Elsevier

Alcohol

Volume 43, Issue 7, November 2009, Pages 509-519
Alcohol

Neurobiological mechanisms contributing to alcohol–stress–anxiety interactions

https://doi.org/10.1016/j.alcohol.2009.01.002Get rights and content

Abstract

This article summarizes the proceedings of a symposium that was presented at a conference entitled “Alcoholism and Stress: A Framework for Future Treatment Strategies.” The conference was held in Volterra, Italy on May 6–9, 2008 and this symposium was chaired by Jeff L. Weiner. The overall goal of this session was to review recent findings that may shed new light on the neurobiological mechanisms that underlie the complex relationships between stress, anxiety, and alcoholism. Dr. Danny Winder described a novel interaction between D1 receptor activation and the corticotrophin-releasing factor (CRF) system that leads to an increase in glutamatergic synaptic transmission in the bed nucleus of the stria terminalis. Dr. Marisa Roberto presented recent data describing how protein kinase C epsilon, ethanol, and CRF interact to alter GABAergic inhibition in the central nucleus of the amygdala. Dr. Jeff Weiner presented recent advances in our understanding of inhibitory circuitry within the basolateral amygdala (BLA) and how acute ethanol exposure enhances GABAergic inhibition in these pathways. Finally, Dr. Brian McCool discussed recent findings on complementary glutamatergic and GABAergic adaptations to chronic ethanol exposure and withdrawal in the BLA. Collectively, these investigators have identified novel mechanisms through which neurotransmitter and neuropeptide systems interact to modulate synaptic activity in stress and anxiety circuits. Their studies have also begun to describe how acute and chronic ethanol exposure influence excitatory and inhibitory synaptic communication in these pathways. These findings point toward a number of novel neurobiological targets that may prove useful for the development of more effective treatment strategies for alcohol use disorders.

Introduction

There is a large and growing body of clinical and preclinical evidence suggesting an important, albeit complex, relationship between stress, anxiety, and alcohol use disorders (AUDs) (Kushner et al., 2000a, Piazza and Le Moal, 1998, Roberts et al., 2000, Weiss et al., 2001). For example, clinical studies have documented a significant degree of comorbidity between anxiety disorders and AUDs (Kessler et al., 1997, Kushner et al., 1999, Regier et al., 1990). Furthermore, ethanol dependence is often viewed as a chronic relapsing disease (Heilig and Egli, 2006) and there is evidence that stress and anxiety may promote relapse and negatively influence treatment prognosis (Fox et al., 2007, Kushner et al., 2005, Miller and Harris, 2000, Sinha and Li, 2007, Willinger et al., 2002).

Although these and many other studies consistently report a strong association between anxiety and AUDs (see Bradizza et al., 2006, Cosci et al., 2007, Kushner et al., 2000a), the etiological nature of this relationship is not well understood. However, recent preclinical findings are beginning to shed light on this clinically important topic. Human and animal studies have shown that acute exposure to low-to-moderate doses of ethanol are anxiolytic (see Koob, 2004, Kushner et al., 2000a for reviews) and repeated exposure and withdrawal are associated with neuroadaptive changes that may lead to persistent increases in a range of anxiety measures (Kliethermes, 2005, Roberts et al., 2000, Santucci et al., 2008, Valdez et al., 2002). Several studies have also shown that, during withdrawal, ethanol-exposed animals display significant increases in voluntary ethanol consumption (Becker and Lopez, 2004, Lopez and Becker, 2005, Roberts et al., 1996). Moreover, increased intake in ethanol-dependent animals can be effectively reduced by treatments that can attenuate withdrawal-associated anxiety (e.g., CRF1-R [receptor] antagonists) (Chu et al., 2007, Roberts et al., 1995, Valdez et al., 2002). These and other recent findings have led to the recognition that ethanol use and abuse likely involve both the positive and negative reinforcing effects of this drug (Koob and Le Moal, 2005). Early on, the positive or euphoric effects of ethanol (associated with the classical activation of the mesolimbic reward circuit) may dominate. However, following prolonged ethanol exposure and/or in some individuals with pre-existing anxiety disorders (Cosci et al., 2007, Kushner et al., 2000b), the negative reinforcing effects of ethanol, including anxiolysis, may become increasingly important and play a major role in both the development of abusive drinking behavior and in relapse (Koob and Le Moal, 2008, Le Moal and Koob, 2007, Lopez and Becker, 2005).

