Effects of atomoxetine, desipramine, D-amphetamine and methylphenidate on impulsivity in juvenile rats, measured in a T-maze procedure
Key-Obs SAS, 3 allée du Titane, F-45100 Orléans, France. Neuroscience Letters
(Impact Factor: 2.03).
02/2011; 489(1):20-4. DOI: 10.1016/j.neulet.2010.11.058
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.
Available from: Natalie E Zlebnik
- "Norepinephrine in the PFC modulates cognitive functioning and has been associated with attention regulation, working memory, and behavioral inhibition (Arnsten 2000; Arnsten and Casey 2011). While results examining the effects of DA receptor agonists and antagonists on delay discounting have been mixed (Hamidovic et al. 2008; Wade et al. 2000; van Gaalen et al. 2006), previous work found decreased impulsive choice during a delay-discounting task with NET inhibition by ATO (Bizot et al. 2011; Robinson et al. 2008, but see Baarendse and Vanderschuren 2012; Broos et al. 2012a, b; Sun et al. 2012). Exercise also increases extracellular levels of NE and DA in the PFC (Ma 2008; Meeusen and De Meirleir 1995; Paluska and Schwenk 2000), and it may be by this mechanism that wheel running augmented the treatment effects of ATO and resulted in differential levels of wheel running in LoI versus HiI rats. "
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Aerobic exercise and the attention-deficit/hyperactivity disorder medication, atomoxetine (ATO), are two monotherapies that have been shown to suppress reinstatement 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).
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).
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 treatment. 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 treatment effects.
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.
Available from: Jeff Wickens
- "Methylphenidate (3 mg/kg), atomoxetine (1 mg/kg), d-amphetamine (1 and 2 mg/kg), and desipramine (8 and 16 mg/kg) all led to an increased choice of the larger delayed reinforcer. The authors suggest that the T-maze procedure in juvenile animals may be suitable for testing the therapeutic potential of drugs for the management of ADHD . "
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ABSTRACT: Attention deficit hyperactivity disorder (ADHD) presents special challenges for drug development. Current treatment with psychostimulants and nonstimulants is effective, but their mechanism of action beyond the cellular level is incompletely understood. We review evidence suggesting that altered reinforcement mechanisms are a fundamental characteristic of ADHD. We show that a deficit in the transfer of dopamine signals from established positive reinforcers to cues that predict such reinforcers may underlie these altered reinforcement mechanisms, and in turn explain key symptoms of ADHD. We argue that the neural substrates controlling the excitation and inhibition of dopamine neurons during the transfer process are a promising target for future drug development. There is a need to develop animal models and behavioral paradigms that can be used to experimentally investigate these mechanisms and their effects on sensitivity to reinforcement. More specific and selective targeting of drug development may be possible through this approach.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-012-0132-y) contains supplementary material, which is available to authorized users.
Available from: Brian Hyland
- "Methylphenidate (3 mg·kg -1 ), atomoxetine (1 mg·kg -1 ), D-amphetamine (1 and 2 mg·kg -1 ) and desipramine (8 and 16 mg·kg -1 ) increased the number of choices of the large-but-delayed reward, that is decreased impulsivity. They suggest that the T-maze procedure in juvenile animals may be suitable for testing the therapeutic potential of drugs for treatment of ADHD (Bizot et al., 2011). "
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ABSTRACT: We review strategies for developing animal models for examining and selecting compounds with potential therapeutic benefit in attention-deficit hyperactivity disorder (ADHD). ADHD is a behavioural disorder of unknown aetiology and pathophysiology. Current understanding suggests that genetic factors play an important role in the aetiology of ADHD. The involvement of dopaminergic and noradrenergic systems in the pathophysiology of ADHD is probable. We review the clinical features of ADHD including inattention, hyperactivity and impulsivity and how these are operationalized for laboratory study. Measures of temporal discounting (but not premature responding) appear to predict known drug effects well (treatment validity). Open-field measures of overactivity commonly used do not have treatment validity in human populations. A number of animal models have been proposed that simulate the symptoms of ADHD. The most commonly used are the spontaneously hypertensive rat (SHR) and the 6-hydroxydopamine-lesioned (6-OHDA) animals. To date, however, the SHR lacks treatment validity, and the effects of drugs on symptoms of impulsivity and inattention have not been studied extensively in 6-OHDA-lesioned animals. At the present stage of development, there are no in vivo models of proven effectiveness for examining and selecting compounds with potential therapeutic benefit in ADHD. However, temporal discounting is an emerging theme in theories of ADHD, and there is good evidence of increased value of delayed reward following treatment with stimulant drugs. Therefore, operant behaviour paradigms that measure the effects of drugs in situations of delayed reinforcement, whether in normal rats or selected models, show promise for the future.
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