Neurotransmitter and neuromodulatory mechanisms involved in alcohol abuse and alcoholism

Nevo, Igal; Hamon, Michel

doi:10.1016/0197-0186(94)00139-l

Cited by 228 publications

(47 citation statements)

References 260 publications

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“…For example, it appears continued alcohol or drug intake results in a hypergluatmatergic state within mesocorticolimbic and extended amygdala reward circuits (Gass & Olive, 2008; Kryger & Wilce, 2010; Vengeliene, Bilbao, Molander, & Spanagel, 2008). Pre-clinical evidence supports clinical findings that alcohol acutely inhibits, and chronically sensitizes and upregulates glutamate neurotransmission, in brain reward regions of the mesocorticolimbic and extended amygdala circuits (e.g., Carlezon & Wise, 1996; Chandler, Newsom, Sumners, & Crews, 1993; Cui et al, 2013; Ding, Engleman, Rodd, & McBride, 2012; Floyd, Jung, & McCool, 2003; Gass & Olive, 2008; Kapasova & Szumlinski, 2008; Nevo & Hamon, 1995; Nie, Madamba, & Siggins, 1994; Nie, Yuan, Madamba, & Siggins, 1993; Tabakoff & Hoffman, 2013; Weitlauf & Woodward, 2008), which may be due, in part, to changes in glutamate clearance (Ding et al, 2013; Kapasova & Szumlinski, 2008; Othman, Sinclair, Haughey, Geiger, & Parkinson, 2002; Parks et al, 2002; Rao, Bell, et al, 2015; Sari et al, 2011; Smith, 1997; Smith & Zsigo, 1996; Thoma et al, 2011). Moreover, recent data showed that 10 weeks of operant binge-like self administration of solutions containing both ethanol and nicotine resulted in elevation of extracellular glutamate levels in the PFC (Deehan, et al, 2015).…”

Section: Some Neurochemical Neuropharmacological As Well As Neurmentioning

confidence: 56%

A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction

Bell

Hauser

Rodd

et al. 2016

International Review of Neurobiology

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The purpose of this review is to present up-to-date pharmacological, genetic and behavioral findings from the alcohol-preferring P rat and summarize similar past work. Behaviorally, the focus will be on how the P rat meets criteria put forth for a valid animal model of alcoholism with a highlight on its use as an animal model of polysubstance abuse, including alcohol, nicotine and psychostimulants. Pharmacologically and genetically, the focus will be on the neurotransmitter and neuropeptide systems that have received the most attention: cholinergic, dopaminergic, GABAergic, glutamatergic, serotonergic, noradrenergic, corticotrophin releasing hormone, opioid, and neuropeptide Y. Herein we sought to place the P rat’s behavioral and neurochemical phenotypes, and to some extent its genotype, in the context of the clinical literature. After reviewing the findings thus far, this paper discusses future directions for expanding the use of this genetic animal model of alcoholism to identify molecular targets for treating drug addiction in general.

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Section: Some Neurochemical Neuropharmacological As Well As Neurmentioning

confidence: 56%

A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction

Bell

Hauser

Rodd

et al. 2016

International Review of Neurobiology

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“…86,120 In addition, these elevations in glutamatergic activity can be conditioned to the environment in which the animal had access to ethanol, with glutamatergic increases seen in the Acb core (AcbCo) or basolateral Amyg (BLA). 103,121,122 …”

Section: Central Glutamate Activity and Alcohol Dependencementioning

confidence: 99%

Ethanol-Associated Changes in Glutamate Reward Neurocircuitry: A Minireview of Clinical and Preclinical Genetic Findings

Bell¹,

Hauser²,

McClintick³

et al. 2016

Progress in Molecular Biology and Translational Science

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Herein, we have reviewed the role of glutamate, the major excitatory neurotransmitter in the brain, in a number of neurochemical, -physiological, and -behavioral processes mediating the development of alcohol dependence. The findings discussed include results from both preclinical as well as neuroimaging and postmortem clinical studies. Expression levels for a number of glutamate-associated genes and/or proteins are modulated by alcohol abuse and dependence. These changes in expression include metabotropic receptors and ionotropic receptor subunits as well as different glutamate transporters. Moreover, these changes in gene expression parallel the pharmacologic manipulation of these same receptors and transporters. Some of these gene expression changes may have predated alcohol abuse and dependence because a number of glutamate-associated polymorphisms are related to a genetic predisposition to develop alcohol dependence. Other glutamate-associated polymorphisms are linked to age at the onset of alcohol-dependence and initial level of response/sensitivity to alcohol. Finally, findings of innate and/or ethanol-induced glutamate-associated gene expression differences/changes observed in a genetic animal model of alcoholism, the P rat, are summarized. Overall, the existing literature indicates that changes in glutamate receptors, transporters, enzymes, and scaffolding proteins are crucial for the development of alcohol dependence and there is a substantial genetic component to these effects. This indicates that continued research into the genetic underpinnings of these glutamate-associated effects will provide important novel molecular targets for treating alcohol abuse and dependence.

