Chronic Daily Ethanol and Withdrawal: 1. Long-Term Changes in the Hypothalamo-Pituitary-Adrenal Axis

Rasmussen, Dennis D.; Boldt, Brian M.; Bryant, Carrie A.; Mitton, Dennis R.; Larsen, Shana A.; Wilkinson, Charles W.

doi:10.1097/00000374-200012000-00013

Cited by 88 publications

(122 citation statements)

References 83 publications

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“…This LTD could thus serve to disengage the inhibitory influence of the BNST on the PVN under stressful conditions. Additionally, the HPA axis has altered function in both human disease states (43) and rodent models of affective disorders (44,45), which may suggest a pathological role for this plasticity or the lack of α 1 -AR LTD and CP-AMPAR function. In future studies, it will be important to delineate the pattern and duration of alcohol/stress exposures necessary to modulate α 1 -AR LTD as well as the persistence of this modulation.…”

Section: Discussionmentioning

confidence: 99%

Distinct forms of G _q -receptor-dependent plasticity of excitatory transmission in the BNST are differentially affected by stress

McElligott

Klug

Nobis

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Long-term depression (LTD) is an important synaptic mechanism for limiting excitatory influence over circuits subserving cognitive and emotional behavior. A major means of LTD induction is through the recruitment of signaling via G q -linked receptors activated by norepinephrine (NE), acetylcholine, and glutamate. Receptors from these transmitter families have been proposed to converge on a common postsynaptic LTD maintenance mechanism, such that hetero-and homosynaptic induction produce similar alterations in glutamate synapse efficacy. We report that in the dorsolateral and ventrolateral bed nucleus of the stria terminalis (BNST), recruitment of G q -linked receptors by glutamate or NE initiates mechanistically distinct forms of postsynaptically maintained LTD and these LTDs are differentially regulated by stress exposure. In particular, we show that although both mGluR5-and α 1 -adrenergic receptor (AR)-dependent LTDs involve postsynaptic endocytosis, the α 1 -AR-initiated LTD exclusively involves modulation of signaling through calcium-permeable AMPA receptors. Further, α 1 -AR-but not mGluR5-dependent LTD is disrupted by restraint stress. α 1 -AR LTD is also impaired in mice chronically exposed to ethanol. These data thus suggest that in the BNST, NE-and glutamate-activated G q -linked signaling pathways differentially tune glutamate synapse efficacy in response to stress.addiction | norepinephrine | metabotropic glutamate receptor | calcium-permeable AMPA receptor | ethanol A lterations in key amygdalar and reward circuitries have been proposed as potential mechanisms underlying interrelated anxiety disorders and addiction. The bed nucleus of the stria terminalis (BNST) is a nucleus within a series of structures known as the "extended amygdala," which receives a mix of glutamatergic inputs from cognitive and systemic brain centers and projects to key nuclei in both the reward and stress circuitries (1, 2). Consistent with this anatomy, a large literature indicates key roles of this region in anxiety-related behaviors, addiction, and other affective disorders (3).The BNST receives intense noradrenergic innervation through the ventral noradrenergic bundle (VNAB) (4). Disruption of the VNAB or noradrenergic signaling in the BNST alters responses to stressors, preference for opiates, and stress-induced reinstatement to drug seeking (5, 6). α 1 -Adrenergic receptors (ARs) are G qlinked G-protein-coupled receptors (GPCRs) that participate in shaping responses to stressors. Signaling through BNST α 1 -ARs within the BNST potently regulates the hypothalamic-pituitaryadrenal (HPA) stress axis and anxiety responses after stressors (7). The α 1 -AR antagonist prazosin has been shown to attenuate ethanol self-administration (SA) in ethanol-dependent rats (8) and reduces opiate SA (9). Furthermore, data from clinical trials have demonstrated that prazosin alleviates symptoms of posttraumatic stress disorder (PTSD) (10) and reduces alcohol drinking behavior in alcoholics (11).Like α 1 -ARs, group I metabotropic glutamat...

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Section: Discussionmentioning

confidence: 99%

Distinct forms of G _q -receptor-dependent plasticity of excitatory transmission in the BNST are differentially affected by stress

McElligott

Klug

Nobis

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…The different outcomes could be caused by different Ca V 3.1 splice variants (46). The changes in excitability after sustained abstinence add to a number of alterations produced by chronic ethanol that persist after acute withdrawal, such as the up-regulation of NMDA receptor activity (47) and aberrant hypothalamo-pituitary-adrenal axis function (48), or that reverse and overshoot the preethanol state, such as for cannabinoid synaptic transmission (49). Key questions are whether the suppressed excitability requires repeated abstinences and can recover and whether the adaptation observed in CI neurons provides resistance to ethanol.…”

Section: Discussionmentioning

confidence: 99%

Bidirectional plasticity in the primate inferior olive induced by chronic ethanol intoxication and sustained abstinence

