Cocaine Pharmacokinetics in Men and in Women During the Follicular and Luteal Phases of the Menstrual Cycle

Several studies in rodents suggest that there are sex differences in response to cocaine that are related to fluctuations in the ovarian hormones of females. Female rhesus monkeys have menstrual cycles that are remarkably similar to human menstrual cycles in both duration and hormonal variations. Therefore, data obtained in monkeys should be an ideal model for assessing the effects of cocaine across the menstrual cycle in humans. The present study assessed the acute effects of intravenous cocaine (0, 0.25, 0.50, and 1.00 mg/kg) in five female rhesus monkeys during four phases of the menstrual cycle: menses, midfollicular, periovulatory, and midluteal. To reduce the effects of stress that can occur from sedation, all animals were trained to enter primate chairs so that repeated blood samples could be obtained in awake animals. Hormone levels for estradiol and progesterone were measured each session before cocaine administration. Cocaine and cocaine metabolite plasma levels were measured at 5, 15, 30, 45, 60, and 90 min after cocaine administration. Similarly, levels of luteinizing hormone (LH) were measured before, 15, 30, 45, 60, and 90 min after cocaine administration. Within 5 min of cocaine administration, cocaine plasma levels peaked and dose-dependent behavioral changes (ie increased motor activity, mydriasis, and refusal of treats) were observed. These effects typically resolved in 15-30 min. There were few differences in the pharmacokinetic profile of cocaine across the menstrual cycle. However, the cocaine metabolites, BZE and EME, did vary across the menstrual cycle, with both being increased in the luteal phase, particularly following the highest dose of cocaine. In addition, unlike previous studies, cocaine did not produce consistent increases in LH levels. Rather, the change in LH levels depended on menstrual cycle phase and cocaine dose. In summary, there is little evidence that the pharmacokinetics of cocaine vary as a function of menstrual cycle phase.

Section: Introductionmentioning

confidence: 94%

Pharmacokinetics of Intravenous Cocaine Across the Menstrual Cycle in Rhesus Monkeys

Evans

Foltin

2004

“…cocaine has proven to be safe and to induce significant changes in mood states and physiological responses in our previous clinical studies. This dose of cocaine usually produces peak plasma cocaine levels of approximately 100 ng/ml Mendelson et al, 1998Mendelson et al, , 2001Sholar et al, 1998).…”

Section: Study Design and Rationale For Drug Dose Selectionmentioning

confidence: 99%

“…This rapid sampling frequency was based on previous observations that cocaine levels in venous blood increase rapidly within 2 min after i.v. administration and reach peak levels within 4 to 5 min (Evans et al, 1996;Sholar et al, 1998;Mendelson et al, 1999Mendelson et al, , 2001Mendelson et al, , 2002.…”

Section: Sample Collection Proceduresmentioning

confidence: 99%

Effects of the Mixed Mu/Kappa Opioid Nalbuphine on Cocaine-Induced Changes in Subjective and Cardiovascular Responses in Men

Mello

Mendelson

Sholar

et al. 2004

Kappa opioid agonists functionally antagonize some abuse-related and locomotor effects of cocaine, and reduce cocaine selfadministration by rhesus monkeys. We compared the cardiovascular and subjective effects of acute doses of the mu/kappa opioid nalbuphine alone (5 mg/70 kg, intravenous (i.v.)), with cocaine alone (0.2 mg/kg, i.v.), and with nalbuphine þ cocaine in combination, under placebo-controlled, double-blind conditions. Subjects met American Psychiatric Association Diagnostic and Statistical Manual (DSM-IV) criteria for current cocaine abuse. Nalbuphine serum levels exceeded 50 ng/ml within 10 min after injection, and cocaine plasma levels exceeded 130 ng/ml within 4 min. Cocaine's pharmacokinetic profile did not change after concurrent nalbuphine administration. The nalbuphine þ cocaine combination was safe and without synergistic effects on heart rate and systolic or diastolic blood pressure. Moreover, the addition of cocaine did not increase the subjective effects of nalbuphine. Visual Analog Scale (VAS) ratings of High, Euphoria, Stimulated, and Good Effect were equivalent after nalbuphine þ cocaine and nalbuphine alone, and both were significantly higher than after cocaine alone (area under the curve analysis) (po0.05-0.01). Peak VAS ratings of High, Stimulated, Good Effect, and Drug Effect were also significantly higher after nalbuphine þ cocaine than after cocaine alone (po0.01). Addiction Research Center Inventory (ARCI) scores were equivalent for nalbuphine þ cocaine and nalbuphine alone, but the PCAG, MBG, and amphetamine scores were significantly higher after both nalbuphine þ cocaine and nalbuphine alone than after cocaine alone (po0.01-0.003). Thus, there were no additive interactions between nalbuphine and cocaine on cardiovascular, subjective, or drug level measures after acute administration.

“…It is estimated that approximately 30% of the 1.8 million Americans who use cocaine are now women, and sex differences in the patterns of cocaine use and addiction are well documented. For example, women begin using cocaine at an earlier age than men; after first use they take less time to become addicted, they enter treatment at a younger age than men, and when they present for treatment, they have a more severe habit than men (Griffin et al, 1989;Kosten et al, 1993;Mendelson et al, 1999). Furthermore, cocaine cues induce more drug craving in female than male addicts (Robbins et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Biological Basis of Sex Differences in the Propensity to Self-administer Cocaine

Crombag

Robinson

et al. 2003

276

230

Women are at greater risk for cocaine addiction than are men, and female rats similarly show a greater propensity to self-administer cocaine than do male rats. This could be due to the intrinsic sex differences in brain organization, to the activational effects of circulating gonadal hormones, or both. For example, estradiol enhances dopamine release in the striatum and nucleus accumbens, and facilitates the behavioral sensitization induced by repeated cocaine exposure. We report here that independent of circulating gonadal hormones, female rats acquire cocaine self-administration behavior more rapidly, and they self-administer more cocaine at a faster rate than do male rats. This indicates that there is an intrinsic difference between male and female subjects in the neural systems mediating drug-seeking behavior due to sexual differentiation of the brain. Furthermore, we find that the administration of estradiol to gonadectomized female subjects greatly facilitates the acquisition of cocaine self-administration. These data demonstrate that both intrinsic sex differences in brain organization and the actions of circulating estradiol contribute to increased vulnerability for cocaine use in female subjects.