The potent psychomotor, rewarding and reinforcing properties of 3-fluoromethamphetamine in rodents.

3-fluoromethamphetamine (3-FMA), a derivative of methamphetamine (METH), produces behavioral impairment and deficits in dopaminergic transmission in the striatum of mice. The abuse potential of 3-FMA has not been fully characterized. The aim of this study was to evaluate the effects of 3-FMA on locomotor activity as well as its rewarding and reinforcing properties in the conditioned place preference (CPP) and self-administration procedures. Intravenous (i.v.) administration of 3-FMA (0.5 and 1.0 mg/kg) significantly increased locomotor activity in a dose-dependent manner in rats. In the CPP procedure, intraperitoneal administration of 3-FMA (10 and 30 mg/kg) produced a significant alteration in place preference in mice. In the self-administration paradigms, 3-FMA showed drug-taking behavior at the dose of 0.1 mg/kg/infusion (i.v.) during 2 hr sessions under fixed ratio schedules and high breakpoints at the dose of 0.3 and 1.0 mg/kg/infusion (i.v.) during 6 hr sessions under progressive ratio schedule of reinforcement in rats. A priming injection of 3-FMA (0.4 mg/kg, i.v.), METH (0.2 mg/kg, i.v.), or cocaine (2.0 mg/kg, i.v.) reinstated 3-FMA-seeking behavior after an extinction period in 3-FMA-trained rats during 2 hr session. Taken together, these findings demonstrate robust psychomotor, rewarding and reinforcing properties of 3-FMA, which may underlie its potential for compulsive use in humans.

Behavioral evidence for the abuse potential of the novel synthetic cathinone alpha-pyrrolidinopentiothiophenone (PVT) in rodents.

RATIONALE: Synthetic cathinones are chemical derivatives of cathinone that are pharmacologically similar to cocaine and methamphetamine. Recently, abuse of synthetic cathinones among young people has increased. OBJECTIVES: The present study aimed to characterize the behavioral effects of alpha-pyrrolidinopentiothiophenone (PVT), an analog of alpha-pyrrolidinovalerophenone and second-generation synthetic cathinone, as well as to evaluate its abuse potential, using conditioned place preference, intravenous self-administration (SA), and drug discrimination paradigms in rodent models. RESULTS: Alpha-PVT produced a significant place preference in mice at doses of 10, 30, and 50 mg/kg. In the SA experiment, alpha-PVT (0.1, 0.3, and 1.0 mg/kg/infusion) produced an inverted U-shaped dose-effect curve in rats. Under a progressive ratio schedule of reinforcement, there appeared to be a positive relationship between alpha-PVT dose and the breakpoints for alpha-PVT reinforcement. Additionally, alpha-PVT fully substituted for the discriminative stimulus effects of both cocaine and methamphetamine in rats. CONCLUSIONS: Our results indicate that alpha-PVT has rewarding and reinforcing effects and shares the interoceptive effects of cocaine and methamphetamine. To the best of our knowledge, the present study is the first to show that alpha-PVT has reinforcing properties when delivered on its own, which suggests possible abuse liability in humans.

Differential discriminative-stimulus effects of cigarette smoke condensate and nicotine in nicotine-discriminating rats.

Although it is widely accepted that nicotine plays a key role in tobacco dependence, nicotine alone cannot account for all of the pharmacological effects associated with cigarette smoke found in preclinical models. Thus, the present study aimed to determine the differential effects of the interoceptive cues of nicotine alone versus those of cigarette smoke condensate (CSC) in nicotine-trained rats. First, the rats were trained to discriminate nicotine (0.4mg/kg, subcutaneous [s.c.]) from saline in a two-lever drug discrimination paradigm. Then, to clarify the different neuropharmacological mechanisms underlying the discriminative-stimulus effects in the nicotine and CSC in nicotine-trained rats, either the α4ß2 nicotinic acetylcholine receptor (nAChR) antagonist dihydro-ß-erythroidine (DHßE; 0.3-1.0mg/kg, s.c.) or the α7 nAChR antagonist methyllycaconitine citrate (MLA; 5-10mg/kg, intraperitoneal [i.p.]) was administered prior to the injection of either nicotine or CSC. Separate set of experiments was performed to compare the duration of action of the discriminative-stimulus effects of CSC and nicotine. CSC exhibited a dose-dependent nicotine generalization, and interestingly, 1.0mg/kg of DHßE antagonized the discriminative effects of nicotine (0.4mg/kg) but not CSC (0.4mg/kg nicotine content). However, pretreatment with MLA had no effect. In the time-course study, CSC had a relatively longer half-life in terms of the discriminative-stimulus effects compared with nicotine alone. Taken together, the present findings indicate that CSC has a distinct influence on interoceptive effects relative to nicotine alone and that these differential effects might be mediated, at least in part, by the α4ß2, but not the α7, nAChR.