Serotonergic Neuroplasticity in Alcohol Addiction

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Abstract

Alcohol addiction is a debilitating disorder producing maladaptive changes in the brain, leading drinkers to become more sensitive to stress and anxiety. These changes are key factors contributing to alcohol craving and maintaining a persistent vulnerability to relapse.

Serotonin (5-Hydroxytryptamine, 5-HT) is a monoamine neurotransmitter widely expressed in the central nervous system where it plays an important role in the regulation of mood. The serotonin system has been extensively implicated in the regulation of stress and anxiety, as well as the reinforcing properties of all of the major classes of drugs of abuse, including alcohol. Dysregulation within the 5-HT system has been postulated to underlie the negative mood states associated with alcohol use disorders.

This review will describe the serotonergic (5-HTergic) neuroplastic changes observed in animal models throughout the alcohol addiction cycle, from prenatal to adulthood exposure. The first section will focus on alcohol-induced 5-HTergic neuroadaptations in offspring prenatally exposed to alcohol and the consequences on the regulation of stress/anxiety. The second section will compare alterations in 5-HT signalling induced by acute or chronic alcohol exposure during adulthood and following alcohol withdrawal, highlighting the impact on the regulation of stress/anxiety signalling pathways. The third section will outline 5-HTergic neuroadaptations observed in various genetically-selected ethanol preferring rat lines. Finally, we will discuss the pharmacological manipulation of the 5-HTergic system on ethanol- and anxiety/stress-related behaviours demonstrated by clinical trials, with an emphasis on current and potential treatments.

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Most cited references 281

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RECOGNITION OF THE FETAL ALCOHOL SYNDROME IN EARLY INFANCY

KennethL. Jones, DavidW. Smith (1973)

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Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse.

Youzhi Li, P Sawchenko, Szeman Chan … (2000)

Two G protein-coupled receptors have been identified that bind corticotropin-releasing factor (CRF) and urocortin (UCN) with high affinity. Hybridization histochemical methods were used to shed light on controversies concerning their localization in rat brain, and to provide normative distributional data in mouse, the standard model for genetic manipulation in mammals. The distribution of CRF-R1 mRNA in mouse was found to be fundamentally similar to that in rat, with expression predominating in the cerebral cortex, sensory relay nuclei, and in the cerebellum and its major afferents. Pronounced species differences in distribution were few, although more subtle variations in the relative strength of R1 expression were seen in several forebrain regions. CRF-R2 mRNA displayed comparable expression in rat and mouse brain, distinct from, and more restricted than that of CRF-R1. Major neuronal sites of CRF-R2 expression included aspects of the olfactory bulb, lateral septal nucleus, bed nucleus of the stria terminalis, ventromedial hypothalamic nucleus, medial and posterior cortical nuclei of the amygdala, ventral hippocampus, mesencephalic raphe nuclei, and novel localizations in the nucleus of the solitary tract and area postrema. Several sites of expression in the limbic forebrain were found to overlap partially with ones of androgen receptor expression. In pituitary, rat and mouse displayed CRF-R1 mRNA signal continuously over the intermediate lobe and over a subset of cells in the anterior lobe, whereas CRF-R2 transcripts were expressed mainly in the posterior lobe. The distinctive expression pattern of CRF-R2 mRNA identifies additional putative central sites of action for CRF and/or UCN. Constitutive expression of CRF-R2 mRNA in the nucleus of the solitary tract, and stress-inducible expression of CRF-R1 transcripts in the paraventricular nucleus may provide a basis for understanding documented effects of CRF-related peptides at a loci shown previously to lack a capacity for CRF-R expression or CRF binding. Other such "mismatches" remain to be reconciled. Copyright 2000 Wiley-Liss, Inc.

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Alcoholism: allostasis and beyond.

George F Koob (2003)

Alcoholism is a chronic relapsing disorder characterized by compulsive drinking, loss of control over intake, and impaired social and occupational function. Animal models have been developed for various stages of the alcohol addiction cycle with a focus on the motivational effects of withdrawal, craving, and protracted abstinence. A conceptual framework focused on allostatic changes in reward function that lead to excessive drinking provides a heuristic framework with which to identify the neurobiologic mechanisms involved in the development of alcoholism. Neuropharmacologic studies in animal models have provided evidence for specific neurochemical mechanisms in specific brain reward and stress circuits that become dysregulated during the development of alcohol dependence. The brain reward system implicated in the development of alcoholism comprises key elements of a basal forebrain macrostructure termed the extended amygdala that includes the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and a transition zone in the medial (shell) part of the nucleus accumbens. There are multiple neurotransmitter systems that converge on the extended amygdala that become dysregulated during the development of alcohol dependence, including gamma-aminobutyric acid, opioid peptides, glutamate, serotonin, and dopamine. In addition, the brain stress systems may contribute significantly to the allostatic state. During the development of alcohol dependence, corticotropin-releasing factor may be recruited, and the neuropeptide Y brain antistress system may be compromised. These changes in the reward and stress systems are hypothesized to maintain hedonic stability in an allostatic state, as opposed to a homeostatic state, and as such convey the vulnerability for relapse in recovering alcoholics. The allostatic model not only integrates molecular, cellular, and circuitry neuroadaptations in brain motivational systems produced by chronic alcohol ingestion with genetic vulnerability but also provides a key to translate advances in animal studies to the human condition.

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Author and article information

Journal

Journal ID (nlm-ta): Brain Plast

Journal ID (iso-abbrev): Brain Plast

Journal ID (publisher-id): BPL

Title: Brain Plasticity

Publisher: IOS Press (Nieuwe Hemweg 6B, 1013 BG Amsterdam, The Netherlands )

ISSN (Print): 2213-6304

ISSN (Electronic): 2213-6312

Publication date (Electronic, preprint): 26 February 2016

Publication date (Electronic, pub): 29 June 2016

Publication date (Electronic, collection): 2016

Volume: 1

Issue: 2

Pages: 177-206

Affiliations

[a ] Translational Research Institute, Queensland University of Technology , Brisbane, Australia

[b ] Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology , Brisbane, Australia

Author notes

[* ]Correspondence to: Arnauld Belmer and Selena E. Bartlett, Addiction Neuroscience and Obesity Group - Translational Research Institute- Institute of Health and Biomedical Innovation - Queensland University of Technology. 37 Kent St, Woolloongabba, 4102, QLD, Australia. Tel.: +61 7 3443 7291; Fax: +61 7 3443 6966; E-mail: arnauld.belmer@ 123456qut.edu.au (A. Belmer), Tel.: +61 7 3443 7238; Fax: +61 7 3443 6966; E-mail: Selena.bartlett@ 123456qut.edu.au (S.E. Bartlett).

Article

Publisher ID: BPL150022

DOI: 10.3233/BPL-150022

PMC ID: 5928559

PubMed ID: 29765841

SO-VID: bbbd8f82-7ad5-445b-a648-95711c1fa6cf

License:

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Serotonergic Neuroplasticity in Alcohol Addiction

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Serotonin and BEYOND

Most cited references 281

RECOGNITION OF THE FETAL ALCOHOL SYNDROME IN EARLY INFANCY

Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse.

Alcoholism: allostasis and beyond.

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