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
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ABSTRACT 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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    ABSTRACT: Successive negative contrast (SNC) describes a change in the behaviour of an animal following a downshift in the quantitative or qualitative value of an expected reward. This behavioural response has been hypothesised to be linked to affective state, with negative states associated with larger and/or prolonged shifts in behaviour. This study has investigated whether different psychopharmacological treatments have dissociable actions on the SNC effect in rats and related these findings to their actions on different neurotransmitter systems and affective state. Animals were trained to perform a nose-poke response to obtain a high-value food reward (four pellets). SNC was quantified during devalue sessions in which the reward was reduced to one pellet. Using a within-subject study design, the effects of acute treatment with anxiolytic, anxiogenic, antidepressant and dopaminergic drugs were investigated during both baseline (four pellets) or devalue sessions (one pellet). The indirect dopamine agonist, amphetamine, attenuated the SNC effect whilst the D1/D2 antagonist, alpha-flupenthixol, potentiated it. The antidepressant citalopram, anxiolytic buspirone and anxiogenic FG7142 had no specific effects on SNC, although FG7142 induced general impairments at higher doses. The α2-adrenoceptor antagonist, yohimbine, increased premature responding but had no specific effect on SNC. Results for the anxiolytic diazepam were mixed with one group showing an attenuation of the SNC effect whilst the other showed no effect. These data suggest that the SNC effect is mediated, at least in part, by dopamine signalling. The SNC effect may also be attenuated by benzodiazepine anxiolytics.
    Psychopharmacology 03/2015; 232(15). DOI:10.1007/s00213-015-3905-2 · 3.88 Impact Factor
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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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    ABSTRACT: The goal of our study was to characterize the relationship between intertemporal choice and interval timing, including determining how drugs that modulate brain serotonin and dopamine levels influence these two processes. In Experiment 1, rats were tested on a standard 40-s peak-interval procedure following administration of fluoxetine (3, 5, or 8mg/kg) or vehicle to assess basic effects on interval timing. In Experiment 2, rats were tested in a novel behavioral paradigm intended to simultaneously examine interval timing and impulsivity. Rats performed a variant of the bi-peak procedure using 10-s and 40-s target durations with an additional "defection" lever that provided the possibility of a small, immediate reward. Timing functions remained relatively intact, and 'patience' across subjects correlated with peak times, indicating a negative relationship between 'patience' and clock speed. We next examined the effects of fluoxetine (5mg/kg), cocaine (15mg/kg), or methamphetamine (1mg/kg) on task performance. Fluoxetine reduced impulsivity as measured by defection time without corresponding changes in clock speed. In contrast, cocaine and methamphetamine both increased impulsivity and clock speed. Thus, variations in timing may mediate intertemporal choice via dopaminergic inputs. However, a separate, serotonergic system can affect intertemporal choice without affecting interval timing directly. This article is part of a Special Issue entitled: Associative and Temporal Learning.
    Behavioural processes 10/2014; 101:123-134. DOI:10.1016/j.beproc.2013.09.013 · 1.57 Impact Factor
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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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    ABSTRACT: Testing impulsive behavior in rodents is challenging and labor-intensive. We developed a new behavioral paradigm-the Variable Delay-to-Signal (VDS) test-that provides rapid and simultaneous assessment of response and decision impulsivity in rodents. Presentation of a light at variable delays signals the permission for action (nose poke) contingent with a reward. 2 blocks of 25 trials at 3 s delay flank a block of 70 trials in which light is presented with randomly selected 6 or 12 s delays. Exposure to such large delays boosts the rate of premature responses when the delay drops to 3 s in the final block, an effect that is blunted by an acute methamphetamine challenge and that correlates with the delay-discounting (DD) paradigm (choice impulsivity). Finally, as expected, treatment with the NMDA antagonist MK-801 caused a generalized response increase in all VDS blocks. The pharmacological validation, particularly with methamphetamine which has a well established dual effect on response and decision impulsivity, and the correlations between the impulsive behavior in the DD and VDS paradigms, suggests that the later is able to provide, in a single session, a multi-dimensional assessment of impulsive behavior.
    Frontiers in Behavioral Neuroscience 10/2013; 7:154. DOI:10.3389/fnbeh.2013.00154 · 3.27 Impact Factor
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