| The goal of these experiments was to investigate the role of sexual dimorphism in the pharmacokinetics and pharmacodynamics of (+)-methamphetamine (METH) and (+)-amphetamine (AMP) in rats. This was accomplished by determining the influence of rat sex, METH dose and schedule of administration in the pharmacological response. First I hypothesized that females could offer improvements over male rats in modeling human METH effects. To test this hypothesis, METH and AMP pharmacokinetics were determined after 1.0 and 3.0 mg/kg METH. The results showed females formed lower amounts of AMP after a METH dose. There were substantial differences in area under the concentration-time curve (METH AUC), Systemic (ClT) and renal clearance (ClR), volume of distribution (Vd), and urinary elimination, suggesting dose-dependent pharmacokinetics in females. AMP formation in female rats is more representative of that in humans, suggesting that females could provide a useful model for studying METH and AMP effects.; The second study determined how these pharmacokinetic differences impact METH- or AMP-induced behavior. Locomotor activity and stereotypy were ascertained in rats after saline, 1.0, and 3.0 mg/kg doses of METH or AMP. The results showed sex-, dose- and time-dependent differences in locomotion, with females displaying longer-lasting effects after METH and AMP, including more stereotypies after the higher doses. METH and AMP had comparable effects within each sex.; The final studies investigated the interplay between sex differences in METH pharmacokinetics and self-administration behavior. Males and females were given multiple METH injections, derived from average self-administration patterns from male rats (27 0.048 mg/kg METH injections, 1.3 sec duration, in 2 hr sessions). Results showed rats achieved relatively steady METH concentrations early in the infusion protocol. Substantial sex differences were found, with females showing greater AUC12020 , lower ClT and lower AMP formation.; In conclusion, males and females were found to be animal models with differing levels of vulnerability in which to study the complex effects of METH and AMP. These findings suggest that METH pharmacokinetics plays a crucial role in the differential pharmacological response to METH in male and female rats. These pharmacokinetic differences could explain previously reported sex differences in self-administration in rats. |
