Differential activation of limbic circuitry associated with chronic ethanol withdrawal in DBA/2J and C57BL/6J mice

Department of Behavioral Neuroscience and Portland Alcohol Research Center, Oregon Health & Science University, Portland, OR 97239-03098, USA.
Alcohol (Fayetteville, N.Y.) (Impact Factor: 2.01). 09/2009; 43(6):411-20. DOI: 10.1016/j.alcohol.2009.05.003
Source: PubMed

ABSTRACT Although no animal model exactly duplicates clinically defined alcoholism, models for specific factors, such as the withdrawal syndrome, are useful for identifying potential neural determinants of liability in humans. The well-documented difference in withdrawal severity following chronic ethanol exposure, between the DBA/2J and C57BL/6J mouse strains, provides an excellent starting point for dissecting the neural circuitry affecting predisposition to physical dependence on ethanol. To induce physical dependence, we used a paradigm in which mice were continuously exposed to ethanol vapor for 72h. Ethanol-exposed and air-exposed (control) mice received daily injections of pyrazole hydrochloride, an alcohol dehydrogenase inhibitor, to stabilize blood ethanol levels. Ethanol-dependent and air-exposed mice were killed 7h after removal from the inhalation chambers. This time point corresponds to the time of peak ethanol withdrawal severity. The brains were processed to assess neural activation associated with ethanol withdrawal indexed by c-Fos immunostaining. Ethanol-withdrawn DBA/2J mice showed significantly (P<.05) greater neural activation than ethanol-withdrawn C57BL/6J mice in the dentate gyrus, hippocampus CA3, lateral septum, basolateral and central nuclei of the amygdala, and prelimbic cortex. Taken together with results using an acute model, our data suggest that progression from acute ethanol withdrawal to the more severe withdrawal associated with physical dependence following chronic ethanol exposure involves recruitment of neurons in the hippocampal formation, amygdala, and prelimbic cortex. To our knowledge, these are the first studies to use c-Fos to identify the brain regions and neurocircuitry that distinguish between chronic and acute ethanol withdrawal severity using informative animal models.

