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

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 (0.048mg/kg) over 2h 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 20min, which remained constant from 20 to 120min. 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 (r(2)=0.71 vs. 0.56; slope=0.95 vs. 0.45, respectively). At 120min, 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.

Drug discrimination in pigeons trained to discriminate among morphine, U50488, a combination of these drugs, and saline.

This study compared fixed-ratio (FR) and fixed-interval (FI) schedules to investigate the discriminative stimulus properties of µ-opioid and/or κ-opioid receptor agonists. Pigeons were trained to discriminate among morphine (µ agonist), U50488 (κ agonist), the combination, and saline under FR 20-s or FI-300-s schedule. After training, correct-key responding averaged 94.4 (FR) and 66.5% (FI) after administration of training drugs. Dose-response curves were generally quantal under the FR and graded under the FI schedules, but highly variable among subjects under the FI. Under the FR schedule, the dose of naltrexone that blocked morphine's discriminative stimuli also blocked U50488. Combining high doses of morphine with low doses of U50488 produced responding on the morphine key and combining high doses of U50488 with low doses of morphine produced responding on the U50488 key. Combining high doses of both drugs produced responding on the drug-combination key. Increasing d,l-pentazocine doses shifted responding from the saline key to the U50488 key, then to the morphine key, and finally to the drug-combination key. Butorphanol and ethylketocyclazocine produced similar effects, except responding on the morphine key increased before responding on the U50488 key. The four-choice procedure under the FR schedule has the potential for determining the discriminative stimulus effects of mixed agonists.

Delay discounting, impulsiveness, and addiction severity in opioid-dependent patients.

Individuals who abuse drugs show higher delay discounting (DD) rate and impulsiveness scores compared with controls; however, it is unclear if DD rate covaries with severity of the addiction or if an individual's discounting rate can be changed by effective substance abuse treatment. This study compared methadone maintenance treatment (MMT) patients (n = 30) who had not used illegal drugs for 2 years with drug-using MMT patients (n = 30) and controls (n = 25) in terms of addiction severity, DD rate, and impulsiveness. Methadone patients abstinent from illegal drugs scored significantly lower on a number of addiction severity measures than the drug-using methadone patients. In addition, both groups of MMT patients showed significantly higher rates of DD and impulsiveness than the control group; however, no differences in DD rate or impulsiveness were found between the groups of patients. Results suggest that DD rate and impulsiveness may not covary with indicators of addiction severity in MMT patients.

Effects of gamma-hydroxybutyrate on punished responding in pigeons.

The abuse of drugs such gamma-hydroxybutyrate (GHB) has become a serious drug abuse problem in recent years; however, data on the behavioral effects of GHB are limited. Drugs that increase punished behavior are frequently subject to abuse. The purpose of the present experiments was to determine whether GHB increases punished responding in pigeons as might be predicted on the basis of its depressant activity and abuse liability in humans. GHB increased punished responding to an extent comparable to pentobarbital, suggesting that GHB has antianxiety effects that might contribute to its abuse liability.

Sex differences in (+)-amphetamine- and (+)-methamphetamine-induced behavioral response in male and female Sprague-Dawley rats.

(+)-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.

Voucher-based incentives for cigarette smoking reduction in a women's residential treatment program.

Participants were women (N = 16) living with their children in a residential substance abuse treatment facility. In this within-subjects repeated measures study, a 1-week baseline was followed by a 4-week intervention and a 2-week follow-up (same as the baseline). The intervention consisted of exposure to an educational video and a smoking cessation workbook, brief individual support meetings, and an escalating schedule of voucher-based reinforcement of abstinence. Throughout the study, three daily breath samples (8 a.m., noon, and 4 p.m.) were collected Monday through Friday to determine carbon monoxide (CO) concentration. In addition, urine cotinine (COT) was assessed on Monday mornings to monitor weekend tobacco use. Participants received vouchers of escalating value for CO-negative breath and COT-negative urine samples. Positive samples reset the voucher value. Significantly more negative tests were submitted during the intervention than during baseline and follow-up. The intensive behavioral intervention evaluated in this study produced a substantial reduction in cigarette smoking, and 25% of participants remained abstinent 2 weeks after the intervention was suspended. Nevertheless, the percentage of CO-negative samples submitted during the follow-up returned to baseline levels. While retaining many real-world characteristics, residential treatment facilities provide important opportunities for smoking cessation treatment and research.

