Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol intake: evidence of disrupted noradrenergic signaling in anxiety-related alcohol use.

Mary J Skelly,Jeff L Weiner

doi:10.1002/brb3.230

Abstract

BackgroundAlcohol use disorders have been linked to increased anxiety, and enhanced central noradrenergic signaling may partly explain this relationship. Pharmacological interventions believed to reduce the excitatory effects of norepinephrine have proven effective in attenuating ethanol intake in alcoholics as well as in rodent models of ethanol dependence. However, most preclinical investigations into the effectiveness of these drugs in decreasing ethanol intake have been limited to acute observations, and none have concurrently assessed their anxiolytic effects. The purpose of these studies was to examine the long-term effectiveness of pharmacological interventions presumed to decrease norepinephrine signaling on concomitant ethanol self-administration and anxiety-like behavior in adult rats with relatively high levels of antecedent anxiety-like behavior.MethodsAdult male Long-Evans rats self-administered ethanol on an intermittent access schedule for eight to ten weeks prior to being implanted with osmotic minipumps containing either an a1-adrenoreceptor antagonist (prazosin, 1.5 mg/kg/day), a β1/2-adrenoreceptor antagonist (propranolol, 2.5 mg/kg/day), a serotonin/norepinephrine reuptake inhibitor (duloxetine, 1.5 mg/kg/day) or vehicle (10% dimethyl sulfoxide). These drugs were continuously delivered across four weeks, during which animals continued to have intermittent access to ethanol. Anxiety-like behavior was assessed on the elevated plus maze before treatment and again near the end of the drug delivery period.ResultsOur results indicate that chronic treatment with a low dose of prazosin or duloxetine significantly decreases ethanol self-administration (P < 0.05). Furthermore, this decrease in drinking is accompanied by significant reductions in the expression of anxiety-like behavior (P < 0.05).ConclusionsThese findings suggest that chronic treatment with putative inhibitors of central noradrenergic signaling may attenuate ethanol intake via a reduction in anxiety-like behavior.

Highlights

The strength of the relationship between alcohol use and anxiety disorders has been extensively documented, and these commonly comorbid conditions are recognized as being among the most prevalent psychiatric diseases afflicting the United States population (Grant et al 2004)
Post hoc analysis revealed that animals receiving prazosin (n = 6) spent significantly more time exploring the open arms than animals receiving propranolol (n = 7, q = 5.095, P < 0.01) or vehicle (n = 7, q = 4.483, P < 0.05) (Fig. 2D)
An analysis of the percent time spent in the open arms revealed a significant difference between group (F = 7.138, P < 0.01), and post hoc analysis revealed that animals receiving prazosin or duloxetine spent significantly more time exploring the open arms than animals receiving propranolol (P < 0.05)

Summary

Introduction

The strength of the relationship between alcohol use and anxiety disorders has been extensively documented, and these commonly comorbid conditions are recognized as being among the most prevalent psychiatric diseases afflicting the United States population (Grant et al 2004). Most preclinical investigations into the effectiveness of these drugs in decreasing ethanol intake have been limited to acute observations, and none have concurrently assessed their anxiolytic effects The purpose of these studies was to examine the long-term effectiveness of pharmacological interventions presumed to decrease norepinephrine signaling on concomitant ethanol self-administration and anxiety-like behavior in adult rats with relatively high levels of antecedent anxiety-like behavior. Methods: Adult male Long-Evans rats self-administered ethanol on an intermittent access schedule for eight to ten weeks prior to being implanted with osmotic minipumps containing either an a1-adrenoreceptor antagonist (prazosin, 1.5 mg/kg/day), a b1/2-adrenoreceptor antagonist (propranolol, 2.5 mg/kg/day), a serotonin/norepinephrine reuptake inhibitor (duloxetine, 1.5 mg/kg/day) or vehicle (10% dimethyl sulfoxide) These drugs were continuously delivered across four weeks, during which animals continued to have intermittent access to ethanol. Conclusions: These findings suggest that chronic treatment with putative inhibitors of central noradrenergic signaling may attenuate ethanol intake via a reduction in anxiety-like behavior

Methods

Results

Conclusion