Abstract
Dysregulation of mesolimbic dopamine transmission is implicated in a number of psychiatric illnesses characterised by disruption of reward processing and goal-directed behaviour, including schizophrenia, drug addiction and impulse control disorders associated with chronic use of dopamine agonists. Amphetamine sensitization (AS) has been proposed to model the development of this aberrant dopamine signalling and the subsequent dysregulation of incentive motivational processes. However, in humans the effects of AS on the dopamine-sensitive neural circuitry associated with reward processing remains unclear. Here we describe the effects of acute amphetamine administration, following a sensitising dosage regime, on blood oxygen level dependent (BOLD) signal in dopaminoceptive brain regions during a rewarded gambling task performed by healthy volunteers. Using a randomised, double-blind, parallel-groups design, we found clear evidence for sensitization to the subjective effects of the drug, while rewarded reaction times were unchanged. Repeated amphetamine exposure was associated with reduced dorsal striatal BOLD signal during decision making, but enhanced ventromedial caudate activity during reward anticipation. The amygdala BOLD response to reward outcomes was blunted following repeated amphetamine exposure. Positive correlations between subjective sensitization and changes in anticipation- and outcome-related BOLD signal were seen for the caudate nucleus and amygdala, respectively. These data show for the first time in humans that AS changes the functional impact of acute stimulant exposure on the processing of reward-related information within dopaminoceptive regions. Our findings accord with pathophysiological models which implicate aberrant dopaminergic modulation of striatal and amygdala activity in psychosis and drug-related compulsive disorders.
Highlights
Repeated intermittent administration of psychostimulants, such as cocaine or amphetamine, is associated with a progressive sensitivity to the drug’s effects [1,2,3], termed sensitization
In rodent models drug-induced hyperlocomotion and increased sensitivity to stressors are commonly observed [4,5], associated with an enhanced ability of the drug [6,7], or a stressor [8], to release dopamine (DA) in the nucleus accumbens. Such dysregulation of mesolimbic DA signalling has been posited as a model of dopaminergic abnormalities during the development of schizophrenia [9,10], drug addiction [11], their co-morbidity [12], druginduced psychosis [13] and impulse control disorders seen in some patients with Parkinson’s disease following chronic exposure to dopamine agonists [14,15]
For the first time, that sensitization would induce altered blood oxygen level dependent (BOLD) signal in key regions of rewardprocessing circuitry, the striatum, the orbitofrontal cortex and the amygdala, during the various phases of our gambling task, given the incentive sensitization hypothesis, we propose that reward anticipation is of most interest in this regard
Summary
Repeated intermittent administration of psychostimulants, such as cocaine or amphetamine, is associated with a progressive sensitivity to the drug’s effects [1,2,3], termed sensitization. These data demonstrated that AS was associated with enhanced druginduced dopamine release in the ventral striatum, extending dorsally into the dorsal caudate and putamen [65] In this present study we used the same amphetamine dosage regime as Boileau et al and employed a rewarded gambling (wheel-of fortune) task [68,69] to explore the impact of sensitization on the ability of a low dose of amphetamine to modulate different aspects of reward processing - namely decision making, anticipation and outcome processing - in dopaminoceptive brain regions. For the first time, that sensitization would induce altered BOLD signal in key regions of rewardprocessing circuitry, the striatum, the orbitofrontal cortex and the amygdala, during the various phases of our gambling task, given the incentive sensitization hypothesis, we propose that reward anticipation is of most interest in this regard
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