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Alcohol and Violence: Neuropeptidergic Modulation of Monoamine Systems

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Alcohol and Violence: Neuropeptidergic Modulation of Monoamine Systems Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: Addiction Reviews Alcohol and violence: neuropeptidergic modulation of monoamine systems Klaus A. Miczek,1,2 Joseph F. DeBold,2 Lara S. Hwa,2 Emily L. Newman,2 and Rosa M. M. de Almeida3 1Departments of Pharmacology, Psychiatry, and Neuroscience, Tufts University, Boston, Massachusetts. 2Department of Psychology, Tufts University, Medford, Massachusetts. 3Department of Psychology, LPNeC, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil Address for correspondence: Klaus A. Miczek, Department of Psychology, Tufts University, 530 Boston Ave (Bacon Hall), Medford, MA 02155. [email protected] Neurobiological processes underlying the epidemiologically established link between alcohol and several types of social, aggressive, and violent behavior remain poorly understood. Acute low doses of alcohol, as well as withdrawal from long-term alcohol use, may lead to escalated aggressive behavior in a subset of individuals. An urgent task will be to disentangle the host of interacting genetic and environmental risk factors in individuals who are predisposed to engage in escalated aggressive behavior. The modulation of 5-hydroxytryptamine impulse flow by gamma- aminobutyric acid (GABA) and glutamate, acting via distinct ionotropic and metabotropic receptor subtypes in the dorsal raphe nucleus during alcohol consumption, is of critical significance in the suppression and escalation of aggressive behavior. In anticipation and reaction to aggressive behavior, neuropeptides such as corticotropin- releasing factor, neuropeptide Y, opioid peptides, and vasopressin interact with monoamines, GABA, and glutamate to attenuate and amplify aggressive behavior in alcohol-consuming individuals. These neuromodulators represent novel molecular targets for intervention that await clinical validation. Intermittent episodes of brief social defeat during aggressive confrontations are sufficient to cause long-lasting neuroadaptations that can lead to the escalation of alcohol consumption. Keywords: violence; aggression; alcohol; GABA; glutamate; serotonin Introduction Initially, this review highlights several funda- mental and essential pharmacological features of Alcohol has been linked to at least half of all vio- the link between alcohol and aggression, ranging lent assaults, cases of child abuse, and other inci- from the acute effects to the effects of withdrawal dents of domestic violence as well as homicides and after long-term use. Next, we consider the rein- murders.1–3 This association has persisted over sev- forcing actions of aggression and alcohol, both eral decades and extends across most regions of acting on neural circuits in mesolimbic monoamin- the world. While the consumption of alcohol fea- ergic systems. Furthermore, this review links alcohol tures prominently in many celebratory and salient and aggression to a postulated deficiency in brain events in social life, it is the antisocial, destructive serotonin and will outline the different serotonin nature of alcohol’s effects that is of profound con- subsystems and their receptor subtypes. Serotonin cern to the criminal justice system, and as a public (5-hydroxytryptamine, 5-HT) and other canon- health problem.4,5 Surprisingly, the neurobiologi- ical monoaminergic pathways are modulated by cal processes underlying the link between alcohol gamma-aminobutyric acid (GABA) and glutamate, and social, aggressive and violent behavior remain and these excitatory and inhibitory amino acids poorly understood, and there is no effective clini- are critical sites of action for alcohol to esca- cal treatment for violence induced or heightened by late aggressive behavior. Finally, we consider some alcohol. doi: 10.1111/nyas.12862 96 Ann. N.Y. Acad. Sci. 1349 (2015) 96–118 C 2015 New York Academy of Sciences. Miczek et al. Alcohol and violence of the prominent neuropeptides and neuroactive and hostile, affective, impulsive, and reactive steroids and their modulatory action on alcohol and “hot” aggression on the other.12–14 Alcohol aggression. profoundly exacerbates the latter subtypes of aggres- There are several new conclusions about the neu- sion. Important features of the epidemiological data robiological processes that mediate the effects of link alcohol and several major types of violent alcohol on aggressive behavior: behavior ranging from homicides, sexual assaults, rapes, and child abuse to other physical assaults. (1) Significant aggression-heightening effects are This link is large in magnitude and costly to the evident after acute, low alcohol doses as well individual, family, and society.15–18 In addition to as