The pharmacokinetics of methamphetamine self-administration in male and female rats

Abstract

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.

Nonmuscle myosin II inhibition disrupts methamphetamine-associated memory in females and adolescents

“…Females pressed the METH-associated active lever less and received fewer METH infusions during self-administration training, when compared to our previous experiments with males. While we have not made direct, statistical comparisons because the experiments were not performed side-by-side, this is consistent with previously published studies demonstrating a greater sensitivity to psychostimulants in females, likely due to greater bioavailability [24]. Another sex difference noted when comparing the current data in females to our prior data in males is related to BLC spine density.…”

“…For instance, women tend escalate to addiction faster, and be more susceptible to feelings of craving and relapse, relative to men [18–23]. Moreover, greater bioavailability of psychostimulants has been shown in female animals, as compared to males, and consistent with this, females tend to self-administer lower drug doses [24]. Adolescents are another population that is under-studied and at significant risk for SUD.…”

Sex differences in subjective and objective responses to a stimulant medication (methylphenidate): Comparisons between overweight/obese adults with and without binge‐eating disorder

“…For instance, a recent study found that female rats achieved a higher peak concentration of methamphetamine, and they demonstrated a lower clearance rate than male rats. 33 In the female group, there was also a significantly greater suppression of appetite and cravings, and a diminution in food consumption, during the snack-food challenge that followed administration of MP, relative to that in the placebo condition. These results are in accord with previous evidence that obese men, compared to those of normal weight and compared to both female weight groups, were relatively inured to the appetite suppression normally seen in response to psychomotor stimulant drugs.…”

Effect of Bile Duct Ligation-induced Liver Dysfunction on Methamphetamine Pharmacokinetics and Locomotor Activity in Rats

“…Future studies would need to modify the BDLsurgical technique to produce a range of hepatic dysfunction and study additional hepatotoxicity biomarkers to determine and characterize potential liver damage due to METH exposure. Additionally, this study was only performed in male rats, but there are known sex differences in METH-induced rat behavior and METH PK (32,(41)(42)(43) and in effects on human behavior and brain function (44).…”