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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, duloxetine, or propranolol does not decrease preference for ethanol (EtOH) relative to vehicle-treated conspecifics. Graphs represent 24 h (daily) EtOH preference relative to water 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 EtOH preference was averaged for each rat. Treatment with prazosin (A), duloxetine (B), or propranolol (C) did not significantly decrease ethanol preference, relative to vehicle-treated conspecifics two-way ANOVAs comparing treatment across time, P > 0.05).
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fig04: Chronic treatment with prazosin, duloxetine, or propranolol does not decrease preference for ethanol (EtOH) relative to vehicle-treated conspecifics. Graphs represent 24 h (daily) EtOH preference relative to water 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 EtOH preference was averaged for each rat. Treatment with prazosin (A), duloxetine (B), or propranolol (C) did not significantly decrease ethanol preference, relative to vehicle-treated conspecifics two-way ANOVAs comparing treatment across time, P > 0.05).

Mentions: A two-way repeated measures ANOVA comparing daily ethanol preference across all treatment groups revealed a significant interaction effect (F = 1.905, P < 0.05). Interestingly, a two-way repeated measures ANOVA comparing preference for ethanol over water following treatment with prazosin or vehicle did not reveal a significant interaction of treatment and time (F = 2.378, P > 0.05) (Fig. 4A); likewise, no significant interaction was observed when comparing ethanol preference in duloxetine-treated animals (Fig. 4B) (F = 1.611, P > 0.05) and propranolol-treated animals (Fig. 4C) (F = 0.975, P > 0.05) to vehicle-treated conspecifics. A two-way repeated measures ANOVA comparing binge-like drinking in the first 30 min of daily access revealed a significant interaction of treatment and time (F = 1.960, P < 0.05), but there was also no significant effect of prazosin (Fig. 5A), duloxetine (Fig. 5B), or propranolol (Fig. 5C) on ethanol intake in the first 30 min of daily exposure, relative to vehicle treatment (prazosin F = 0.722, P > 0.05, duloxetine F = 0.507, P > 0.05, propranolol F = 0.076, P > 0.05).


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, duloxetine, or propranolol does not decrease preference for ethanol (EtOH) relative to vehicle-treated conspecifics. Graphs represent 24 h (daily) EtOH preference relative to water 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 EtOH preference was averaged for each rat. Treatment with prazosin (A), duloxetine (B), or propranolol (C) did not significantly decrease ethanol preference, relative to vehicle-treated conspecifics two-way ANOVAs comparing treatment across time, P > 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig04: Chronic treatment with prazosin, duloxetine, or propranolol does not decrease preference for ethanol (EtOH) relative to vehicle-treated conspecifics. Graphs represent 24 h (daily) EtOH preference relative to water 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 EtOH preference was averaged for each rat. Treatment with prazosin (A), duloxetine (B), or propranolol (C) did not significantly decrease ethanol preference, relative to vehicle-treated conspecifics two-way ANOVAs comparing treatment across time, P > 0.05).
Mentions: A two-way repeated measures ANOVA comparing daily ethanol preference across all treatment groups revealed a significant interaction effect (F = 1.905, P < 0.05). Interestingly, a two-way repeated measures ANOVA comparing preference for ethanol over water following treatment with prazosin or vehicle did not reveal a significant interaction of treatment and time (F = 2.378, P > 0.05) (Fig. 4A); likewise, no significant interaction was observed when comparing ethanol preference in duloxetine-treated animals (Fig. 4B) (F = 1.611, P > 0.05) and propranolol-treated animals (Fig. 4C) (F = 0.975, P > 0.05) to vehicle-treated conspecifics. A two-way repeated measures ANOVA comparing binge-like drinking in the first 30 min of daily access revealed a significant interaction of treatment and time (F = 1.960, P < 0.05), but there was also no significant effect of prazosin (Fig. 5A), duloxetine (Fig. 5B), or propranolol (Fig. 5C) on ethanol intake in the first 30 min of daily exposure, relative to vehicle treatment (prazosin F = 0.722, P > 0.05, duloxetine F = 0.507, P > 0.05, propranolol F = 0.076, P > 0.05).

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