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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

Experimental timeline. Adult male Long-Evans rats were singly housed upon arrival and allowed to acclimate to the environment for 2 weeks. Following this, baseline anxiety-like behavior was assessed using the elevated plus maze and open field tests. Animals were then given intermittent access to ethanol (20% v/v) and water 3 days a week (MWF) for 24 h; this homecage drinking continued for 8–10 weeks. Animals were weighed prior to ethanol access on drinking days. Following this intermittent access period, all animals underwent a surgical procedure during which osmotic minipumps were implanted containing either vehicle (10% DMSO in sterile saline), propranolol (2.5 mg/kg/day), prazosin (1.5 mg/kg/day), or duloxetine (1.5 mg/kg/day). Animals were then allowed to continue intermittent access homecage drinking for four additional weeks. During the last week, animals were again exposed to the elevated plus maze and open field on nondrinking days. Animals underwent a second surgery to remove the osmotic minipumps, and were again exposed to the drinking procedure for 4 weeks prior to being sacrificed.
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fig01: Experimental timeline. Adult male Long-Evans rats were singly housed upon arrival and allowed to acclimate to the environment for 2 weeks. Following this, baseline anxiety-like behavior was assessed using the elevated plus maze and open field tests. Animals were then given intermittent access to ethanol (20% v/v) and water 3 days a week (MWF) for 24 h; this homecage drinking continued for 8–10 weeks. Animals were weighed prior to ethanol access on drinking days. Following this intermittent access period, all animals underwent a surgical procedure during which osmotic minipumps were implanted containing either vehicle (10% DMSO in sterile saline), propranolol (2.5 mg/kg/day), prazosin (1.5 mg/kg/day), or duloxetine (1.5 mg/kg/day). Animals were then allowed to continue intermittent access homecage drinking for four additional weeks. During the last week, animals were again exposed to the elevated plus maze and open field on nondrinking days. Animals underwent a second surgery to remove the osmotic minipumps, and were again exposed to the drinking procedure for 4 weeks prior to being sacrificed.

Mentions: Following 2 weeks of acclimation to the housing environment, baseline anxiety-like behavior was assessed using elevated plus mazes (Med Associates, St. Albans, VT) (Fig. 1). The mazes were elevated 72.4 cm from floor level, with runways measuring 10.2 cm wide by 50.8 cm long. Open runways had 1.3 cm high lips and closed runways were enclosed in 40.6 cm high black polypropylene walls. Exits and entries from each runway were detected via infrared sensors attached to the opening of each arm of the maze. Data were obtained and recorded via personal computer interfaced with control units and MED-PC programming (Med Associates). Animals were placed at the junction of the four arms at the beginning of the session, and activity was measured for 5 min. Anxiety-like behavior was assessed by measuring the total time spent on the open arms of the maze as well as the total percentage of entries into the open arms. General locomotor activity was assessed by measuring the total number of closed arm entries.


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)

Experimental timeline. Adult male Long-Evans rats were singly housed upon arrival and allowed to acclimate to the environment for 2 weeks. Following this, baseline anxiety-like behavior was assessed using the elevated plus maze and open field tests. Animals were then given intermittent access to ethanol (20% v/v) and water 3 days a week (MWF) for 24 h; this homecage drinking continued for 8–10 weeks. Animals were weighed prior to ethanol access on drinking days. Following this intermittent access period, all animals underwent a surgical procedure during which osmotic minipumps were implanted containing either vehicle (10% DMSO in sterile saline), propranolol (2.5 mg/kg/day), prazosin (1.5 mg/kg/day), or duloxetine (1.5 mg/kg/day). Animals were then allowed to continue intermittent access homecage drinking for four additional weeks. During the last week, animals were again exposed to the elevated plus maze and open field on nondrinking days. Animals underwent a second surgery to remove the osmotic minipumps, and were again exposed to the drinking procedure for 4 weeks prior to being sacrificed.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig01: Experimental timeline. Adult male Long-Evans rats were singly housed upon arrival and allowed to acclimate to the environment for 2 weeks. Following this, baseline anxiety-like behavior was assessed using the elevated plus maze and open field tests. Animals were then given intermittent access to ethanol (20% v/v) and water 3 days a week (MWF) for 24 h; this homecage drinking continued for 8–10 weeks. Animals were weighed prior to ethanol access on drinking days. Following this intermittent access period, all animals underwent a surgical procedure during which osmotic minipumps were implanted containing either vehicle (10% DMSO in sterile saline), propranolol (2.5 mg/kg/day), prazosin (1.5 mg/kg/day), or duloxetine (1.5 mg/kg/day). Animals were then allowed to continue intermittent access homecage drinking for four additional weeks. During the last week, animals were again exposed to the elevated plus maze and open field on nondrinking days. Animals underwent a second surgery to remove the osmotic minipumps, and were again exposed to the drinking procedure for 4 weeks prior to being sacrificed.
Mentions: Following 2 weeks of acclimation to the housing environment, baseline anxiety-like behavior was assessed using elevated plus mazes (Med Associates, St. Albans, VT) (Fig. 1). The mazes were elevated 72.4 cm from floor level, with runways measuring 10.2 cm wide by 50.8 cm long. Open runways had 1.3 cm high lips and closed runways were enclosed in 40.6 cm high black polypropylene walls. Exits and entries from each runway were detected via infrared sensors attached to the opening of each arm of the maze. Data were obtained and recorded via personal computer interfaced with control units and MED-PC programming (Med Associates). Animals were placed at the junction of the four arms at the beginning of the session, and activity was measured for 5 min. Anxiety-like behavior was assessed by measuring the total time spent on the open arms of the maze as well as the total percentage of entries into the open arms. General locomotor activity was assessed by measuring the total number of closed arm entries.

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