Sex differences in the pentylenetetrazol-like stimulus induced by ethanol withdrawal

This study investigated sex differences in responding to the pentylenetetrazol (PTZ, a gamma-aminobutyric acid A antagonist) discriminative stimulus and to substitution to PTZ during ethanol withdrawal. The PTZ stimulus has served as an anxiogenic stimulus in numerous studies. Adult male and female rats were trained to discriminate PTZ (16 mg/kg i.p.) from saline in a two-lever food-reinforced task. They were then gonadectomized or sham-operated. Ovariectomized (OVX) rats were also tested during 17beta-estradiol (2.5 mg, 21 days release, s.c.) replacement. The PTZ dose response (0-16 mg/kg i.p.) was tested in all groups. In general, fewer females than males responded to PTZ. Diazepam (DZP; 0-10 mg/kg i.p.) injected before PTZ (16 mg/kg) decreased the number of rats selecting the PTZ lever. This effect was greater in sham female and estradiol-replaced-OVX rats than in male or OVX rats. Rats then received chronic ethanol diet (6.5%) for 10 days. During ethanol withdrawal (12 h after termination of the ethanol diet), they were tested for PTZ lever selection. PTZ lever selection differed between groups: sham or castrated male rats > OVX > sham female or estradiol-replaced-OVX rats. In sham female rats, estradiol concentrations showed a cyclic pattern with an estradiol surge that did not influence their PTZ discrimination performance. After i.p. injection of ethanol (2 g/kg), blood ethanol concentrations were not different in male and female rats. These findings suggest that 1) female rats are less sensitive to the anxiogenic effects of PTZ; 2) female rats are less sensitive to the anxiogenic effects of ethanol withdrawal; and 3) estrogen plays some role in mediation of these sex differences.