Dopamine D3R antagonism facilitates the extinction of drug-seeking behaviours in opiate CPA model and is associated with decreased Iba1 levels in the medial prefrontal cortex

Opioid misuse for pain management has become a major global health problem, causing what has been called the opioid epidemic. Recently, D3 receptor (D3R) antagonists have arisen as a potential treatment to enhance cognition in memory-related diseases. In this work, we first used a 3-day extinction training (ET) previously reported to be successful to extinguish opiates-seeking behaviours motivated by their withdrawal-related contextual memories, such as the morphine withdrawal-induced conditioned place aversion (CPA) in rats. Secondly, we evaluated the impact of D3R blockade in the extinction of morphine withdrawal-induced CPA. Then, we studied the potential modulation of neuroinflammation by a D3R antagonist (PG-01037) in areas related to motivation and cognition, such as the infralimbic cortex (IL), through D3R, NeuN, GFAP and iba1 immunostaining. Both the 3 day-ET and the D3R antagonist at 30 mg/kg after 1-day ET facilitated the extinction of CPA in rats. As opposed to the 3-day ET, CPA extinction after the administration of PG-01037 was accompanied by a decrease in motivation reflected in the increased time that animals spent in the neutral corridor and the decrease in their body weight (which may suggest a reduction in food intake). Glial immunostainings in rats treated with the D3R antagonist revealed a diminution of Iba1 levels in IL compared to the 3-day ET, hence suggesting an anti-inflammatory effect of PG-01037 in this area. Together, our data endorse the ability of D3R antagonists to facilitate the extinction of drug seeking behaviours induced by behavioural cues through anti-inflammatory mechanisms on the related nuclei.