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

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.