Pulling habits out of rats: adenosine 2A receptor antagonism in dorsomedial striatum rescues meth‐amphetamine‐induced deficits in goal‐directed action

Abstract

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.

Contexts Paired with Junk Food Impair Goal-Directed Behavior in Rats: Implications for Decision Making in Obesogenic Environments

“…The current findings are consistent with past studies showing similar impairments in sensitivity to devaluation in contexts paired with ethanol (Ostlund et al, 2010) and methamphetamine (Furlong et al, 2015). While rats ate more JF than chow, and thus may have associated eating freely available food with the JF context which may, in some way, have interfered with having to earn food, as noted above, rats continued to respond in the JF context, they just did so indiscriminately.…”

“…Devaluation tests revealed that responding was insensitive to devaluation when rats were tested in the alcohol-paired context but goal-directed in the saline context (Ostlund et al, 2010). The second study used a similar procedure to demonstrate habitual control over behavior produced by contexts paired with methamphetamine (Furlong et al, 2015). Importantly, instrumental performance was reinforced with food rather than drug rewards and the animals were drug-free at test, indicating that the contexts, rather than acute intoxication, influenced the decision-making processes that promoted habitual responding.…”

“…Importantly, instrumental performance was reinforced with food rather than drug rewards and the animals were drug-free at test, indicating that the contexts, rather than acute intoxication, influenced the decision-making processes that promoted habitual responding. We adopted a similar experimental procedure to Ostlund et al (2010) and Furlong et al (2015) to assess whether junk food (JF)-paired contexts would disrupt sensitivity to outcome devaluation.…”

DRD2: Bridging the Genome and Ingestive Behavior

“…goal-directed/action – object responding) to model-free (i.e. habitual/stimulus – response responding) learning following repeated exposure to reinforcers including drugs and food [51–53] is a hallmark of addictive behavior [54] and observed in diet induced obesity [7]. …”

Habit Formation after Random Interval Training Is Associated with Increased Adenosine A2A Receptor and Dopamine D2 Receptor Heterodimers in the Striatum

“…By these functional interactions, striatopallidal A 2A Rs can modulate dopamine and glutamate signaling and striatal synaptic plasticity and cognitions including instrumental behaviors (Chen, 2014). Indeed, genetic inactivation of striatal A 2A Rs impaired habit formation (Yu et al, 2009) and pharmacological reduction of A 2A R-mediated cAMP-pCREB signaling in the dorsal medium striatum (DMS) enhanced goal-directed ethanol drinking (Nam et al, 2013) and reversed meth-amphetamine-induced facilitation of habit formation (Furlong et al, 2015). However, the mechanism underlying the A 2A R modulation of instrumental behaviors is not known.…”