RSA 2005 Abstracts Scripps

RSA 2005 Abstracts

THE SCRIPPS RESEARCH INSTITUTE, LA JOLLA

DELTA OPIOID RECEPTOR ROLE IN ETHANOL REINFORCEMENT AND AMYGDALA ELECTROPHYSIOLOGICAL PARAMETERS

S.D. Moore, B.L. Kieffer, A.J. Roberts, M.-H. Kang-Park, G.R. Siggins

Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037

Delta opioid receptors (DOR) appear to have an interesting role in mediating the effects of ethanol, especially with regard to behaviors and physiology postulated to involve extended amygdala circuitry. DOR KO mice develop a preference for ethanol following operant ethanol self-administration training and consume amounts of ethanol equivalent to that observed in ethanol-preferring mouse strains. In addition, DOR KO mice showed evidence of increased anxiety-like behavior relative to wild-type (WT) littermates in two tests of anxiety, the elevated plus-maze and light-dark box. This anxiety-like behavior of KO mice was attenuated by self-administered ethanol. This is a very important finding because it suggests that one role of the delta receptor may be in mediating the interaction between anxiety states and ethanol consumption. It has been hypothesized that extended amygdala circuitry is involved in both reward and anxiety-like behaviors; therefore, we have begun to examine the role of DOR in GABA-induced inhibitory currents in neurons of the central nucleus of the amygdala (CeA). Ethanol increases GABA currents in the CeA of WT mice, an effect that is further enhanced in slices treated with a DOR antagonist. Consistent with this finding, CeA slices from DOR KO mice also show enhanced release following ethanol application. This effect is hypothesized to be due to less inhibitory feedback on GABA release in the absence of DOR function. Therefore, lack of DOR functioning appears to be allowing for greater inhibitory GABA activity, which may account for increased rewarding and anxiolytic-like effects of ethanol in these mice. These same behavioral and physiological experiments have been performed in mice lacking the mu opioid receptor (MOR). MOR KO mice do not self-administer ethanol and their CeA slice preparations do not show the enhanced ethanol-induced GABA current observed in slices of DOR KO mice. These data suggest that that DOR and MOR may regulate at least some of the effects of ethanol in an opposing manner. Supported by the Integrative Neuroscience Initiative on Alcoholism

ETHANOL-CRF INTERACTIONS AT GABAERGIC SYNAPSES IN RAT CENTRAL AMYGDALA

Marisa Roberto, Paul Schweitzer, Samuel G. Madamba, Zhiguo Nie and George Robert Siggins

The Scripps Research Institute, Department of Neuropharmacology, 10550 N. Torrey Pines, La Jolla, CA 92037

Corticotropin-releasing factor (CRF) in the central nucleus of the amygdala (CeA) plays an important role in regulating ethanol consumption and in the anxiogenic response to ethanol withdrawal. We previously showed that acute ethanol augmented evoked GABAA receptor-mediated inhibitory postsynaptic potentials and currents (GABAA-IPSP/Cs) in most CeA neurons from both rat and mouse, in part by a presynaptic mechanism (Roberto et al., 2003 PNAS 100:2053-58). In mouse CeA this presynaptic ethanol effect is mediated by presynaptic CRF1 receptors (CRF1Rs) (Nie et al., 2004 Science 303:1412-14). In CeA from chronic ethanol-treated (CET) rats, acute ethanol significantly enhanced GABAA-IPSP/Cs to an equivalent extent to that in slices from naïve rats, suggesting lack of tolerance (Roberto et al., 2004 J. of Neurosci. 24:10159-66). Here we have examined the effects of CRF and (acute and chronic) ethanol on GABAergic transmission in rat CeA neurons. We found that 200 nM CRF significantly enhanced (to 140%, n = 9) evoked IPSP/C amplitudes in CeA of naïve rats. Notably, 44 mM ethanol in the presence of CRF further increased (to 195%) IPSP/C amplitudes. CRF also decreased the PPF ratio of IPSP/Cs in rat CeA and co-applied with ethanol further decreased PPF ratio, suggesting additive presynaptic effects at these concentrations. The selective CRF1R antagonists NIH-3 and Antalarmin decreased basal IPSP/C amplitudes and prevented their increase by ethanol. Both NIH-3 and Antalarmin increased (by 20%) the PPF ratio of IPSP/Cs, suggesting a decreased GABA release that opposes the ethanol effect. Interestingly, in CeA of CET rats the ability of 200 nM CRF to increase IPSP/Cs was enhanced (to 165%, n = 9) compared to naïve CeA. In contrast, after CET acute ethanol in the presence of CRF only slightly increased IPSP/C amplitudes. In CeA slices from CET rats the inhibition of basal IPSP/Cs by Antalarmin was greater compared to control rats. These findings suggest an important ethanol-CRF interaction on GABAergic transmission in CeA that plays a significant role in the development of ethanol dependence. Supported by grants from the National Institute of Alcohol Abuse and Alcoholism, NIH U01 AA013517-INIA Project, U01 AA013498-INIA Project and R01 AA-06420.

THE ROLE OF ANXIETY AND ABSTINENCE ON MOUSE DRINKING BEHAVIOR

K. Chu, G.F. Koob, A.J. Roberts

Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037

The affective signs of ethanol withdrawal such as anxiety, increased responsiveness to stressors, and depressed mood, appear to be critically important in relapse to drinking in alcoholics. However the results of animal experiments examining the relationship between affect and ethanol consumption have been inconsistent. As most studies to date have focused on non-dependent animals, it is possible that anxiety-like behavior and ethanol self-administration are significantly correlated (increased anxiety-like behavior will be associated with increased ethanol self-administration) only in ethanol dependent individuals. Therefore we have developed a mouse model of increased operant ethanol self-administration in mice made dependent and then allowed a period of abstinence. Most mice experiencing protracted abstinence respond for more than 1 g/kg ethanol in the first 30 minutes of the test session, which represents a doubling of intake under these conditions. Using a similar procedure, mice have been shown to display increased anxiety-like behavior during protracted abstinence. Recently we have been exploring these phenomena from a mechanistic standpoint. For example, corticotropin releasing factor (CRF) Receptor 1 (CRF1) null mutant mice do not display increased anxiety-like behavior during ethanol withdrawal, and the CRF1 antagonist, antalarmin, blocks the increased ethanol self-administration observed during abstinence. 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, at least in part, by CRF. Supported by the Integrated Neuroscience Initiative on Alcoholism (AA13482 and AA13523).

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