Pulling habits out of rats: Adenosine 2A receptor antagonism in dorsomedial striatum rescues methamphetamine-induced deficits in goal-direct action

摘要

Addiction is characterised by a persistent loss of behavioural control resulting in insensitivity to negative feedback and abnormal decision-making. Here we investigated the influence of methamphetamine (METH)-paired contextual cues on decision-making in rats. Choice between goal-directed actions was sensitive to outcome devaluation in a saline-paired context but was impaired in the METH-paired context, a deficit that was also found when negative feedback was provided. Reductions in c-Fos-related immunoreactivity were found in dorsomedial but not dorsolateral striatum after exposure to the METH context suggesting this effect reflected a loss specifically in goal-directed control in the METH context. This reduction in c-Fos was localized to non-enkephalin expressing neurons in the DMS, likely dopamine D1-expressing direct pathway neurons, suggesting a relative change in control by the D1-direct vs. D2-indirect pathways originating in the DMS may have been induced by METH context exposure. To test this suggestion we infused the adenosine 2A receptor antagonist ZM241385 into the dorsomedial striatum prior to test to reduce activity in D2 neurons relative to D1 neurons in the hope of reducing the inhibitory output from this region of the striatum. We found that this treatment fully restored sensitivity to negative feedback in a test conducted in the METH-paired context. These results suggest that drug-exposure alters decision-making by down-regulation of the circuitry mediating goal-directed action, an effect that can be ameliorated by acute A2A receptor inhibition in this circuit.