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

Skelly MJ, Weiner JL - Brain Behav (2014)

Bottom Line: Our 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).These findings suggest that chronic treatment with putative inhibitors of central noradrenergic signaling may attenuate ethanol intake via a reduction in anxiety-like behavior.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Medical Center Boulevard Winston-Salem, North Carolina, 27157.

ABSTRACT

Background: Alcohol 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.

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 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.

Results: Our 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).

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.

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Related in: MedlinePlus

Chronic treatment with prazosin or duloxetine decreases binge-like ethanol (EtOH) self-administration relative to pretreatment baseline. Graphs represent EtOH intake in the first 30 min of daily access (binge-like intake) during the last of eight consecutive baseline weeks, followed by 4 week treatment with prazosin (n = 6, 1.5 mg/kg/day), duloxetine (n = 6, 1.5 mg/kg/day), propranolol (n = 7, 2.5 mg/kg/day), or vehicle (n = 7, 10% DMSO), and four additional posttreatment weeks. Animals had access to EtOH (20% v/v) 3 days a week for 24 h; weekly intake was averaged for each rat. Binge-like EtOH intake was significantly reduced by the third week of prazosin delivery (C), and by the final week of treatment with duloxetine (D). Propranolol (B) and vehicle-treated (A) animals did not change their binge-like EtOH intake in response to treatment (*, significant difference relative to the last baseline week, one-way repeated measures ANOVAs and Newman–Keuls post hoc tests, P < 0.05; †, significant difference relative to the last treatment week, one-way repeated measures ANOVAs and Newman–Keuls post hoc tests, P < 0.05).
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fig08: Chronic treatment with prazosin or duloxetine decreases binge-like ethanol (EtOH) self-administration relative to pretreatment baseline. Graphs represent EtOH intake in the first 30 min of daily access (binge-like intake) during the last of eight consecutive baseline weeks, followed by 4 week treatment with prazosin (n = 6, 1.5 mg/kg/day), duloxetine (n = 6, 1.5 mg/kg/day), propranolol (n = 7, 2.5 mg/kg/day), or vehicle (n = 7, 10% DMSO), and four additional posttreatment weeks. Animals had access to EtOH (20% v/v) 3 days a week for 24 h; weekly intake was averaged for each rat. Binge-like EtOH intake was significantly reduced by the third week of prazosin delivery (C), and by the final week of treatment with duloxetine (D). Propranolol (B) and vehicle-treated (A) animals did not change their binge-like EtOH intake in response to treatment (*, significant difference relative to the last baseline week, one-way repeated measures ANOVAs and Newman–Keuls post hoc tests, P < 0.05; †, significant difference relative to the last treatment week, one-way repeated measures ANOVAs and Newman–Keuls post hoc tests, P < 0.05).

Mentions: Correspondingly, one-way repeated measures ANOVAs revealed a significant change in binge-like intake (g/kg in the first 30 min of daily ethanol access) relative to baseline drinking following both prazosin (Fig. 8D) and duloxetine treatment (Fig. 8D) (F = 3.379, P < 0.05 and F = 3.394, P < 0.05, respectively). Post hoc analyses revealed no significant change in 30 min intake during the first 2 weeks of prazosin treatment (q = 2.244, P > 0.05 week one, and q = 2.929, P > 0.05 week two); however, by week 3 binge-like drinking had significantly decreased as compared to baseline (q = 4.119, P < 0.05) and this persisted through treatment week 4 (q = 4.700, P < 0.05). Similarly, binge-like intake was not significantly decreased during the first 3 weeks of duloxetine treatment relative to baseline (q = 1.669, P > 0.05 week one; q = 1.323, P > 0.05 week two; q = 3.060, P > 0.05 week three) (Fig. 8). During week 4, however, drinking during the first 30 min of daily access decreased significantly (q = 4.835, P < 0.05). Neither propranolol (Fig. 8B) nor vehicle treatment (Fig. 8A) decreased binge-like intake relative to baseline at any time point (F = 2.009, P > 0.05 and F = 0.787, P > 0.05, respectively). It is important to note that while we did not measure blood ethanol concentrations, we have reported previously that blood ethanol levels measured following the first thirty minutes of daily ethanol access are strongly correlated with ethanol intake during this period (Chappell et al. 2013).


