Abstract
Repeated exposure to the psychostimulant amphetamine has been shown to disrupt goal-directed instrumental actions and promote the early and abnormal development of goal-insensitive habitual responding (Nelson and Killcross, 2006). To investigate the neuropharmacological specificity of this effect as well as restore goal-directed responding in animals with pre-training amphetamine exposure, animals were treated with the non-selective dopamine antagonist α-flupenthixol, the selective D1 antagonist SCH 23390 or the selective D2 antagonist eticlopride, prior to instrumental training (three sessions). Subsequently, the reinforcer was paired with LiCL-induced gastric-malaise and animals were given a test of goal-sensitivity both in extinction and reacquisition. The effect of these dopaminergic antagonists on the sensitivity of lever press performance to outcome devaluation was assessed in animals with pre-training exposure to amphetamine (Experiments 1A–C) or in non-sensitized animals (Experiment 2). Both α-flupenthixol and SCH23390 reversed accelerated habit formation following amphetamine sensitization. However, eticlopride appeared to enhance this effect and render instrumental performance compulsive as these animals were unable to inhibit responding both in extinction and reacquisition, even though a consumption test confirmed they had acquired an aversion to the reinforcer. These findings demonstrate that amphetamine induced-disruption of goal-directed behavior is mediated by activity at distinct dopamine receptor subtypes and may represent a putative model of the neurochemical processes involved in the loss of voluntary control over behavior.
Highlights
Repeated administration of psychostimulants such as amphetamine leads to behavioral sensitization and induces the appearance of repetitive and stereotyped behaviors that become more exaggerated following additional drug exposure (Kalivas et al, 1993; Canales et al, 2002; Capper-Loup et al, 2002)
During the early stages of acquisition, instrumental performance is normally sensitive to post-conditioning changes in reward value (Adams and Dickinson, 1981; Dickinson and Balleine, 1994) but as training proceeds, response control is ceded to the habit system and as a consequence becomes less sensitive to changes in reward value (Adams, 1982)
As imbalances in systems that control instrumental behavior are likely to be involved in the development of habitual drug-taking (Everitt and Robbins, 2005; Hogarth et al, 2013) as well as contribute to the production of involuntary and repetitive behaviors associated with OCD and Tourette’s Syndrome (Ridley, 1994; Graybiel and Rauch, 2000; Leckman and Riddle, 2000; Gillan et al, 2011), it is of critical importance to understand the neural mechanisms that underpin the transfer of response control from the goal-directed to the habit system
Summary
Repeated administration of psychostimulants such as amphetamine leads to behavioral sensitization and induces the appearance of repetitive and stereotyped behaviors that become more exaggerated following additional drug exposure (Kalivas et al, 1993; Canales et al, 2002; Capper-Loup et al, 2002). Following pretraining exposure to amphetamine, animals display habit-based instrumental performance that is insensitive to outcome devaluation even with only limited amounts of training (Nelson and Killcross, 2006; Nordquist et al, 2007) This finding supports evidence from lesion studies for a dissociation of neural systems that subserve the performance of voluntary goal-directed actions and reflexive, stimulus-bound habitual responding respectively (Coutureau and Killcross, 2003; Killcross and Coutureau, 2003; Yin et al, 2004, 2005; Naneix et al, 2009; Balleine and O’Doherty, 2010) and suggests that the balance between these two systems is acutely sensitive to manipulations of forebrain dopamine (e.g., Faure et al, 2005; Belin and Everitt, 2008). In Experiments 1A–C the dopamine antagonists were administered to animals that had received pretraining exposure to amphetamine and in Experiment 2 the effect of these dopamine antagonists was assessed in non-sensitized animals
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