Effects of atomoxetine, desipramine, D-amphetamine and methylphenidate on impulsivity in juvenile rats, measured in a T-maze procedure
ABSTRACT Impulsivity is a core symptom of Attention Deficit/Hyperactivity Disorder (ADHD). In the present study, we assessed the effects of two stimulants, methylphenidate and d-amphetamine and of two non stimulant noradrenaline reuptake inhibitors, atomoxetine and desipramine, on the tolerance to delay of reward, taken as an index of impulsivity, in juvenile Wistar rats. Animals were trained in a T-maze to choose between a small-and-immediate reward and a large-but-30s-delayed reward. The effects of drugs were studied on the performance of animals at 30-40 day of age. Methylphenidate (3mg/kg), atomoxetine (1mg/kg), d-amphetamine (1 and 2mg/kg) and desipramine (8 and 16mg/kg) increased the number of choices of the large-but-delayed reward, i.e. decreased impulsivity. Given that these drugs are commonly prescribed in ADHD, these data indicate that the T-maze procedure in juvenile animals may be suitable for testing the therapeutic potential of drugs intended to the treatment of ADHD in children.
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ABSTRACT: Background Aerobic exercise and the attention-deficit/hyper-activity disorder medication, atomoxetine (ATO), are two monotherapies that have been shown to suppress reinstate-ment of cocaine-seeking in an animal model of relapse. The present study investigated the effects of combining wheel running and ATO versus each treatment alone on cocaine-seeking precipitated by cocaine and cocaine-paired cues in rats with differing susceptibility to drug abuse (i.e., high vs. low impulsive). Methods Rats were screened for high (HiI) or low impulsivity (LoI) based on their performance on a delay-discounting task and then trained to self-administer cocaine (0.4 mg/kg/inf) for 10 days. Following 14 days of extinction, both groups were tested for reinstatement of cocaine-seeking precipitated by cocaine or cocaine-paired cues in the presence of concurrent running wheel access (W), pretreatment with ATO, or both (W+ATO). Results HiI rats acquired cocaine self-administration more quickly than LoI rats. While both individual treatments and W+ATO significantly attenuated cue-induced cocaine seeking in HiI and LoI rats, only W+ATO was effective in reducing cocaine-induced reinstatement compared with vehicle treat-ment. There were dose-dependent and phenotype-specific effects of ATO with HiI rats responsive to the low but not high ATO dose. Floor effects of ATO and W on cue-induced reinstatement prevented the assessment of combined treat-ment effects. Conclusions These findings demonstrated greater attenuation of cue-versus cocaine-induced reinstatement by ATO and W alone and recapitulate impulsivity phenotype differences in both acquisition of cocaine self-administration and receptivity to treatment.Psychopharmacology 09/2014; 232(6). DOI:10.1007/s00213-014-3744-6 · 3.99 Impact Factor
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ABSTRACT: Lisdexamfetamine dimesylate (LDX) is a novel prodrug of d-amphetamine that is currently used for the treatment of attention-deficit/hyperactivity disorder in children aged ≥6 years and adults. LDX is enzymatically cleaved to form d-amphetamine following contact with red blood cells which reduces the rate of appearance and magnitude of d-amphetamine concentration in the blood and hence the brain when compared with immediate-release d-amphetamine at equi-molar doses. Thus, the increase of striatal dopamine efflux and subsequent increase of locomotor activity following d-amphetamine is less prominent and slower to attain maximal effect following an equimolar dose of LDX. Furthermore, unlike d-amphetamine, the pharmacodynamic effects of LDX are independent of the route of administration underlining the requirement to be hydrolysed by contact with red blood cells. It is conceivable that these pharmacokinetic and pharmacodynamic differences may impact the psychostimulant properties of LDX in the clinic. This article reviews the preclinical pharmacokinetics, pharmacology, and toxicology of LDX.Neuropharmacology 03/2014; 87. DOI:10.1016/j.neuropharm.2014.02.014 · 4.82 Impact Factor