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(+)-Methamphetamine (METH) and (+)-amphetamine (AMP) are structurally similar drugs that are reported to induce similar pharmacological effects in rats of the same sex. Because pharmacokinetic data suggest female rats should be more affected than males, the current studies sought to test the hypothesis that the behavioral and temporal actions of METH and AMP should be greater in female Sprague-Dawley rats than in males. Using a dosing regimen designed to reduce the possibility of tolerance and sensitization, rats were administered 1.0 and 3.0 mg/kg intravenous drug doses. Distance traveled, rearing events and focal stereotypies (e.g., head weaving, sniffing) were measured. Female rats traveled significantly greater distances and displayed a greater number of rearing events than males after both doses. Analysis of stereotypy ratings after 3.0 mg/kg revealed that focal stereotypies were more pronounced and lasted longer in females. The second study compared the potencies of METH and AMP in inducing locomotor activity and focal stereotypies in each sex. No differences in potency were found when METH and AMP effects were compared within males or females. In summary, these studies showed female rats displayed greater and longer-lasting locomotor activity and more stereotypic behaviors, supporting earlier evidence of significant sexual dimorphism in pharmacokinetics.

This article is available online at http://dmd.aspetjournals.org ABSTRACT:These studies examined the effects of a high-affinity anti-(؉)-methamphetamine monoclonal antibody (mAb; Pharmacotherapies for drug abuse treatment and rehabilitation are generally limited to drug receptor agonists and antagonists (Kreek et al., 2002). Although monoclonal antibodies (mAbs 2 ) and antigen binding fragments (Fabs) have been used clinically to reverse toxicity resulting from digoxin and snake venom for some time (Sullivan, 1986), their usefulness for drug abuse treatment is still at the stage of preclinical investigation. In addition to treating drug overdose, investigators are exploring passive immunization as a mechanism to reduce or prevent drug effects and/or toxicity (e.g., Malin et al., 2001;Hardin et al., 2002). Pretreatment with a highly specific anti-drug mAb could potentially block or suppress the effects of the drug, which could aid the patient in discontinuing use of the drug. In addition, mAb pretreatment could prevent or reduce toxicity associated with excessive drug exposure.KThere are other potential advantages of mAb treatment over conventional small molecule receptor agonists and antagonists. First, mAbs target the drug rather than the receptor; therefore they should have no intrinsic effect on receptor activity. Second, mAbs have a relatively small volume of distribution (Vd) and do not readily penetrate tissues (Bazin-Redureau et al., 1997). Through high-affinity binding, they are thus able to reverse toxicity by altering disposition of the drug and preventing the drug from reaching its site of action. Finally, mAbs have a relatively long half-life (ϳ21 days in humans; Knapp and Colburn, 1990), which would allow long intervals between treatments and thus improve compliance of patients in drug abuse rehabilitation programs.Previous studies, from our laboratory and others, have examined the use of mAbs in overdose treatment scenarios (i.e., administration of mAb after a high dose of drug). Our laboratory has shown that administration of anti-drug mAb or Fab reverses drug-induced behavioral effects and alters drug pharmacokinetics in rat models of (ϩ)-methamphetamine [(ϩ)-METH] and phencyclidine (PCP) overdose (e.g., Proksch et al., 2000;Byrnes-Blake et al., 2003). The mAb "pretreatment" or "protection" model for reduction or prevention of drug effects has not been examined as thoroughly. We have shown that pretreatment with an anti-PCP mAb will substantially reduce behavioral effects resulting from repeated PCP chal-

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Background Because methamphetamine (METH) pharmacokinetics after single iv doses show significant differences between male and female rats, we hypothesized that pharmacokinetic differences in METH disposition could be a contributing factor to the patterns of METH self-administration behaviors in rats. Methods For the studies, we used a passive (non-contingent) METH dosing schedule consisting of 27 METH iv bolus injections (0.048 mg/kg) over 2 hrs derived from a previous active (contingent) METH self-administration behavioral study in male rats. After METH dosing of male and female Sprague-Dawley rats (n=5/group), METH and amphetamine serum concentrations were determined by LC-MS/MS. Pharmacokinetic analysis, including predictive mathematical simulations of the data, was then conducted. Results Male and female rats achieved relatively stable METH serum concentrations within 20 min, which remained constant from 20–120 min. While not statistically different, METH clearance and volume of distribution values for females were 25% and 33% lower (respectively) than males. Linear regression analysis of predicted METH concentrations from pharmacokinetic simulations versus observed concentrations showed a substantially better correlation with male data than female data (r2 = 0.71 vs. 0.56; slope = 0.95 vs. 0.45, respectively). At 120 min, the time of predicted peak METH serum concentrations, female values were 42% higher than expected, while male values were within 3%. Conclusions Unlike METH male pharmacokinetic data, the female data was less predictable during multiple METH administrations and produced overall higher than expected METH concentrations. These findings demonstrate that METH pharmacokinetics could contribute to differences in METH self-administration behaviors in rats.