Pulling habits out of rats: adenosine 2A receptor antagonism in dorsomedial striatum rescues meth‐amphetamine‐induced deficits in goal‐directed action. (30th October 2015)

• Record Type: Journal Article
• Authors: Furlong, Teri M.; Supit, Alva S.A.; Corbit, Laura H.; Killcross, Simon; Balleine, Bernard W.
• Is Part Of: Addiction biology. Volume 22:Number 1(2017)
• Page Start: 172
• Page End: 183
• Publication Date: 2015-10-30
• Subjects: Adenosine 2A receptor -- dorsolateral striatum -- dorsomedial striatum -- drug seeking -- goal‐directed action -- habit -- methamphetamine; Substance abuse -- Periodicals; Substance abuse -- Physiological aspects -- Periodicals; Substance-Related Disorders -- periodicals; 616.86
• DOI: 10.1111/adb.12316
• Languages: English
• ISSNs: 1355-6215

Abstract

Abstract: Addiction is characterized by a persistent loss of behavioral 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 striatum (DMS) 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 versus 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 DMS 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 downregulation of the circuitry mediating goal‐directed action, an effect that can be ameliorated by acute A2A receptor inhibition in this circuit. Abstract : We investigated the influence of a methamphetamine (METH)‐paired context on decision‐making in rats. Goal‐directed action was sensitive to outcome devaluation in a saline‐paired context but not in a METH‐paired context, even when negative feedback was provided. Reduced c‐Fos immunoreactivity was seen in dorsomedial striatum in the METH context. Intrastriatal infusion of an adenosine receptor antagonist restored sensitivity to negative feedback in the METH context. These results suggest that drug exposure alters decision‐making by downregulation of the circuitry mediating goal‐directed action.