Dopamine D3 receptor blockade accelerates the extinction of opioid withdrawal-induced drug-seeking behaviours and alters microglia in dopaminoceptive nuclei

Abstract

BACKGROUND AND PURPOSE: Among all drugs of abuse, opioids cause most of the deaths and treatment seeking. Despite abundant research in multifaceted therapeutic strategies, a high rate of relapse still characterises this condition. Dopamine D(3) receptor antagonists combined with cue-exposure therapies have been proposed to ameliorate the abused drugs-induced cognitive deficits, which consequently would aid to prevent the maladaptive behaviours responsible for drug use. EXPERIMENTAL APPROACH: We used the morphine withdrawal-induced conditioned place aversion (CPA) paradigm to assess, in male rats, the efficacy of D(3) receptor blockade to improve the extinction of drug-seeking behaviours associated with the aversive contextual stimuli of its withdrawal. Then, using immunohistochemical methods, we evaluated the participation of neuroimmune mechanisms in the striatum and infralimbic cortex in D(3) receptor modulation of CPA extinction. KEY RESULTS: Whereas the selective D(3) antagonist PG01037 accelerated the extinction of the morphine withdrawal-induced CPA, our findings indicate that decreased motivation might be involved in this action. Increased D(3) receptor expression in glial cells and the modulation of microglia activation state in specific dopaminoceptive areas could intervene in the behavioural outcomes of D(3) receptor blockade. CONCLUSIONS AND IMPLICATIONS: Our findings reveal a facilitatory role of D(3) antagonists in the inhibition of morphine-seeking behaviours triggered by contextual stimuli associated with its withdrawal. Nonetheless, their potential ability to reduce motivation might influence their therapeutic use. Future investigations elucidating the precise function of D(3) receptors will facilitate the identification of this receptor as a valuable therapeutic target for mitigating the recurrence of opioid withdrawal-induced drug-seeking behaviour.