17 β-Estradiol exacerbates methamphetamine-induced anxiety-like behavior in female mice

Abstract

The present experiment investigated the effect of 17 β-estradiol (E2) on anxiety-like behavior following methamphetamine administration in female, Swiss-Webster mice. Mice underwent bilateral ovariectomy (OVX) followed by a subcutaneous implantation of a Silastic capsule containing either sesame oil (OVX + Oil) or E2 (36 μg/ml; OVX + E2). One week later, mice were placed in an open-field chamber for an 8-h session. During the first 3 h of the session, mice were permitted to run in the absence of any drug (baseline). Then, mice were injected intraperitoneally with methamphetamine (0.25, 0.5 or 1.0 mg/kg) or vehicle (physiological saline) and returned to the open-field chamber for the remaining five hours of the session. Mice were injected with vehicle or a different methamphetamine dose once a week for 4 weeks. Four measures of anxiety were assessed: distanced traveled, vertical counts, time in the center, and time resting in the perimeter of the chamber. OVX + E2 were less active and spent less time in the center than OVX + Oil mice during Hour 1 at certain doses, but not during remaining baseline hours (Hours 2–3). Furthermore, group differences were not observed during the Stimulant Phase (Hour 4) following injection of any methamphetamine dose (0.25, 0.5 or 1.0 mg/kg) or the vehicle. However, OVX + E2 mice were less active, spent less time in the center, and spent more time resting in the perimeter of the chamber compared to OVX + Oil mice during certain hours of the Clearance Phase (Hours 5–8) following injection of the high (1.0 mg/kg), but not the low (0.25 mg/kg) or moderate (0.5 mg/kg), methamphetamine doses. These results suggest that E2 exacerbates anxiety-like behavior during acute clearance from a high methamphetamine dose in OVX female mice, perhaps indicating that E2 contributes to drug relapse in women by worsening anxiety-related withdrawal symptoms.