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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 (A) or duloxetine (B) decreases intermittent ethanol (EtOH) self-administration relative to vehicle-treated conspecifics. Graphs represent 24 h (daily) EtOH intake each week for 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. Both prazosin (A) and duloxetine-treated (B) rats self-administered significantly less EtOH than vehicle-treated animals by the third week of drug delivery; this effect persisted through the final treatment week and was abolished following cessation of treatment (*, significant difference relative to vehicle-treated animals, two-way ANOVAs comparing treatment across time and Newman–Keuls post hoc tests, P < 0.05). Daily ethanol intake among propranolol-treated animals did not differ significantly from controls at any point (C) (two-way ANOVA comparing propranolol-treated animals to vehicle-treated conspecifics, P > 0.05).
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fig03: Chronic treatment with prazosin (A) or duloxetine (B) decreases intermittent ethanol (EtOH) self-administration relative to vehicle-treated conspecifics. Graphs represent 24 h (daily) EtOH intake each week for 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. Both prazosin (A) and duloxetine-treated (B) rats self-administered significantly less EtOH than vehicle-treated animals by the third week of drug delivery; this effect persisted through the final treatment week and was abolished following cessation of treatment (*, significant difference relative to vehicle-treated animals, two-way ANOVAs comparing treatment across time and Newman–Keuls post hoc tests, P < 0.05). Daily ethanol intake among propranolol-treated animals did not differ significantly from controls at any point (C) (two-way ANOVA comparing propranolol-treated animals to vehicle-treated conspecifics, P > 0.05).

Mentions: A two-way repeated measures ANOVA comparing daily ethanol intake across all treatment groups revealed a significant interaction effect (F = 3.388, P < 0.05), and a follow-up two-way repeated measures ANOVA comparing prazosin and vehicle-treated animals at baseline and across 4 weeks of drug treatment revealed a significant treatment by time interaction (F = 3.094, P < 0.01) (Fig. 3A). Post hoc analysis revealed no difference between the two groups during the last week of baseline drinking (q = 1.042, P > 0.05), nor the first week of drug treatment (q = 2.159, P > 0.05). However, by the second week of drug treatment prazosin-treated animals were drinking marginally less than vehicle controls (q = 2.453, P < 0.09), and by week three they were drinking significantly less (q = 3.613, P < 0.05); this difference persisted through week four of drug treatment (q = 2.886, P < 0.05). Similarly, a two-way repeated measures ANOVA comparing daily ethanol intake in duloxetine and vehicle-treated animals revealed a significant interaction of treatment and time (F = 3.388, P < 0.05) (Fig. 3B). Post hoc analyses exposed no difference in drinking between groups at baseline (q = 0.057, P > 0.05) nor following 1 week of drug exposure (q = 0.0524, P > 0.05). However, by the second week of drug treatment duloxetine-treated animals were drinking marginally less ethanol than vehicle-treated conspecifics (q = 2.702, P < 0.07); this effect was significant following 3 weeks of drug exposure (q = 3.085, P < 0.05) and persisted through drug week 4 (q = 2.932, P < 0.05). There was no significant effect of propranolol treatment on ethanol intake, compared to vehicle (F = 1.437, P > 0.05) (Fig. 3C).


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 (A) or duloxetine (B) decreases intermittent ethanol (EtOH) self-administration relative to vehicle-treated conspecifics. Graphs represent 24 h (daily) EtOH intake each week for 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. Both prazosin (A) and duloxetine-treated (B) rats self-administered significantly less EtOH than vehicle-treated animals by the third week of drug delivery; this effect persisted through the final treatment week and was abolished following cessation of treatment (*, significant difference relative to vehicle-treated animals, two-way ANOVAs comparing treatment across time and Newman–Keuls post hoc tests, P < 0.05). Daily ethanol intake among propranolol-treated animals did not differ significantly from controls at any point (C) (two-way ANOVA comparing propranolol-treated animals to vehicle-treated conspecifics, P > 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig03: Chronic treatment with prazosin (A) or duloxetine (B) decreases intermittent ethanol (EtOH) self-administration relative to vehicle-treated conspecifics. Graphs represent 24 h (daily) EtOH intake each week for 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. Both prazosin (A) and duloxetine-treated (B) rats self-administered significantly less EtOH than vehicle-treated animals by the third week of drug delivery; this effect persisted through the final treatment week and was abolished following cessation of treatment (*, significant difference relative to vehicle-treated animals, two-way ANOVAs comparing treatment across time and Newman–Keuls post hoc tests, P < 0.05). Daily ethanol intake among propranolol-treated animals did not differ significantly from controls at any point (C) (two-way ANOVA comparing propranolol-treated animals to vehicle-treated conspecifics, P > 0.05).
Mentions: A two-way repeated measures ANOVA comparing daily ethanol intake across all treatment groups revealed a significant interaction effect (F = 3.388, P < 0.05), and a follow-up two-way repeated measures ANOVA comparing prazosin and vehicle-treated animals at baseline and across 4 weeks of drug treatment revealed a significant treatment by time interaction (F = 3.094, P < 0.01) (Fig. 3A). Post hoc analysis revealed no difference between the two groups during the last week of baseline drinking (q = 1.042, P > 0.05), nor the first week of drug treatment (q = 2.159, P > 0.05). However, by the second week of drug treatment prazosin-treated animals were drinking marginally less than vehicle controls (q = 2.453, P < 0.09), and by week three they were drinking significantly less (q = 3.613, P < 0.05); this difference persisted through week four of drug treatment (q = 2.886, P < 0.05). Similarly, a two-way repeated measures ANOVA comparing daily ethanol intake in duloxetine and vehicle-treated animals revealed a significant interaction of treatment and time (F = 3.388, P < 0.05) (Fig. 3B). Post hoc analyses exposed no difference in drinking between groups at baseline (q = 0.057, P > 0.05) nor following 1 week of drug exposure (q = 0.0524, P > 0.05). However, by the second week of drug treatment duloxetine-treated animals were drinking marginally less ethanol than vehicle-treated conspecifics (q = 2.702, P < 0.07); this effect was significant following 3 weeks of drug exposure (q = 3.085, P < 0.05) and persisted through drug week 4 (q = 2.932, P < 0.05). There was no significant effect of propranolol treatment on ethanol intake, compared to vehicle (F = 1.437, P > 0.05) (Fig. 3C).

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