Opposite Effects of Amphetamine on Impulsive Action with Fixed and Variable Delays to Respond

Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 02/2012; 37(3):651-9. DOI: 10.1038/npp.2011.236
Source: PubMed


Impulsive action, the failure to withhold an inappropriate response, is treated clinically with dopamine agonists such as amphetamine. Despite the therapeutic efficacy, these drugs have inconsistent effects on impulsive action in rodents, causing improvements or disruptions in different tasks. Thus, we hypothesized that amphetamine is producing an effect by altering distinct cognitive processes in each task. To test this idea, we used the response inhibition (RI) task and trained rats to withhold responding for sucrose until a signal is presented. We then varied the duration that subjects were required to inhibit responding (short=4 s; long=60 s; or variable=1-60 s) and examined whether this influenced the pattern of premature responses. We also tested the effects of amphetamine (0.0, 0.125, 0.25, 0.5, and 1.0 mg/kg) on each task variant. The probability of premature responding varied across the premature interval with a unique pattern of time-dependent errors emerging in each condition. Amphetamine also had distinct effects on each version: the drug promoted premature responding when subjects expected a consistent delay, regardless of its duration, but reduced premature responding when the delay was unpredictable. We propose that the ability to inhibit a motor response is controlled by a different combination of cognitive processes in the three task conditions. These include timing, conditioned avoidance, and attention, which then interact with amphetamine to increase or decrease impulsive action. The effect of amphetamine on impulsive action, therefore, is not universal, but depends on the subject's experience and expectation of the task demands.

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    • "Baseline drug testing was carried out on a Tuesday, and devalue sessions were run on a Friday with animals being run under baseline conditions without treatment on Monday, Wednesday and Thursday. Doses of drugs were based on previous SNC and 5CSRTT studies or doses shown to have anxiolytic or anxiogenic effects in other rodent tasks (Stuart et al. 2013; Torres et al. 1995; Yeung et al. 2013; Cai et al. 2012; Hayton et al. 2012; Cole and Robbins 1987). The first cohort of animals received a total of 16 treatments with drugs in the following order: "
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    • "Even those investigators reporting decreases in impulsivity following amphetamine administration have recognized that special factors are likely involved, e.g., low drug doses, specific subject populations, as well as the careful selection of the time course involving the interaction of pharmacodynamics and the behavioral task (Rivalan et al., 2007). Moreover, these investigators have argued that impulsivity is most likely to be observed in instances where time estimation is a major component of the behavioral task due to the enhanced clock-speed effects of amphetamine (e.g., Hayton et al., 2012; Rivalan et al., 2007). The conclusion being that one has to take a variety of factors into account and attempt to develop a set of behavioral tasks that address different dimensions of self control and impuls- ivity. "
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    • "Methamphetamine was used in VDS 1 session to lessen impulsive behavior. A dose of 1 mg/Kg of the racemic mixture (effective dose of 0.5 mg/Kg) was administered intraperitoneally in a freshly prepared solution at a concentration of 1 mg/mL (in saline) 30 min before the initiation of the session (Hayton et al., 2012). Methamphetamine hydrochloride was synthesized by an adaptation of a previously described method (Milhazes et al., 2007). "
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