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Available from: Laura B Kozell, Sep 27, 2015
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    • "Separate studies gave bilateral microinjections of ALLO or FIN into the substantia nigra reticulata (SNR) or ventral tegmental area (VTA). The SNR is important in the propagation of convulsive activity (e.g., Gale, 1988; Velı´sˇkovaánd Moshe´, 2006), and both the SNR and VTA exhibit an activation in c-fos expression during acute (Kozell et al., 2005) and chronic (Chen et al., 2009; Olive et al., 2001) EtOH withdrawal. We predicted that WSP-1 male mice would exhibit behavioral tolerance to the anticonvulsant effect of intra-SNR and intra- VTA ALLO during EtOH withdrawal and that intra-SNR and intra-VTA FIN would enhance EtOH withdrawal severity. "
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    ABSTRACT: Background: Allopregnanolone (ALLO) is a potent positive modulator of γ-aminobutyric acidA receptors (GABAA Rs) that affects ethanol (EtOH) withdrawal. Finasteride (FIN), a 5α-reductase inhibitor that blocks the formation of ALLO and other GABAergic neurosteroids, alters EtOH sensitivity. Recently, we found that Withdrawal Seizure-Prone mice from the first genetic replicate (WSP-1) exhibited behavioral tolerance to the anticonvulsant effect of intrahippocampal ALLO during EtOH withdrawal and that intrahippocampal FIN significantly increased EtOH withdrawal severity. The purpose of this study was to determine whether neurosteroid manipulations in the substantia nigra reticulata (SNR) and ventral tegmental area (VTA) produced effects during EtOH withdrawal comparable to those seen with intrahippocampal ALLO and FIN. Methods: Male WSP-1 mice were surgically implanted with bilateral guide cannulae aimed at the SNR or VTA at 2 weeks prior to EtOH vapor or air exposure for 72 hours. Initial studies examined the anticonvulsant effect of a single ALLO infusion (0, 100, or 400 ng/side) at a time corresponding to peak withdrawal in the air- and EtOH-exposed mice. Separate studies examined the effect of 4 FIN infusions (0 or 10 μg/side/d) during the development of physical dependence on the expression of EtOH withdrawal. Results: ALLO infusion exerted a potent anticonvulsant effect in EtOH-naïve mice, but a diminished anticonvulsant effect during EtOH withdrawal. Administration of FIN into the SNR exerted a delayed proconvulsant effect in EtOH-naïve mice, whereas infusion into the VTA increased EtOH withdrawal duration. Conclusions: Activation of local GABAA Rs in the SNR and VTA via ALLO infusion is sufficient to exert an anticonvulsant effect in naïve mice and to produce behavioral tolerance to the anticonvulsant effect of ALLO infusion during EtOH withdrawal. Thus, EtOH withdrawal reduced sensitivity of GABAA Rs to GABAergic neurosteroids in 2 neuroanatomical substrates within the basal ganglia in WSP-1 male mice.
    Alcoholism Clinical and Experimental Research 12/2012; 37(5). DOI:10.1111/acer.12027 · 3.21 Impact Factor
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    • "The LS, in particular, has been shown to regulate ethanol consumption [8], [55]. Moreover, the LS showed greater neural activity following alcohol withdrawal [56]. This particular study used the parent strains of the BXD RI line (B6 and D2), which are known to differ in sensitivity to alcohol and to its withdrawal [57]. "
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    ABSTRACT: The lateral septum has strong efferent projections to hypothalamic and midbrain regions, and has been associated with modulation of social behavior, anxiety, fear conditioning, memory-related behaviors, and the mesolimbic reward pathways. Understanding natural variation of lateral septal anatomy and function, as well as its genetic modulation, may provide important insights into individual differences in these evolutionarily important functions. Here we address these issues by using efficient and unbiased stereological probes to estimate the volume of the lateral septum in the BXD line of recombinant inbred mice. Lateral septum volume is a highly variable trait, with a 2.5-fold difference among animals. We find that this trait covaries with a number of behavioral and physiological phenotypes, many of which have already been associated with behaviors modulated by the lateral septum, such as spatial learning, anxiety, and reward-seeking. Heritability of lateral septal volume is moderate (h(2) = 0.52), and much of the heritable variation is caused by a locus on the distal portion of chromosome (Chr) 1. Composite interval analysis identified a secondary interval on Chr 2 that works additively with the Chr 1 locus to increase lateral septum volume. Using bioinformatic resources, we identified plausible candidate genes in both intervals that may influence the volume of this key nucleus, as well as associated behaviors.
    PLoS ONE 08/2012; 7(8):e44236. DOI:10.1371/journal.pone.0044236 · 3.23 Impact Factor
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    • "Neuroimaging studies also suggest that this part of the striatum may be associated with alcohol craving (Heinz et al., 2005; Olbrich et al., 2006). The ventral putamen receives projections from the amygdala (Russchen & Price, 1984), which is implicated in ethanol and barbiturate withdrawal (Chen et al., 2009, and unpublished data), and has a prominent role in alcohol preference (Dhaher et al., 2008). Notably, alcohol withdrawal convulsions and preference/ consumption are significantly genetically correlated in mice (Metten & Crabbe, 2005). "
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    ABSTRACT: Different regions of the striatum may have distinct roles in acute intoxication, alcohol seeking, dependence, and withdrawal. The recent advances are reviewed and discussed in our understanding of the role of the dorsolateral striatum (DLS), dorsomedial striatum (DMS), and ventral striatum in behavioral responses to alcohol, including alcohol craving in abstinent alcoholics, and alcohol consumption and withdrawal in rat, mouse, and nonhuman primate models. Reduced neuronal activity as well as dysfunctional connectivity between the ventral striatum and the dorsolateral prefrontal cortex is associated with alcohol craving and impairment of new learning processes in abstinent alcoholics. Within the DLS of mice and nonhuman primates withdrawn from alcohol after chronic exposure, glutamatergic transmission in striatal projection neurons is increased, while GABAergic transmission is decreased. Glutamatergic transmission in DMS projection neurons is also increased in ethanol withdrawn rats. Ex vivo or in vivo ethanol exposure and withdrawal causes a long-lasting increase in NR2B subunit-containing NMDA receptor activity in the DMS, contributing to ethanol drinking. Analyses of neuronal activation associated with alcohol withdrawal and site-directed lesions in mice implicate the rostroventral caudate putamen, a ventrolateral segment of the DMS, in genetically determined differences in risk for alcohol withdrawal involved in physical association of the multi-PDZ domain protein, MPDZ, with 5-HT(2C) receptors and/or NR2B. Alterations of dopaminergic, glutamatergic, and GABAergic signaling within different regions of the striatum by alcohol is critical for alcohol craving, consumption, dependence, and withdrawal in humans and animal models.
    Alcoholism Clinical and Experimental Research 05/2011; 35(10):1739-48. DOI:10.1111/j.1530-0277.2011.01520.x · 3.21 Impact Factor
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