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

Skelly MJ, Weiner JL - Brain Behav (2014)

Chronic treatment with prazosin or duloxetine decreases binge-like ethanol (EtOH) self-administration relative to pretreatment baseline. Graphs represent EtOH intake in the first 30 min of daily access (binge-like intake) during the last of eight consecutive baseline weeks, followed by 4 week treatment with prazosin (n = 6, 1.5 mg/kg/day), duloxetine (n = 6, 1.5 mg/kg/day), propranolol (n = 7, 2.5 mg/kg/day), or vehicle (n = 7, 10% DMSO), and four additional posttreatment weeks. Animals had access to EtOH (20% v/v) 3 days a week for 24 h; weekly intake was averaged for each rat. Binge-like EtOH intake was significantly reduced by the third week of prazosin delivery (C), and by the final week of treatment with duloxetine (D). Propranolol (B) and vehicle-treated (A) animals did not change their binge-like EtOH intake in response to treatment (*, significant difference relative to the last baseline week, one-way repeated measures ANOVAs and Newman–Keuls post hoc tests, P < 0.05; †, significant difference relative to the last treatment week, one-way repeated measures ANOVAs and Newman–Keuls post hoc tests, P < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4128029&req=5

fig08: Chronic treatment with prazosin or duloxetine decreases binge-like ethanol (EtOH) self-administration relative to pretreatment baseline. Graphs represent EtOH intake in the first 30 min of daily access (binge-like intake) during the last of eight consecutive baseline weeks, followed by 4 week treatment with prazosin (n = 6, 1.5 mg/kg/day), duloxetine (n = 6, 1.5 mg/kg/day), propranolol (n = 7, 2.5 mg/kg/day), or vehicle (n = 7, 10% DMSO), and four additional posttreatment weeks. Animals had access to EtOH (20% v/v) 3 days a week for 24 h; weekly intake was averaged for each rat. Binge-like EtOH intake was significantly reduced by the third week of prazosin delivery (C), and by the final week of treatment with duloxetine (D). Propranolol (B) and vehicle-treated (A) animals did not change their binge-like EtOH intake in response to treatment (*, significant difference relative to the last baseline week, one-way repeated measures ANOVAs and Newman–Keuls post hoc tests, P < 0.05; †, significant difference relative to the last treatment week, one-way repeated measures ANOVAs and Newman–Keuls post hoc tests, P < 0.05).
Mentions: Correspondingly, one-way repeated measures ANOVAs revealed a significant change in binge-like intake (g/kg in the first 30 min of daily ethanol access) relative to baseline drinking following both prazosin (Fig. 8D) and duloxetine treatment (Fig. 8D) (F = 3.379, P < 0.05 and F = 3.394, P < 0.05, respectively). Post hoc analyses revealed no significant change in 30 min intake during the first 2 weeks of prazosin treatment (q = 2.244, P > 0.05 week one, and q = 2.929, P > 0.05 week two); however, by week 3 binge-like drinking had significantly decreased as compared to baseline (q = 4.119, P < 0.05) and this persisted through treatment week 4 (q = 4.700, P < 0.05). Similarly, binge-like intake was not significantly decreased during the first 3 weeks of duloxetine treatment relative to baseline (q = 1.669, P > 0.05 week one; q = 1.323, P > 0.05 week two; q = 3.060, P > 0.05 week three) (Fig. 8). During week 4, however, drinking during the first 30 min of daily access decreased significantly (q = 4.835, P < 0.05). Neither propranolol (Fig. 8B) nor vehicle treatment (Fig. 8A) decreased binge-like intake relative to baseline at any time point (F = 2.009, P > 0.05 and F = 0.787, P > 0.05, respectively). It is important to note that while we did not measure blood ethanol concentrations, we have reported previously that blood ethanol levels measured following the first thirty minutes of daily ethanol access are strongly correlated with ethanol intake during this period (Chappell et al. 2013).

Bottom Line: Our 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).These findings suggest that chronic treatment with putative inhibitors of central noradrenergic signaling may attenuate ethanol intake via a reduction in anxiety-like behavior.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Medical Center Boulevard Winston-Salem, North Carolina, 27157.

ABSTRACT

Background: Alcohol 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.

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 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.

Results: Our 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).

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.

Show MeSH
Related in: MedlinePlus