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“…As such, the average incidence of undesirable neurological problems would be quite low. In any case, since there is evidence that the density of glutamate receptors is increased as a consequence of chronic alcohol consumption (26,27), the effect on the glutamate receptors by DETC-MeSO may actually be of positive benefit during treatment of the alcoholic with disulfiram. Furthermore, the physiology of the disulfiram-ethanol reaction cannot be completely explained by accumulation of acetaldehyde due to inactivation of aldehyde dehydrogenase (25).…”

Section: Nmda and Non-nmda Subtypes Of Brain Glutamate Receptors Werementioning

confidence: 99%

Carbamoylation of Brain Glutamate Receptors by a Disulfiram Metabolite

Nagendra¹,

Faiman²,

Davis³

et al. 1997

Journal of Biological Chemistry

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Considerable effort has been devoted to discovery of glutamate antagonists (1, 2) in recent years, due to increasing evidence linking glutamate excitotoxicity to various neurological disorders (3). Unfortunately, while known antagonists can provide neuroprotection, excessive action of these classical blocking agents can obtain undesirable side effects (1, 2). To minimize these undesirable side effects, modification of the redox modulatory sulfhydryl groups of the glutamate receptor has been suggested as a possibly superior therapeutic strategy (4). Unlike classical antagonists, that can give complete inhibition by interaction at the glutamate receptor (e.g. CGS 19755) or directly at receptor-linked, calcium ion channels (e.g. phencyclidine or MK-801) (2), inhibition via the redox modulatory sites are expected to give only partial inhibition of function and thereby limit unwanted side effects associated with excessive antagonism (4). At present S-nitrosylation of glutamate receptors by an NO ϩ donor (e.g. nitroglycerin) is the only mechanism for partially blocking receptor response in vivo that would achieve this effect by interaction with the redox modulatory sites (5, 6).Disulfiram has been used in the treatment of alcoholism for almost 50 years (7,8). It has recently been demonstrated that disulfiram exerts its anti-alcohol effect in vivo only after bioactivation to the active metabolite S-methyl-N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO) 1 (9) that is a potent and selective carbamoylating agent for sulfhydryl groups (10). We now report that DETC-MeSO also partially blocks glutamate binding to synaptic membrane preparations isolated from the brains of mice, and in addition, DETC-MeSO prevents seizures induced in mice by glutamate analogs or by exposure to hyperbaric oxygen. MATERIALS AND METHODS Animals-MaleSwiss Webster mice (20 -30 g) or male SpragueDawley rats (250 -300 g) were used in the study. All experiments that employed animals were conducted in strict compliance with the National Institutes of Health guidelines on animal use and institutional regulations concerning animal experimentation. Animals were exposed to hyperbaric oxygen in a specially designed pressure chamber as described previously (11, 12). The time to first clonic-tonic seizure after bringing animals to a final pressure of 5 atmospheres of 100% oxygen or after intraperitoneal injection of convulsants was noted by criteria outlined previously (11, 12). Unless otherwise specified, the ability of DETC-MeSO to prevent seizures was tested by intraperitoneal injection of 5.2 mg/kg DETC-MeSO 1-2 h prior to bringing the animal to a final pressure of 5 atmospheres of 100% oxygen or intraperitoneal injection of N-methyl-D-aspartate (NMDA) (125 mg/kg) or L-methionine sulfoximine (MetSOX) (250 mg/kg). Evaluation of the statistics for whole animal experiments or for changes in brain glutamate binding after administration of DETC-MeSO was conducted by use of the program GraphPAD InStat from GraphPAD Software (San Diego, CA).Binding Studies-Synap...

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Neurotransmitter and neuromodulatory mechanisms involved in alcohol abuse and alcoholism

Cited by 228 publications

References 260 publications

A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction

A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction

Ethanol-Associated Changes in Glutamate Reward Neurocircuitry: A Minireview of Clinical and Preclinical Genetic Findings

Carbamoylation of Brain Glutamate Receptors by a Disulfiram Metabolite

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