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Dose- and Time-Dependent Expression of Anxiety-Like Behavior in the Elevated Plus-Maze During Withdrawal From Acute and Repeated Intermittent Ethanol Intoxication in Rats

Authors

  • Zhongqi Zhang,

    1. From the Department of Anesthesiology, UC San Diego School of Medicine and VA San Diego Healthcare System, San Diego, California (ZZ, ACM, GS); and Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California (ACM, GFK, GS).
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  • Andrew C. Morse,

    1. From the Department of Anesthesiology, UC San Diego School of Medicine and VA San Diego Healthcare System, San Diego, California (ZZ, ACM, GS); and Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California (ACM, GFK, GS).
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  • George F. Koob,

    1. From the Department of Anesthesiology, UC San Diego School of Medicine and VA San Diego Healthcare System, San Diego, California (ZZ, ACM, GS); and Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California (ACM, GFK, GS).
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  • Gery Schulteis

    1. From the Department of Anesthesiology, UC San Diego School of Medicine and VA San Diego Healthcare System, San Diego, California (ZZ, ACM, GS); and Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California (ACM, GFK, GS).
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  • This work was supported by a VA Merit Award (GS), NIAAA Grants AA12800 (GS), AA08459 (GFK), and NIAAA Center Grant AA06420 (GFK). Andrew Morse was supported by NIAAA Training Grant T32-AA07456.

Reprint requests: Gery Schulteis, PhD, Department of Anesthesiology, UC San Diego School of Medicine, and VA San Diego Healthcare System, 3350 La Jolla Village Drive, VAMC 125a, San Diego, CA 92161-5008; Fax: 858-822-5009; E-mail: gschulteis@vapop.ucsd.edu

Abstract

Background:  Withdrawal from acute bolus intraperitoneal (IP) injection of high doses of ethanol elicits anxiety-like behavior (e.g. Doremus et al., 2003; Gauvin et al., 1989, 1992) and conditioned place aversion (Morse et al., 2000). More recently we demonstrated that withdrawal from a single moderate dose of ethanol (2.0 g/kg) is accompanied by elevations in brain reward thresholds, and that repeated intermittent treatment with this dose results in a significant potentiation of reward deficit (Schulteis and Liu, 2006).

Methods:  In the current study, the time- and dose-dependent emergence of anxiety-like behavior was measured in the elevated plus-maze at various times (3 to 24 hours) after acute or 3 daily IP injections of ethanol (1.0, 2.0, or 3.0 g/kg). Rats receiving daily handling for 2 days, and a single anxiety opportunity to explore the maze on a third day were divided into 1 of several treatment protocols: (1) NAIVE conditions: vehicle IP on all 3 days; (2) ACUTE conditions: vehicle on the first 2 days, ethanol on the third day; or (3) REPEAT conditions: ethanol on all 3 days.

Results:  ACUTE ethanol elicited reduced exploration of the open arms of the elevated plus-maze in a dose- and time-dependent fashion: 1.0 g/kg failed to elicit any significant effects, whereas 2.0 and 3.0 g/kg ethanol elicited a significant anxiety-like response at 6 hours and 9 to 12 hours postinjection, respectively. REPEAT treatment was still without effect at any time point tested following 1.0 g/kg ethanol, but extended the time course of anxiety-like behavior after treatment with either 2.0 or 3.0 g/kg doses. REPEAT treatment with 2.0 and 3.0 g/kg ethanol also produced significant hypoactivity in the maze at some time points postinjection.

Conclusions:  Withdrawal from a single exposure to ethanol produces transient but significant anxiety-like behavior, and repeated intermittent bouts of intoxication result in a significant extension of the duration of effect. The rapid emergence and progression of negative emotional signs of withdrawal may be a significant factor in determining susceptibility to transition from casual drinking to loss of control and escalating patterns of consumption that result in alcoholism.

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