Relapse in cocaine use a critical clinical concern when treating its addiction, being stress one of its most important triggers (1). Cocaine relapse requires the activity of the basolateral amygdala (BLA) and the dentate gyrus (DG), which are responsible for emotional and contextual memories processing, respectively (2). Further, D3 receptor (D3R) antagonists have a promising therapeutic potential in attenuating cocaine reward and relapse in preclinical studies (3)

Through western blot we assessed the effect of D3R blockade in the activity of the Akt/mTOR and MEK/ERK1/2 pathways in the BLA and DG during the reinstatement of cocaine-induced conditioned place preference (CPP) evoked by psychological – restraint – and physiological – tail pinch– stress. We also studied the effects on plasmatic corticosterone levels through radioimmunoassay.

Both acute restraint or tail pinch reactivated the cocaine-CPP and increased corticosterone secretion. Additionally, the locomotor activity of animals restrained to induce the CPP diminished, in contrast to mice tail-pinched. Besides the different blood corticosterone levels, the disparity in the locomotor activity of animals depending upon the triggering stressor of the reinstatement of CPP might be related with the decreases in p-Akt, p-mTOR and p-ERK1/2 in the BLA and DG in animals restrained, that were not found in those tail pinched. Relevantly, D3R blockade prevented the reactivation of cocaine-CPP in mice psychologically or physiologically stressed and the parallel enhanced corticosterone plasma concentration. Moreover, the effects of the D3R antagonist on the activity of Akt, mTOR and ERK1/2 in the BLA and DG was determined by the kind of stressor that reinstated the cocaine-CPP and the dose administered. Corticosterone may be partly responsible for these variations in mice restrained as we found high correlations between its plasma levels and the activity of mTOR and/or Akt in the BLA and DG of animals injected with the antagonist. Besides, our correlation analyses uncover that the locomotor activity of animals injected with SB-277011-A prior the stress session might be partially related with mTOR and ERK1/2 activities in the BLA and the DG, respectively.

This study supports the therapeutic potential of D3R antagonists to prevent the stress-induced relapses in drug use through a complex and balanced Akt/mTOR and MEK/ERK1/2 regulation in brain nuclei implicated in memory processing. Bibliography 1. Mantsch JR, Baker DA, Funk D, Lê AD, Shaham Y. Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress. Neuropsychopharmacology. 2016;41(1):335-56. 2. Torregrossa MM, Corlett PR, Taylor JR. Aberrant learning and memory in addiction. Neurobiology of Learning and Memory. 2011;96(4):609-23. 3. Guerrero-Bautista R, Do Couto BR, Hidalgo JM, Cárceles-Moreno FJ, Molina G, Laorden ML, et al. Modulation of stress- and cocaine prime-induced reinstatement of conditioned place preference after memory extinction through dopamine D3 receptor. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2019;92:308-20. This study was financially supported by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe” (grants SAF2017-85679-R and PID2020-113557RB-I00), and by Fundación Séneca, Región de Murcia, Spain (grant 21133/SF/19). Aurelio Franco-García is granted by “Ayuda para la Formación de Profesorado Universitario” program of MICINN (FPU19/01722).