Institute, La Jolla
ETHANOL DRINKING AND ANXIETY-LIKE BEHAVIOR DURING ABSTINENCE: ROLE OF CRF
A. J. Roberts, G. R. Valdez, L. O?Dell, and G. F. Koob
Department of Neuropharmacology, The Scripps Research Institute La Jolla, CA 92037
A model of ethanol self-administration in dependent rats was developed several years ago. In this model, rats are trained to lever press for ethanol and then made dependent through ethanol vapor exposure and finally allowed to lever press again during the early phases of ethanol withdrawal or following more extended periods of abstinence. Both early withdrawal and protracted abstinence are associated with increases in ethanol self-administration. Over the past few years this model has been optimized and used to study the changes in the reinforcing efficacy of ethanol associated with dependence. One area of considerable interest has been the role of the stress system, and specifically corticotropin-releasing factor (CRF), in these dependence-induced increases in ethanol self-administration. It has been known for quite some time that ethanol withdrawal and abstinence states are associated with increased stress axis activity and increased anxiety states in animal models as well as in humans. It has been speculated that this state of ?stress? contributes to relapse ethanol consumption. Indeed, recent studies examining the role of CRF in ethanol self-administration and anxiety-like behavior associated with withdrawal and protracted abstinence support this hypothesis. For example, administration of a CRF receptor antagonist had no effect on self-administration in non-dependent rats, but significantly decreased self-administration in dependent rats, both during withdrawal and following protracted abstinence. In a separate study it was shown that rats in protracted abstinence were more sensitive to stressor-induced increases in anxiety-like behavior and that this was reversed by administration of a CRF receptor antagonist. Taken together, these data suggest that the increased ethanol self-administration in dependent animals is associated with an increased behavioral responsiveness to stress and that this link is mediated by CRF. Supported by the TSRI Alcohol Research Center (AA06420) and the NIAAA Integrative Neuroscience Initiative on Alcoholism (AA13517).
NOCICEPTIN/ORPHANIN FQ BLOCKS THE ETHANOL-INDUCED ENHANCEMENT OF GABAERGIC TRANSMISSION IN THE CENTRAL AMYGDALA
Marisa Roberto, Samuel G. Madamba, and George R. Siggins
The Scripps Research Institute, 10550 N. Torrey Pines, La Jolla, CA 92037.
Behavioral studies indicate that the GABAergic system in the central nucleus of the amygdala (CeA) plays a major role in the reinforcing effects of ethanol and in the anxiogenic response to ethanol withdrawal. The corticotrophin releasing factor (CRF) and nociceptin/orphanin FQ (N/OFQ) peptides within the CeA are also implicated in regulating voluntary ethanol intake. N/OFQ participates in the response to acute stress exposure and exerts marked antagonist effects on endogenous opioid and CRF systems. N/OFQ reduces ethanol self-administration and prevents the reinstatement of ethanol-seeking behavior elicited by alcohol-related cues. N/OFQ also has anxiolytic and anti-stress effects. We recently reported that in most CeA neurons ethanol augmented GABA receptor-mediated inhibitory responses (GABA-IPSP/Cs) acting at both pre-and postsynaptic sites. Like ethanol CRF (100 nM) increased the amplitude of GABAA-IPSP/Cs. Interestingly, N/OFQ (500 nM) slightly decreased the amplitude of GABAA-IPSP/Cs and blocked the increase of GABAA-IPSP/Cs induced by 44 mM ethanol. N/OFQ also increased paired-pulse facilitation (PPF) opposing the ethanol effect. In addition, N/OFQ blocked the CRF-induced increase in GABA-IPSP/Cs. However, the effect of N/OFQ on CRF appeared to have a different time-course compared to its effect on ethanol, suggesting different mechanism. Our findings are consistent with an overall reduction in the activity and output of the CeA and may account in part for the anxiolytic or ?tension-reducing? effect of ethanol consumption. Our data support the hypothesis that the anxiolytic and anti-stress properties of N/OFQ may be mediated by interactions with the CRF-GABAergic systems in CeA. Supported by grants from NIH (AA013517, AA06420, DA03665).