Welsh¹,

Han

Rossi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The brain adapts to chronic ethanol intoxication by altering synaptic and ion-channel function to increase excitability, a homeostatic counterbalance to inhibition by alcohol. Delirium tremens occurs when those adaptations are unmasked during withdrawal, but little is known about whether the primate brain returns to normal with repeated bouts of ethanol abuse and abstinence. Here, we show a form of bidirectional plasticity of pacemaking currents induced by chronic heavy drinking within the inferior olive of cynomolgus monkeys. Intracellular recordings of inferior olive neurons demonstrated that ethanol inhibited the tail current triggered by release from hyperpolarization (I tail ). Both the slow deactivation of hyperpolarization-activated cyclic nucleotide-gated channels conducting the hyperpolarization-activated inward current and the activation of Ca v 3.1 channels conducting the T-type calcium current (I T ) contributed to I tail , but ethanol inhibited only the I T component of I tail . Recordings of inferior olive neurons obtained from chronically intoxicated monkeys revealed a significant up-regulation in I tail that was induced by 1 y of daily ethanol self-administration. The up-regulation was caused by a specific increase in I T which (i) greatly increased neurons' susceptibility for rebound excitation following hyperpolarization and (ii) may have accounted for intention tremors observed during ethanol withdrawal. In another set of monkeys, sustained abstinence produced the opposite effects: (i) a reduction in rebound excitability and (ii) a down-regulation of I tail caused by the down-regulation of both the hyperpolarizationactivated inward current and I T . Bidirectional plasticity of two hyperpolarization-sensitive currents following chronic ethanol abuse and abstinence may underlie persistent brain dysfunction in primates and be a target for therapy.A cute ethanol withdrawal affects millions of people and can require management of a syndrome that consists of dysautonomia, seizures, cognitive disturbance, and tremor (1, 2). It generally is agreed that the washout of ethanol from the brain during acute withdrawal unmasks the physiological adaptations of neurons that allow them to function while they are bathed in ethanol (3, 4). It sometimes is assumed that once the symptoms of acute withdrawal are managed, long-term abstinence from ethanol gradually restores the brain to a preethanol state. Nevertheless, an alcoholic's drive to ingest ethanol can persist even after months or years of abstinence, and alcoholics can undergo multiple abstinences from alcohol in their lifetime.We tested the hypothesis that adaptations in the intrinsic electrical properties of inferior olive (IO) neurons are changed by chronic ethanol intake and by subsequent abstinence. We used patch-clamp recordings of IO neurons in acutely prepared brainstem slices from chronically intoxicated cynomolgus monkeys (5-7) to examine changes in intrinsic electrical properties with ethanol intake and repeated abstinences. We addressed two qu...

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“…These interactions might suggest that stress hormones could regulate the response of pre-proCRF to chronic ethanol. However, there is conflicting evidence regarding the effects of chronic ethanol on resting levels of corticosterone (Guaza et al, 1983;Rasmussen et al, 2000). Despite these contrasting reports, chronic exposure can blunt both circadian cycling of corticosterone (Sipp et al, 1993) as well as the responsiveness of the HPA axis to external stressors (Ogilvie et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Chronic ethanol ingestion modulates proanxiety factors expressed in rat central amygdala

Läck

Floyd

McCool

2005

Alcohol

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Withdrawal anxiety following chronic ethanol is often associated with relapse in recovering alcoholics. It is likely that brain regions regulating anxiety-like behaviors adapt during chronic ethanol to ultimately regulate such behaviors. The central amygdala contains numerous neurotransmitter systems that have been implicated in the regulation of anxiety-like behavior, including corticotropin releasing factor (CRF) and N-methyl-D-Aspartate (NMDA)-type glutamate receptors. Chronic ethanol exposure causes functional adaptations in both CRF and NMDA receptors that are likely to regulate anxiety-like behaviors expressed during withdrawal. However, the molecular mechanisms governing these adaptations remain un-explored. We therefore evaluated these neurotransmitter systems in Sprague-Dawley rats during chronic ingestion of an ethanolcontaining liquid diet. Quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) demonstrated that pre-proCRF mRNA was significantly up-regulated by chronic ethanol exposure while CRF binding protein mRNA expression did not change. There were also no significant changes observed in any of the NMDA subunit mRNAs, although there was a trend toward greater NR2A mRNA expression during chronic ethanol. Using Western blotting analysis we measured NMDA receptor subunit protein expression. Chronic ethanol exposure did not affect protein levels of the NR1 and NR2B subunits. Like the mRNA measures, chronic ethanol did influence NR2A protein levels but the effects were modest. Our results demonstrate that NMDA receptor subunit mRNA and protein expression are not strongly influenced by exposure to chronic ethanol. This suggests that the functional NMDA receptor adaptations identified by previous studies (Roberto et al., 2004) are likely to be mediated by post-translational events. In contrast, enhanced levels of CRF during/after chronic ethanol are likely to be mediated by increased levels of preproCRF mRNA. Together, our findings suggest that adaptations to chronic ethanol by pro-anxiety factors expressed in the central nucleus appear to be mediated by distinct cellular and molecular mechanisms.

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Chronic Daily Ethanol and Withdrawal: 1. Long-Term Changes in the Hypothalamo-Pituitary-Adrenal Axis

Cited by 88 publications

References 83 publications

Distinct forms of G _q -receptor-dependent plasticity of excitatory transmission in the BNST are differentially affected by stress

Distinct forms of G _q -receptor-dependent plasticity of excitatory transmission in the BNST are differentially affected by stress

Bidirectional plasticity in the primate inferior olive induced by chronic ethanol intoxication and sustained abstinence

Chronic ethanol ingestion modulates proanxiety factors expressed in rat central amygdala

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Chronic Daily Ethanol and Withdrawal: 1. Long-Term Changes in the Hypothalamo-Pituitary-Adrenal Axis

Cited by 88 publications

References 83 publications

Distinct forms of G q -receptor-dependent plasticity of excitatory transmission in the BNST are differentially affected by stress

Distinct forms of G q -receptor-dependent plasticity of excitatory transmission in the BNST are differentially affected by stress

Bidirectional plasticity in the primate inferior olive induced by chronic ethanol intoxication and sustained abstinence

Chronic ethanol ingestion modulates proanxiety factors expressed in rat central amygdala

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Product

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Distinct forms of G _q -receptor-dependent plasticity of excitatory transmission in the BNST are differentially affected by stress

Distinct forms of G _q -receptor-dependent plasticity of excitatory transmission in the BNST are differentially affected by stress