Ethanol-related behaviors in mice lacking the NMDA receptor NR2A subunit

Boyce-Rustay, Janel M.; Holmes, Andrew

doi:10.1007/s00213-006-0448-6

Cited by 67 publications

(71 citation statements)

References 41 publications

(65 reference statements)

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“…Wire-hanging test. The wire-hanging test is a standard behavioral assay of motor impairment and is sensitive to ethanol-induced deficits (45)(46)(47). It is particularly useful for assessing the effect of chemical substances on muscle strength.…”

Section: Methodsmentioning

confidence: 99%

Oxytocin prevents ethanol actions at δ subunit-containing GABA _A receptors and attenuates ethanol-induced motor impairment in rats

Bowen

Peters

Absalom

et al. 2015

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

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Even moderate doses of alcohol cause considerable impairment of motor coordination, an effect that substantially involves potentiation of GABAergic activity at δ subunit-containing GABA A receptors (δ-GABA A Rs). Here, we demonstrate that oxytocin selectively attenuates ethanol-induced motor impairment and ethanol-induced increases in GABAergic activity at δ-GABA A Rs and that this effect does not involve the oxytocin receptor. Specifically, oxytocin (1 μg i.c.v.) given before ethanol (1.5 g/kg i.p.) attenuated the sedation and ataxia induced by ethanol in the open-field locomotor test, wire-hanging test, and righting-reflex test in male rats. Using twoelectrode voltage-clamp electrophysiology in Xenopus oocytes, oxytocin was found to completely block ethanol-enhanced activity at α4β1δ and α4β3δ recombinant GABA A Rs. Conversely, ethanol had no effect when applied to α4β1 or α4β3 cells, demonstrating the critical presence of the δ subunit in this effect. Oxytocin had no effect on the motor impairment or in vitro effects induced by the δ-selective GABA A R agonist 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol, which binds at a different site on δ-GABA A Rs than ethanol. Vasopressin, which is a nonapeptide with substantial structural similarity to oxytocin, did not alter ethanol effects at δ-GABA A Rs. This pattern of results confirms the specificity of the interaction between oxytocin and ethanol at δ-GABA A Rs. Finally, our in vitro constructs did not express any oxytocin receptors, meaning that the observed interactions occur directly at δ-GABA A Rs. The profound and direct interaction observed between oxytocin and ethanol at the behavioral and cellular level may have relevance for the development of novel therapeutics for alcohol intoxication and dependence.A receptors (δ-GABA A Rs) play a major role in regulating tonic inhibition in the central nervous system (CNS) (1). The δ-GABA A Rs also represent one of the major targets of ethanol in the CNS, particularly at relatively low ethanol concentrations, and mediate some of the rewarding and ataxic effects of ethanol (2-8). For instance, a genetic polymorphism that exaggerates the actions of ethanol at δ-GABA A Rs also potentiates ethanolinduced motor impairment (2). Further, knockdown of δ subunit expression in the medial shell of the nucleus accumbens reduces alcohol intake in rats (6). Finally, overstimulation and subsequent internalization of α4βδ extrasynaptic GABA A Rs after persistent stimulation by ethanol seem to underlie the development of rapid tolerance to the ataxic effects of ethanol (4).The neuropeptide oxytocin (OT) is well-known for its regulatory role in mammalian sociability and various other central and peripheral physiological processes (9). Early preclinical studies suggested that OT can prevent the development of tolerance to the sedative and ataxic effects of ethanol in rodents (10) and also modulate the severity of ethanol withdrawal (11). More recent studies show that OT reduces alcohol intake in rats (12) and reduces the severity of a...

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Section: Methodsmentioning

confidence: 99%

Oxytocin prevents ethanol actions at δ subunit-containing GABA _A receptors and attenuates ethanol-induced motor impairment in rats

Bowen

Peters

Absalom

et al. 2015

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

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“…Voluntary EtOH consumption was measured using a 2-bottle choice paradigm as previously described [6]. EtOH-naïve mice were individually-housed in 'Space Saver' cages (Model 1145T, Tecniplast, Buguggiate, Italy) with lids fitted for 2 fluid bottles (Model 1145T482SUDB--Polysulfone cage-top to accommodate 2 water bottles (top flow design; Tecniplast, Buguggiate, Italy)).…”

Section: Nih Public Accessmentioning

confidence: 99%

“…EtOH-induced sedation/hypnosis was assessed as previously described [6]. EtOH-naïve mice were given 0 or 14 consecutive days of stress as above and tested 24 hr later for sleep time responses to 4 g/kg EtOH (200 proof, prepared in 0.9% v/v saline to produce a 20% v/v ethanol solution).…”

Section: Nih Public Accessmentioning

confidence: 99%

“…All experimental procedures were approved by the National Institute on Alcohol Abuse and Alcoholism Animal Care and Use Committee, and followed the National Institute of Health guidelines outlined in 'Using Animals in Intramural Research. 'Voluntary EtOH consumption was measured using a 2-bottle choice paradigm as previously described [6]. EtOH-naïve mice were individually-housed in 'Space Saver' cages (Model 1145T, Tecniplast, Buguggiate, Italy) with lids fitted for 2 fluid bottles (Model 1145T482SUDB--Polysulfone cage-top to accommodate 2 water bottles (top flow design; Tecniplast, Buguggiate, Italy)).…”