Interestingly, although much is known about the basic neurophysiological mechanisms underlying ethanol's positive reinforcing effects, the neural substrates responsible for the negative reinforcing effects of this drug (including relief from anxiety) are much less understood. To that end, this symposium sought to highlight recent advances in our understanding of how synaptic communication in brain regions that regulate stress- and anxiety-related behaviors (e.g., amygdala, bed nucleus of the stria terminalis) can be modulated by endogenous factors such as dopamine and corticotrophin-releasing factor (CRF) as well as acute and chronic ethanol.

Section snippets

Maureen Cruz, Michal Bajo, George R. Siggins, Robert O. Messing, and Marisa Roberto

CRF is an anxiogenic neuropeptide and an important component of the stress circuits that modulate anxiety associated with drug dependence. The anxiogenic effects of CRF are mediated by type 1 CRF receptors (CRF-R1s), which are abundantly expressed in the cortex, cerebellum, hippocampus, amygdala, olfactory bulb, and pituitary (Chalmers et al., 1996, Palchaudhuri et al., 1998, Potter et al., 1994). CRF-R1 activation also plays an important role in regulating voluntary ethanol intake. The central

Thomas L. Kash and Danny G. Winder

Drugs of abuse, including alcohol, are thought to exert effects on behavior through modulation of neuronal activity and plasticity in specific brain regions. A great deal of effort has been focused on understanding the impact of drugs of abuse on the mesolimbic dopamine system, in particular the dopamine neurons of the ventral tegmental area (VTA) (Borgland et al., 2006) and the medium spiny neurons of the nucleus accumbens (Thomas et al., 2001), as this network is thought to serve as a common

Yuval Silberman and Jeff L. Weiner

Along with the BNST and CeA discussed earlier, the basolateral amygdala (BLA) is also an integral element of both stress/anxiety (Davis et al., 1994, LeDoux, 1993) and reward neurocircuitry (Balleine and Killcross, 2006, Tye et al., 2008). The groups of cells within the lateral, basal, and accessory basal nuclei of the amygdala are typically referred to as the BLA. This brain region consists primarily of glutamatergic pyramidal neurons (∼90% of all cells in the BLA), which provide the main

Anna K. Lack, Marvin R. Diaz, Daniel T. Christian, Ann M. Chappell, and Brian A. McCool

The lateral/BLA is a central component of the brain's fear/anxiety circuit and acts as the primary input nuclei of the amygdala. For example, the BLA receives extensive input from sensory/limbic/insular cortex and thalamic nuclei (Angleton et al., 1980). The region in turn provides major excitatory input to the neighboring central nucleus (Nose et al., 1991), to the nucleus accumbens (North et al., 1987), and has extensive reciprocal connections with medial prefrontal and orbitofrontal cortex (

Summary

The results of these studies provide new insight into some of the modulatory mechanisms that regulate fast synaptic communication within brain regions involved in both reward and stress/anxiety systems. In particular, CRF signaling has emerged as an important presynaptic regulator of excitatory and inhibitory synaptic transmission in some of these areas. In the BNST, activation of CRF-R1s mediates dopamine enhancement of glutamate release (Kash et al., 2008), whereas CRF-R1s in the CeA can

Acknowledgments

This work was supported by NIH grants AA017039 (Y.S.); AA017576 (M.R.D.); AA017668 and AA016025 (T.L.K.); AA10994 and AA013498 (G.R.S.); AA013588 (R.O.M.); DA 019112 and AA 013641 (D.G.W.); AA017581, AA016985, AA015566, and AA06420 (M.R.); AA014445, AA016671, and AA017053 (B.A.W.); AA013960 and AA017053 (J.L.W.) and by the Helen Dorris Neurological Research Center (M.R.).

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