SB242084, flumazenil, and CRA1000 block ethanol withdrawal-induced anxiety in rats - PubMed (original) (raw)

Comparative Study

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

Darin J Knapp et al. Alcohol. 2004 Feb.

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.

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Figures

Fig. 1

Fig. 1

Mean social interaction time and locomotor activity scores for control and ethanol-withdrawn rats. For 17 days, rats were exposed to ethanol (8–12 g/kg/day), and their behavior was subsequently tested between 5 and 6 h into withdrawal. Bars (means ± S.E.M.) that do not share common letters are significantly different from each other (P < .05).

Fig. 2

Fig. 2

Mean social interaction time and locomotor activity scores for control and ethanol-withdrawn (ETW) rats treated with the 5-hydroxytryptamine (serotonin) 2C (5-HT2C) receptor antagonist SB242084, the benzodiazepine receptor antagonist flumazenil (Flum), or the _N_-methyl-

d

-aspartate (NMDA)–type glutamate receptor antagonist ifenprodil (Ifen). Rats were treated for 17 days with 7% (weight/volume) ethanol diet and tested between 5 and 6 h into withdrawal. Bars (means ± S.E.M.) that do not share common letters are significantly different from each other (P < .05). CMC = 0.5% solution of carboxymethylcellulose vehicle.

Fig. 3

Fig. 3

Mean time in open arms and number of closed-arm entries in the elevated plus-maze test of anxiety in ethanol-withdrawn (ETW) rats treated with vehicle [0.5% solution of carboxymethylcellulose (CMC)], the benzodiazepine receptor antagonist flumazenil (Flum), the 5-hydroxytryptamine (serotonin) 2C (5-HT2C) receptor antagonist SB242084, or the _N_-methyl-

d

-aspartate (NMDA)–type glutamate receptor antagonist ifenprodil (Ifen). Rats were treated for 17 days with 7% (weight/volume) ethanol diet and tested between 5 and 6 h into withdrawal. Bars (means ± S.E.M.) that do not share common letters are significantly different from each other (P < .05).

Fig. 4

Fig. 4

Mean social interaction time and locomotor activity scores for control and ethanol-withdrawn (ETW) rats treated with the 5-hydroxytryptamine (serotonin) 3 (5-HT3) receptor antagonist MDL 72222 (MDL), the corticotropin-releasing factor (CRF) antagonist CRA1000, or the _N_-methyl-

d

-aspartate (NMDA)–type glutamate receptor antagonist ifenprodil (Ifen). Rats were treated for 17 days with 7% (weight/volume) ethanol diet and tested between 5 and 6 h into withdrawal. Bars (means ± S.E.M.) that do not share common letters are significantly different from each other (P < .05). CMC = 0.5% solution of carboxymethylcellulose vehicle.

Fig. 5

Fig. 5

Mean social interaction time and locomotor activity scores for control and ethanol-withdrawn (ETW) rats treated with vehicle [0.5% solution of carboxymethylcellulose (CMC)], the benzodiazepine receptor antagonist flumazenil (Flum), the benzodiazepine receptor agonist zolpidem (Zolp), and the _N_-methyl-

d

-aspartate (NMDA)–type glutamate receptor antagonist ifenprodil (Ifen). Rats were treated for 17 days with 7% (weight/volume) ethanol diet and tested between 5 and 6 h into withdrawal. Bars (means ± S.E.M.) that do not share common letters are significantly different from each other (P < .05).

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