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

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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.