Neural substrates of amphetamine induced impulsive behaviour

Impulsivity is a pathological feature of drug addiction. Amphetamine is a highly addictive drug that is amongst the most harmful recreational drugs abused within the UK (Nutt, King, & Phillips, 2010). Interestingly, however, amphetamine has a paradoxical relationship with impulsivity and can both alleviate and induce impulsive behaviour depending on pre-baseline levels of impulsivity and the dimension of impulsivity that is being measured. The current thesis sought to investigate the relationship between different patterns of amphetamine administration and impulsivity in the form of behavioural inhibition, and the neural substrates of amphetamine induced behavioural disinhibition, using the symmetrically reinforced Go/No-go task in rats (Harrison, Everitt, & Robbins, 1999). To assess the effects of different patterns of amphetamine administration on behavioural inhibition, separate groups of rats were treated with subchronic (4-day) and chronic (11-day) amphetamine and were tested on the Go/No-go task during drug treatment and drug withdrawal. Following two weeks of drug withdrawal, sensitivity to the acute effects of amphetamine in rats was tested with acute drug challenges. To assess the role of nucleus accumbens core D2 and GABAA receptors in the mediation of behavioural inhibition and amphetamine-induced behavioural disinhibition, separate groups of rats were also treated with intra-nucleus accumbens core infusions of the D2 antagonist eticlopride and GABAA agonist muscimol. Results revealed that short duration and high frequency binge-like amphetamine administration produced longer term increases in behavioural disinhibition than longer term and less frequent but overall higher dosing of amphetamine in rats. However, neither the binge-like (4-day) or longer term amphetamine regimes (11-day) caused any enduring changes in sensitivity to the acute disinhibitory effects of amphetamine in rats. Infusions of either eticlopride or muscimol into the NAcb core had no effect on behavioural inhibition assessed under baseline conditions, however, eticlopride infusions produced full behavioural reversal of amphetamine induced behavioural disinhibition and muscimol infusions produced partial reversal of amphetamine induced behavioural disinhibition. Taken together, these results demonstrate that different patterns of amphetamine administration produce different effects on the duration of behavioural disinhibition in rats, and further, that amphetamine induced activation of the D2 receptors within the nucleus accumbens core mediates amphetamine induced behavioural disinhibition on the symmetrically reinforced Go/No-go task. Results additionally support the possibility of dopamine-GABA interactions in the mediation of amphetamine induced behavioural disinhibition on the symmetrically reinforced Go/No-go task in rats.