Norepinephrine signaling through beta-adrenergic receptors is critical for expression of cocaine-induced anxiety

Abstract

Background: Cocaine is a widely abused psychostimulant that has both rewarding and aversive properties. While the mechanisms underlying cocaine's rewarding effects have been studied extensively, less attention has been paid to the unpleasant behavioral states induced by cocaine, such as anxiety.

Methods: In this study, we evaluated the performance of dopamine beta-hydroxylase knockout (Dbh -/-) mice, which lack norepinephrine (NE), in the elevated plus maze (EPM) to examine the contribution of noradrenergic signaling to cocaine-induced anxiety.

Results: We found that cocaine dose-dependently increased anxiety-like behavior in control (Dbh +/-) mice, as measured by a decrease in open arm exploration. The Dbh -/- mice had normal baseline performance in the EPM but were completely resistant to the anxiogenic effects of cocaine. Cocaine-induced anxiety was also attenuated in Dbh +/- mice following administration of disulfiram, a dopamine beta-hydroxylase (DBH) inhibitor. In experiments using specific adrenergic antagonists, we found that pretreatment with the beta-adrenergic receptor antagonist propranolol blocked cocaine-induced anxiety-like behavior in Dbh +/- and wild-type C57BL6/J mice, while the alpha(1) antagonist prazosin and the alpha(2) antagonist yohimbine had no effect.

Conclusions: These results indicate that noradrenergic signaling via beta-adrenergic receptors is required for cocaine-induced anxiety in mice.

Figure 1

Effects of cocaine on performance in the elevated plus maze in Dbh +/− and Dbh −/− mice. Cocaine was administered to mice 20 minutes prior to the EPM. Shown is percent open arm time during the five minute test. **p<0.01 compared to vehicle control for that genotype. ##p<0.01, ###p<0.001 compared to Dbh +/− mice for that dose (N=8 per group).

Figure 2

NE replacement alters anxiety behavior in Dbh −/− mice. DOPS + benserazide or vehicle was administered approximately five hours prior to EPM testing, when brain restoration of NE peaks in Dbh −/− mice treated with DOPS. Shown is percent open arm time of Dbh −/− mice given vehicle or cocaine (10 mg/kg, i.p.) 20 minutes before the five minute EPM test. *p<0.05 compared to Vehicle-Cocaine group (N=6–8 per group).

Figure 3

Disulfiram attenuates cocaine-induced anxiety in Dbh +/− mice. Dbh +/− mice were injected with disulfiram (3 × 200 mg/kg, i.p., two hours between each injection) or vehicle. Two hours following the last disulfiram treatment, mice were injected with saline or cocaine (10 mg/kg, i.p.), and tested in the EPM 20 minutes later. Shown is percent open arm time during the five minute EPM test. *p < 0.05 compared to Vehicle-Saline group (N=8 per group).

Figure 4

The β-adrenergic antagonist propranolol attenuates cocaine-induced anxiety. Dbh +/− mice were treated with vehicle, the α₁-adrenergic antagonist prazosin, the α₂-adrenergic antagonist yohimbine, or the β-adrenergic antagonist propranolol 10 minutes prior to cocaine injection (10 mg/kg, i.p.), and mice were tested in the EPM 20 minutes later. Shown is percent open arm time during the five minute EPM test. ** p < 0.01 compared to vehicle control (N=10–17 per group).

Figure 5

The β-adrenergic antagonist propranolol attenuates cocaine-induced anxiety in wild type C57BL6/J mice. Wild-type C57BL6/J mice were treated with either propranolol or saline 10 minutes prior to cocaine injection, and mice were tested on the EPM 20 mniutes later. Shown is percent open time during the five minute EPM test. *p<0.05 compared to saline control (N=7 per group).