SB242084, flumazenil, and CRA1000 block ethanol withdrawal–induced anxiety in rats

Abstract

Anxiety-like behaviors are integral features of withdrawal from chronic ethanol exposure. In the experiments in the current study, we tested the hypothesis that anxiety can be regulated independently of other withdrawal signs and thus may be responsive to selective pharmacological agents. For 17 days, rats were fed ethanol (8-12 g/kg/day) in a liquid diet. Between 5 and 6 h after cessation of ethanol treatment, rats were tested in either the social interaction or plus-maze test of anxiety-like behavior after treatment with drugs hypothesized to have anxiolytic action. SB242084, flumazenil, and CRA1000-antagonists for 5-hydroxytryptamine (serotonin) (5-HT) 2C (5-HT 2C ), benzodiazepine, and corticotropin-releasing factor type 1 (CRF 1 ) receptors, respectively-attenuated decreased social interaction without concomitant effects on activity measures. In contrast, ifenprodil, MDL 72222, and zolpidem-antagonists for N-methyl-D-aspartate (NMDA) and 5-HT 3 receptors, and agonist for benzodiazepine type 1 receptors, respectively-did not share this effect. Results for SB242084, flumazenil, and ifenprodil in the elevated plus-maze test were comparable to those in the social interaction test. These results support the suggestion that multiple neuronal systems (CRF 1 , 5-HT 2C , and benzodiazepine receptors) contribute to the ethanol withdrawal sign of decreased social interaction. Furthermore, the selective effects of pharmacological agents on social interaction seem to indicate that this behavior can be dissociated from other signs. Because anxiety may be a complicating factor in alcohol withdrawal and relapse, future studies of this type are needed to provide focus for the effort to define selective and novel antianxiety agents for these disorders.

Prior Multiple Ethanol Withdrawals Enhance Stress-Induced Anxiety-Like Behavior: Inhibition by CRF1- and Benzodiazepine-Receptor Antagonists and a 5-HT1a-Receptor Agonist

“…These treatments previously blocked the reduced social interaction seen following this repeated ethanol cycling (Overstreet et al, 2003a(Overstreet et al, , b, 2004bKnapp et al, 2004bKnapp et al, , 2005. Treatment with the these drugs during the initial repeated withdrawal cycles prevented the stressinduced reduction in social interaction induced 3 days after removal from the multiple-withdrawal protocol (Figure 4).…”

“…The data were initially analyzed by ANOVAs, with one-or two-way ANOVAs carried out depending upon the research design. If the main and/or interaction effects were statistically significant, post hoc analyses were performed using Tukey's protected t tests (see Knapp et al, 2004b;Overstreet et al, 2003b).…”

Conceptual framework for the etiology of alcoholism: a ?kindling?/stress hypothesis

“…Thus, sensitization of anxiety-like behavior by repeated withdrawals is not due solely to the presence of alcohol. Selected drugs [i.e., a corticotropin-releasing factor type-1 (CRF-1) receptor antagonist, flumazenil and buspirone] administered during the initial two withdrawals, but not the final withdrawal of the repeated cycling, block the increase in anxiety-associated behavior Knapp et al 2004b;Overstreet et al 2003bOverstreet et al , 2004a. This latter observation affords critical evidence that repeated withdrawals induce adaptation that accumulates from one cycle to the next to sensitize this withdrawal symptom.…”

“…Whereas an antagonist for the CRF 2 receptor was unable to block repeated withdrawal-induced "anxiety," data implicated CRF 1 receptors in the repeated withdrawal and the stress/withdrawal protocols Knapp et al 2001Knapp et al , 2003Knapp et al , 2004bOverstreet et al 2003bOverstreet et al , 2004a. However, removal of the gene for the CRF 2 receptor resulted in anxiety (Bale et al 2000;Kishimoto et al 2000).…”

“…Therefore, the conditioned fear inferred from the CER study may not share overlapping sensitization with brain circuits/regions supporting anxiety (McHugh et al 2004;Walker et al 2003). Comparing the effects of pharmacological challenges on CER and anxiety-like behavior (Overstreet et al 2003bKnapp et al 2004b) should assist in resolving differences in interpretation of these persistent consequences associated with repeated withdrawals.…”