ETHANOL INCREASES GABA RELEASE IN RAT CENTRAL AMYGDALA
Roberto M., Madamba S.G., Stouffer D.G., Parsons L.H. and Siggins G.R.
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA
We previously demonstrated that in central amygdala (CeA) slices acute ethanol augmented GABAA receptor-mediated inhibitory postsynaptic potentials and currents (GABAA-IPSP/Cs) in most CeA neurons, possibly by a presynaptic mechanism. Coupled with the behavioral observation that GABAA receptor antagonism in the CeA reduces operant ethanol self-administration in rats, this finding suggests that ethanol reinforcement is mediated in part through increased GABAergic transmission in the CeA. Here we examined the interaction of acute ethanol with the GABAergic system in ethanol-dependent rats using an in vitro CeA slice preparation and in vivo by brain microdialysis. We found that in CeA slices from ethanol-dependent rats acute superfusion of 44 mM ethanol significantly enhanced the GABAA-IPSP/Cs, with recovery on washout of ethanol. This ethanol enhancement of GABAA-IPSP/Cs was equivalent in magnitude to that in slices from non-dependent rats, suggesting lack of tolerance. Notably, baseline GABAA-IPSP/C input-output curves were significantly higher and baseline PPF of GABAA-IPSP/Cs was significantly decreased in neurons from dependent rats compared to non-dependent rats, suggesting that GABA release was augmented after chronic ethanol. Invivo administration of ethanol (0.1, 0.3 and 1.0M) via microdialysis probe produced a dose-dependent increase in GABA release in the CeA dialysate in both ethanol-dependent and non-dependent rats. Interestingly, in dependent rats there was about 4 fold increase in baseline GABA microdialysate content compared to the non-dependent rats, indicating greatly increased GABAergic tone in dependent rats. These electrophysiological and microdialysis findings suggest that acute and chronic ethanol increases GABA release in CeA and support the hypothesis that the development and maintenance of ethanol dependence may be mediated, in part, by increased GABAergic tone in the CeA. Supported by grants from NIH (AA013517, AA06420, DA03665, AA12294).
ETHANOL EFFECTS ON GABAA RECEPTOR-MEDIATED SYNAPTIC FUNCTIONS INCREASED IN THE CENTRAL NUCLEUS OF AMYGDALA NEURONS IN SLICES FROM DELTA-OPIOID RECEPTOR KNOCKOUT MICE
Maeng-Hee Parka, Amanda J Robertsb, George R. Sigginsb, and Scott D Moorec,d
aDepartment of Molecular Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
bDepartment of Neuropharmacology, Scripps Research Institute, La Jolla, CA 92037, USA
cDepartment of Psychiatry, Duke University Medical Center, Durham, NC 27710, USA
dResearch Service, Veterans Administration Medical Center, 508 Fulton Street, Neurology Research Building 16, Room 25, Durham, NC 27705, USA
Endogenous opioid systems are implicated in the actions of ethanol. Delta opioid receptor (DOR) knockout (KO) mice showed an increased ethanol consumption and anxiety-like behavior. To find the molecular mechanisms underlying these behaviors, we examined the ethanol effect in brain slices from DOR KO mice using whole cell patch recording techniques. We focused our study in the central nucleus of amygdala (CeA) since CeA is implicated in alcohol drinking behavior as well as stress behavior. We found that ethanol potentiated the GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) more efficiently in DOR KO mice as compared to wild type (WT) mice. Ethanol enhanced the peak response of evoked IPSCs significantly more in DOR KO mice than WT mice (35 % vs 20 %, N = 11, p < 0.01). Ethanol also increased the frequency of spontaneous IPSCs significantly more in DOR KO mice than in WT mice. (36% vs 75 %, n = 11, p < 0.01). It is speculated that ethanol-induced endogenous opioids may inhibit ethanol action on IPSCs in WT mice through in part DOR-mediated inhibitions of neurotransmitter releases and/or postsynaptic responses, and that ethanol action on IPSCs is less affected by endogenous opioids in DOR KO mice. This result supports that activation of GABAA receptor in CeA, possibly leading to stress reduction, is involved in mediating ethanol-seeking/drinking behavior.
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