during withdrawal from long-term alcohol the pervasive escalation of many types of impulsive use; alcohol may lead to the distortion of social and reactive violent acts, possibly due to the myopic signals from benign to threatening. perception of threatening stimuli,19 some epidemi- (2) A significant subset of individuals engages ological data point to geographic hot spots and epi- in alcohol-heightened aggression, while most demics of the alcohol-violence link.20 Rather than alcohol-consuming individuals do not exhibit proposing a neurogenetic deterministic account of significant changes in aggressive behavior. the genesis of alcohol-heightened aggressive behav- (3) Subsystems of 5-HT neurons originating in ior, this evidence points to several risk factors that the dorsal raphe nuclei and maturing during may interact with the social context.21,22 specific critical periods appear to contribute to the emergence of aggressive behavior. (4) The modulation of 5-HT impulse flow by Discovery of ethanol’s action on discrete GABA and glutamate, acting via distinct receptors in the brain: 1980–1990 ionotropic and metabotropic receptor sub- A major shift in research on neural sites and mech- types, is of critical significance in the suppres- anisms of ethanol and by implication on the aggres- sion and escalation of aggressive behavior. sogenic effects of ethanol began in the 1980s when (5) In anticipation and reaction to aggressive the focus on the disordering effects of alcohol was behavior, neuropeptides such as cortico- redirected from the lipid component of cell mem- tropin-releasing factor (CRF), neuropeptide Y branes to the action of ethanol on protein compo- (NPY), opioid peptides, and vasopressin inter- nents in neuronal membranes.23 This latter action act with monoamines, GABA, and glutamate was identified at several ionotropic receptors at mil- to attenuate and amplify aggressive behav- limolar concentrations that were more relevant to ior. These neuromodulators represent novel the excitatory effects of ethanol (Fig. 1). targets for intervention and await clinical GABA receptors were among the first ionotropic validation. A receptors shown to increase chloride ion (Cl)-flux (6) Intermittent episodes of brief social defeat as a result of action by 20–100 mM ethanol, and during aggressive confrontations are sufficient this effect was blocked by GABA antagonists.24–27 to cause long-lasting neuroadaptations that A GABA receptors are pentameric ligand-gated ion lead to the escalation of alcohol consumption. A channel complexes composed of at least 16 sub- Activation of the CRF system is necessary for units, with two alpha and beta subunits plus either this social stress-induced escalation of alcohol a gamma or delta subunit being the most typical consumption. compositions for receptors in the mammalian cen- tral nervous system (CNS).28 With the aid of molec- Epidemiological background ular genetic techniques, it appears feasible to learn A consistent series of epidemiological and criminal which subunits need to be expressed in specific brain statistics documents the association between alco- regions for alcohol to achieve specific behavioral hol and violent crimes starting in the 1950s and effects. For example, GABAA receptors that contain extending to the present (Refs. 6–11 and Table 1). a delta subunit instead of a gamma subunit are sen- Clinical diagnoses distinguish among instru- sitive to concentrations of ethanol that are in the mental, calculating, premeditated, and proac- mild to moderately intoxicating range29,30 (but see tive “cold” aggressive acts on the one hand, Ref. 31). Ann. N.Y. Acad. Sci. 1349 (2015) 96–118 C 2015 New York Academy of Sciences. 97 Alcohol and violence Miczek et al. Table 1. Estimates of association between alcohol consumption and homicide rates, hazardous drinking pattern score, and estimated fraction of homicides attributable to alcohol consumption3 Country/area, Parameter Level of hazardous Attributable Author(s) period estimate (SE) drinking pattern fraction (AF) Rossow275 North Europe, 0.124 High 0.50 1950–1995 (0.038) Rossow275 Central Europe, 0.085 Medium 0.55 1950–1995 (0.023) Rossow275 South Europe, 0.055 Low 0.61 1950–1995 (0.017) Rossow276 Canada, Ontario, 0.093 Medium 0.58 1950–1995 (0.040) Rossow276 Canada, Quebec, –0.030 Low na 1950–1995 (0.077) ns Bye277 Belarus and Russia, 0.072 Very high 0.57 1959–2004 (0.016) Bye277 Former Czechoslovakia, 0.117 Medium 0.73 1953–1989 (0.067) Landberg and Norstrom¨ 278 United States, 0.094 Medium 0.57 1950–2002 (0.044) Landberg and Norstrom¨ 278 Russia, 0.081 Very high 0.73 1959–1998 (0.015) Norstrom¨ 279 United States, 0.035 Low na 1950–2002, dry (0.047) ns Norstrom¨ 279 United States, 0.071 Medium 0.51 1950–2002, moderate (0.037) Norstrom¨ 279 United States, 0.174 High 0.80 1950–2002, wet (0.045) Ramstedt11 Australia,
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