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

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.

Prazosin Prevents Increased Anxiety Behavior That Occurs in Response to Stress During Alcohol Deprivations

“…However, stimulation of noradrenergic activation enhances, and blockade reduces, memory for material with emotional impact (O'Carroll et al, 1999), so prazosin treatment could potentially decrease stress-enhanced increases of alcohol deprivation-induced anxiety by decreasing memory of the stress. Another possibility is that anxiolytic effects of prazosin (Skelly and Weiner, 2014) may have decreased the perceived stressfulness of the stressor, consistent with subjective evidence in the current study suggesting that rats treated with prazosin struggled less and appeared to relax more quickly during the 1-h restraint. A potentially related mechanism is suggested by evidence that pretreatment with prazosin, at the same dose and time of administration as those used in the current study, reduces 1 h restraint stress-induced immediate early gene expression in several telencephalic, diencephalic and brainstem areas of the rodent brain, without altering motor coordination (Stone and Zhang, 1995).…”

“…Prazosin, an α1-adrenergic receptor antagonist, decreases brain CRF signaling (Itoi et al, 1994) and is anxiolytic (Skelly and Weiner, 2014). We hypothesized that prazosin-a wellcharacterized, safe, well-tolerated and FDA-approved drug may be useful in reducing responses to stress during repetitive alcohol deprivations that lead to increased anxiety.…”

Hypothalamic Norepinephrine Mediates Acupunctural Effects on Hypothalamic–Pituitary–Adrenal Axis During Ethanol Withdrawal

“…Nonetheless, it is now widely acknowledged that central NEergic activity increases during withdrawal from drugs of abuse, at least during the early stage of withdrawal, which elevates the activity of the stress system and promotes relapse after periods of abstinence [14,15]. Recently, Skelly and Weiner [16] reported Figure 2 Acupuncture at the ST36 but not at the nonacupoint significantly reduced EW-induced increased levels of hypothalamic NE and MHPG. Data are expressed as mean AE standard error of the mean of the levels of NE or MHPG.…”

Anxiolytic Effect of Borago officinalis (Boraginaceae) Extract in Male Rats

“…In the other word, the extract was able to produce anxiolytic effect in rats. An increase in the percentage of entrances into the open arms and time spent in open arms, lacking a changed locomotors activity are confirmed as a potent sign for an anxiolytic compounds effect (23). Borage is of great interest among medical and nutritional research groups due to its high content of some useful compounds (10,11,39).…”

“…There is a variety of animal tests for the investigation of anxiolytic effects of substances (22). One of the most widely used models for detecting both anxiolytic-and anxiogenic-like effects of agents in small rodents is elevated plus-maze test (EPM) (23,24). In this animal model, the increase percentage of entries into the open arms compared to the total entries reveals an anxiolytic effect of substances.…”