Effects of priming injections of MDMA and cocaine on reinstatement of MDMA- and cocaine-seeking in rats.

Exposure to self-administered drugs is sufficient to produce drug-seeking in animal models. In many cases priming injections of drugs that share discriminative stimulus properties with the self-administered drug also can lead to drug-seeking, suggesting that exposure might precipitate relapse. The present investigation examined the ability of MDMA or cocaine priming injections to reinstate extinguished drug-seeking in rats. Priming injections of cocaine (0-20.0 mg/kg) and MDMA (0.0-10.0 mg/kg) reinstated extinguished drug-taking for both the cocaine- and MDMA-trained rats. In a separate group of cocaine-trained rats that received repeated exposure to 10.0 mg/kg MDMA, the initial exposure to MDMA (10.0 mg/kg, i.p.) failed to reinstate extinguished responding but MDMA became an effective prime for reinstatement of extinguished cocaine-taking behavior with repeated exposure. Effects of MDMA in MDMA-trained rats was greater than the effect in cocaine-trained rats suggesting that extensive experience with MDMA self-administration might have sensitized rats to this effect. These findings show that extinguished MDMA self-administration, like self-administration of other drugs of abuse, can be reinstated by exposure to psychostimulants thereby precipitating relapse.

MDMA self-administration in rats: acquisition, progressive ratio responding and serotonin transporter binding.

3,4-Methylenedioxymethamphetamine (MDMA) self-administration has been shown in animals with extensive drug histories, but only a small number of studies have examined high rates of responding maintained by MDMA in previously drug-naïve animals. In the present study, influence of dose (0.25 or 1.0 mg/kg/infusion) on the acquisition of MDMA self-administration was measured during daily 6-h sessions. Dose-effect data were obtained for MDMA (0.25-1.0 mg/kg/infusion) self-administration under a progressive ratio (PR) schedule of reinforcement. The effect of experimenter- or self-administered MDMA on [3H] paroxetine binding in several brain regions was measured. Acquisition of MDMA self-administration was highly variable and not different for 0.25 or 1.0 mg/kg/infusion progressed with approximately 60% of the rats acquiring reliable self-administration during the 15-day test period. The percentage of rats that acquired MDMA self-administration was lower than the percentage of rats that acquired cocaine (0.5 mg/kg/infusion) self-administration, and cocaine self-administration was acquired with a shorter latency. Responding maintained by MDMA was dose dependent, and breakpoints under a PR schedule increased with dose. Radioligand binding and autoradiography demonstrated lower densities of serotonin transporter sites (SERT) in MDMA self-administering rats as compared with controls across brain regions. The reduction in SERT densities was comparable in magnitude to rats treated with experimenter-administered doses of MDMA. These data support the idea that MDMA is a drug with high abuse liability, and long-term self-administration may lead to long-lasting deficits in serotonin neurotransmission.

N-benzylpiperazine has characteristics of a drug of abuse.

The ability of benzylpiperazine (BZP) to substitute for cocaine and to initiate self-administration in drug-naive subjects was assessed to determine whether BZP has abuse liability. Further, the effects of a pretreatment with dopamine D1-like receptor antagonist (SCH23390) were examined to elucidate the mechanisms associated with BZP reward. First, the ability for BZP (0.125, 0.25 and 0.5 mg/kg/infusion) to substitute for cocaine self-administration was assessed, and the acquisition of BZP (0.5 mg/kg/infusion) self-administration by drug-naive and untrained rats was determined during a 15-day period. Subsequently, dose-effect curves for cocaine (0.06, 0.125, 0.25 or 0.5 mg/kg/infusion) and BZP self-administration (0.125, 0.25, 0.5 or 1.0 mg/kg/infusion) and the effect of SCH23390 (0.00 or 0.02 mg/kg) on BZP and cocaine self-administration were examined. BZP substituted for cocaine, and drug-naive rats rapidly acquired BZP self-administration. BZP self-administration was maintained by a more restricted range of doses than was cocaine self-administration, and responding maintained by BZP was sensitive to dopamine antagonism. The present findings indicate that BZP self-administration, like cocaine self-administration, is readily acquired and mediated by dopaminergic mechanisms.

Triple therapy with glimepiride in patients with type 2 diabetes mellitus inadequately controlled by metformin and a thiazolidinedione: results of a 30-week, randomized, double-blind, placebo-controlled, parallel-group study.

OBJECTIVE: This study evaluated the efficacy and tolerability of glimepiride in patients with type 2 diabetes mellitus that was inadequately controlled with a combination of immediate- or extended-release metformin and a thiazolidinedione. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 2-arm study consisting of a 4-week stabilization and eligibility period and a 26-week treatment period. Patients with a diagnosis of type 2 diabetes for a minimum of 1 year received glimepiride (titrated sequentially from 2 to 4 to 8 mg/d over 6 weeks, followed by 20 weeks of maintenance therapy) or placebo in combination with an established regimen of immediate- or extended release metformin and rosiglitazone or pioglitazone. The primary efficacy outcome was the change in glycosylated hemoglobin (HbA(1c)) from baseline. The safety analysis was based on the incidence of hypo glycemia, adverse events, and laboratory abnormalities. Changes in lipid levels (high-density lipoprotein cholesterol, total cholesterol, low-density lipoprotein cholesterol, very low density lipoprotein cholesterol, and triglycerides) were evaluated, and health-related quality of life was assessed based on scores on the Diabetes Care Profile (DCP) and Health Utilities Index Mark 3 (HU13). RESULTS: Of 170 randomized patients, 159 were included in the efficacy analysis and 168 were included in the safety analysis. Demographic variables were similar at baseline between the glimepiride and placebo groups (mean age, 56.5 and 56.4 years, respectively; percent men/women, 61.0%/39.0% and 62.3%/37.7%; weight, 100.9 and 96.3 kg). HbA(1c) was significantly improved at end point with glimepiride combination therapy compared with placebo (mean [SE], -1.31% [0.08] vs -0.33% [0.08], respectively; P < 0.001). The majority of patients (62.2%) who received glimepiride achieved an HbA(1c) value of < or =7%, compared with 26.0% of patients receiving placebo (P < 0.001 between groups). At end point, the adjusted mean differences between treatments significantly favored the glimepiride combination in terms of fasting plasma glucose (-37.4 [4.0] mg/dL; P < 0.001), fasting insulin (4.06 [1.69] microIU/mL; P < 0.03), and C-peptide (124.5 [35.9] pmol/L; P < 0.001). The adjusted mean changes in body mass index from baseline to end point were 1.26 (0.16) kg/m(2) with glimepiride and 0.17 (0.16) kg/m(2) with placebo (P < 0.001). Similarly, the mean change in weight was greater with glimepiride than with placebo (3.76 [0.54] vs 0.45 [0.52] kg; P < 0.001). There were no significant differences in lipid levels between groups. Clinically significant adverse events, laboratory abnormalities, and rates of severe hypoglycemia were similar between treatment groups. The overall incidence of hypoglycemia, however, was 51.2% in the glimepiride group and 8.3% in the placebo group (P < 0.001). In general, there was no significant difference between treatment groups with respect to scores on the DCP or HUI3 over the study period. CONCLUSIONS: In these patients with type 2 diabetes that was not adequately controlled by dual combination therapy with metformin and a thiazolidinedione, the addition of glimepiride improved glycemic control compared with placebo with an acceptable tolerability profile. Although there were significantly more episodes of hypoglycemia with triple therapy than with dual therapy and placebo, the risk for severe hypoglycemia was low.