Retention of sequential drug discriminations under fixed-interval schedules for long time periods without training.

The experiments showed that sequential drug discriminations can be learned and retained under a fixed-interval (FI) schedule for more than 18 months without additional training under a complex three-choice procedure. Pigeons were trained to discriminate among 5 mg/kg pentobarbital, 2 mg/kg D-amphetamine, and saline. After responding stabilized, dose-response curves were determined for other drugs. Subsequently, pentobarbital was replaced with 5 mg/kg morphine as a training drug, and D-amphetamine was replaced with 30 mg/kg caffeine. After the pigeons learned these new discriminations, dose-response curves were redetermined. Initially, chlordiazepoxide substituted for pentobarbital, cocaine substituted for D-amphetamine, and nicotine partially substituted for D-amphetamine. Morphine, Delta9-tetrahydrocannabinol, and caffeine did not substitute for either drug. After retraining with morphine and caffeine, responding occurred on the pentobarbital/morphine key after pentobarbital, chlordiazepoxide and morphine and on the D-amphetamine/caffeine key after D-amphetamine, cocaine and caffeine. After nicotine and Delta9-tetrahyrdocannabinol, responding occurred on the saline key. These data show that drug discriminations learned under fixed-interval schedules are retained for long time periods, even when discrimination training with other drugs occurs during the retention period.

Sensitivity to acute methadone dose changes in maintenance patients.

This study assessed whether methadone patients can identify acute dose changes in their maintenance dose, and explored the relationships between self-reported drug effects and real or perceived dose changes. Four times each week patients (N = 10) unpredictably received either 80%, 90%, 100%, 110% or 120% of their usual daily dose (50-100 mg). Approximately 24 hr later they indicated which dose they had received on the previous day, and rated the previous day's dose in terms of good effects, bad effects, and change in medication taste. Correct estimation of the doses received was always at the levels expected by chance alone. Furthermore, this sample of patients could not detect dose-related changes in medication taste. However, self-reports of good effects were significantly higher when patients believed that they had received a dose increment, and ratings of bad effects were higher when patients believed that they had received a dose decrement.

Continuing implications of the early evidence against the drive-reduction hypothesis of the behavioral effects of drugs.

RATIONALE: Early psychopharmacologists often explained the behavioral effects of drugs as due to changes in the hypothetical construct of motivation, implying that drug effects would depend on the inherent properties of the reinforcer that maintains responding. The work of Dews, Morse, and Kelleher offered an alternative explanation that the scheduling of reinforcers, and the patterns and rates of responding maintained, were more important determinants of drug effects. OBJECTIVE: The present paper reviews the literature on the influence on drug effects of the type of reinforcer that maintains responding. METHODS: Studies that examined the effects of drugs on behaviors maintained by different reinforcers were compared with studies that examined behaviors maintained by the same reinforcer under various conditions. RESULTS: Over a wide range of conditions, the effects of drugs depend more on the schedule-controlled patterns and rates of responding than on the particular reinforcer. However, there are some conditions under which the reinforcer that maintains behavior can also determine drug effects. The broad implications of these findings in selected areas of psychopharmacology are discussed. CONCLUSIONS: Under some conditions drug effects are ostensibly consistent with explanations in terms of traditional hypothetical constructs, though under a wide range of other conditions they are not. A more general understanding of the behavioral effects of drugs comes from directing the emphasis of research away from hypothetical constructs and towards the empirically defined determinants of the behavioral effects of drugs.