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confidence: 99%

“…These data were used to calculate EtOH consumption and percent EtOH preference (EtOH consumption/total fluid consumption × 100). The effect of stress and strain on EtOH consumption and EtOH preference was analyzed both during stress and the 10 days after the cessation of stress using multifactorial analysis of variance (ANOVA) and Newman-Keuls post-hoc tests where appropriate.EtOH-induced sedation/hypnosis was assessed as previously described [6]. EtOH-naïve mice were given 0 or 14 consecutive days of stress as above and tested 24 hr later for sleep time responses to 4 g/kg EtOH (200 proof, prepared in 0.9% v/v saline to produce a 20% v/v ethanol solution).…”

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confidence: 99%

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Effects of chronic swim stress on EtOH-related behaviors in C57BL/6J, DBA/2J and BALB/cByJ mice

Boyce-Rustay

Janos

Holmes

2008

Behavioural Brain Research

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There is a strong clinical relationship between stress and stress-related disorders and the incidence of alcohol abuse and alcoholism, and this relationship appears to be partly genetic in origin. There are marked strain differences in ethanol (EtOH)-related behaviors and reactivity to stress, but little investigation of the interaction between the two. The present study assessed the effects of chronic exposure to swim stress on EtOH-related behavior in three common inbred strains of mice, C57BL/ 6J, DBA/2J and BALB/cByJ. After establishing baseline (10%) EtOH self-administration in a twobottle free choice test, mice were exposed to daily swim stress for 14 consecutive days and EtOH consumption measured as a percent of baseline both during stress and for 10 days afterwards. A separate experiment examined the effects of 14 days of swim stress on sensitivity to the sedative/ hypnotic effects of an acute injection of 4 g/kg EtOH. Results showed that stress produced a marked and prolonged decrease in EtOH consumption in DBA/2J and BALB/cByJ, but not C57BL/6J mice. By contrast, stress increased sensitivity to the sedative/hypnotic effects of EtOH across all 3 strains. These findings demonstrate that chronic swim stress produces reductions in EtOH self-administration in a strain-dependent manner, and that these effects may be restricted to low-consuming strains. Present data also indicate a dissociation between effects of this stressor on EtOH self-administration and sensitivity to EtOH's sedative/hypnotic effects. In conclusion, strain differences, that are likely in large part genetic in nature, modify the effects of this stressor on EtOH's effects in a behaviorspecific manner. Keywords mouse; strain; ethanol; sedation; gene; drinking; swim stress; preference; two-bottle choice There is a strong epidemiological link between stress-related psychiatric disorders and alcoholism. Individuals suffering from depression or anxiety disorders, conditions often associated with stress, are more likely to abuse alcohol and become alcoholic, and tend to respond less well to therapeutic interventions [8,9,29,54]. Moreover, a history of adverse life events positively correlates with increased rates of alcoholism; although, interestingly, a proportion of individuals become abstinent following stress [19,35,46,51]. These clinic data lend support to the influential hypothesis that stress represent a significant risk factor for alcoholism [12,28]. *Corresponding author: R4N5 AP9A-L018, Abbott Laboratories, 100 Abbott Park Rd, Abbott Park, IL 60064, Ph. +1-847-937-2559, Fax +1-847-938-0072, E-mail: janel.boyce-rustay@abbott.com. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered wh...

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Systematic Analysis of Glutamatergic Neurotransmission Genes in Alcohol Dependence and Adolescent Risky Drinking Behavior

Schumann¹,

Johann²,

Frank³

et al. 2008

Arch Gen Psychiatry

110

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Ethanol-related behaviors in mice lacking the NMDA receptor NR2A subunit

Cited by 67 publications

References 41 publications

Oxytocin prevents ethanol actions at δ subunit-containing GABA _A receptors and attenuates ethanol-induced motor impairment in rats

Oxytocin prevents ethanol actions at δ subunit-containing GABA _A receptors and attenuates ethanol-induced motor impairment in rats

Effects of chronic swim stress on EtOH-related behaviors in C57BL/6J, DBA/2J and BALB/cByJ mice

Systematic Analysis of Glutamatergic Neurotransmission Genes in Alcohol Dependence and Adolescent Risky Drinking Behavior

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Ethanol-related behaviors in mice lacking the NMDA receptor NR2A subunit

Cited by 67 publications

References 41 publications

Oxytocin prevents ethanol actions at δ subunit-containing GABA A receptors and attenuates ethanol-induced motor impairment in rats

Oxytocin prevents ethanol actions at δ subunit-containing GABA A receptors and attenuates ethanol-induced motor impairment in rats

Effects of chronic swim stress on EtOH-related behaviors in C57BL/6J, DBA/2J and BALB/cByJ mice

Systematic Analysis of Glutamatergic Neurotransmission Genes in Alcohol Dependence and Adolescent Risky Drinking Behavior

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Oxytocin prevents ethanol actions at δ subunit-containing GABA _A receptors and attenuates ethanol-induced motor impairment in rats

Oxytocin prevents ethanol actions at δ subunit-containing GABA _A receptors and attenuates ethanol-induced motor impairment in rats