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

Abstract

Aims: Stress-induced anxiety is a risk factor for relapse to alcohol drinking. The aim of this study was to test the hypothesis that the central nervous system (CNS)-active α₁-adrenergic receptor antagonist, prazosin, would block the stress-induced increase in anxiety that occurs during alcohol deprivations.

Methods: Selectively bred male alcohol-preferring (P) rats were given three cycles of 5 days of ad libitum voluntary alcohol drinking interrupted by 2 days of alcohol deprivation, with or without 1 h of restraint stress 4 h after the start of each of the first two alcohol deprivation cycles. Prazosin (1.0 or 1.5 mg/kg, IP) or vehicle was administered before each restraint stress. Anxiety-like behavior during alcohol deprivation following the third 5-day cycle of alcohol drinking (7 days after the most recent restraint stress ± prazosin treatment) was measured by performance in an elevated plus-maze and in social approach/avoidance testing.

Results: Rats that received constant alcohol access, or alcohol access and deprivations without stress or prazosin treatments in the first two alcohol deprivations did not exhibit augmented anxiety-like behavior during the third deprivation. In contrast, rats that had been stressed during the first two alcohol deprivations exhibited increased anxiety-like behavior (compared with control rats) in both anxiety tests during the third deprivation. Prazosin given before stresses in the first two cycles of alcohol withdrawal prevented increased anxiety-like behavior during the third alcohol deprivation.

Conclusion: Prazosin treatment before stresses experienced during alcohol deprivations may prevent the increased anxiety during subsequent deprivation/abstinence that is a risk factor for relapse to alcohol drinking.

Short summary: Administration of prazosin before stresses during repetitive alcohol deprivations in male alcohol-preferring (P) rats prevents increased anxiety during a subsequent deprivation without further prazosin treatment. Prazosin treatment during repeated alcohol deprivations may prevent the increased anxiety that is a risk factor for relapse to alcohol drinking.

Fig. 1.

Experimental protocol. Praz, prazosin; Dep, alcohol deprivation; d, days.

Fig. 2.

Social Approach/Avoidance Test. Rats that had been stressed at the start of the first two alcohol deprivations (D + Stress + Veh) exhibited increased anxiety-like behavior (i.e. decreased social approach) in the social approach/avoidance test during the third (final) deprivation, compared with Control rats (P= 0.05). Prazosin (1.5 mg/kg) treatment before each of the two stresses blocked this stress effect (P< 0.05). Lower dose prazosin (1 mg/kg) treatment before each of the two stresses tended (P = 0.09) to decrease the stress effect. Each bar represents the mean + SEM of 6–7 rats/group.

Fig. 3.

Elevated plus-maze test. Rats that had been stressed at the start of the first two alcohol deprivations (D + Stress + Veh) exhibited increased anxiety-like behavior (i.e. decreased open arm time [left panel] and decreased open arm entries [right panel]) in the elevated plus-maze test during the third (final) deprivation, compared with Control rats. Treatment with either dose of prazosin (1 or 1.5 mg/kg) before each of the two stresses in the first two deprivations blocked this stress effect. Each bar represents the mean + SEM of 6–7 rats/group.

Fig. 4.

Composite anxiety-like behavior score. When anxiety-like behavior was expressed as a composite of the results of social interaction and elevated plus-maze tests, with increasing values reflecting increasing anxiety-like behavior (as described in Results), rats that had been stressed at the start of the first two alcohol deprivations exhibited robust increases (P< 0.01) in anxiety-like behavior in the subsequent (final) deprivation when compared with Control rats and with rats that had received constant access to alcohol, as well as more modest increases (P= 0.05) when compared with rats that had received alcohol deprivations without added stresses. This [deprivation + stress] induced increase in the composite index of anxiety-like behavior was suppressed by treatment with prazosin 1 mg/kg and prazosin 1.5 mg/kg (P < 0.01 and P < 0.001, respectively) before each of the stresses in the first two deprivations, compared with the [deprivation + stress + vehicle] rats. Each bar represents the mean + SEM of 6–7 rats/group.