Dopamine D3 Receptor Modulates Akt/mTOR and ERK[sub.1/2] Pathways Differently during the Reinstatement of Cocaine-Seeking Behavior Induced by Psychological versus Physiological Stress

• Published in: International journal of molecular sciences 2023-07, Vol.24 (13)
• Main Authors: Franco-García, Aurelio, Guerrero-Bautista, Rocío, Hidalgo, Juana María, Gómez-Murcia, Victoria, Milanés, María Victoria, Núñez, Cristina
• Format: Article
• Language: English
• Subjects: Cardiac glycosides; Cardiotonic agents; Cocaine; Physiological aspects; Social aspects; Stress (Physiology)
• ISSN: 1422-0067
• DOI: 10.3390/ijms241311214

Stress triggers relapses in cocaine use that engage the activity of memory-related nuclei, such as the basolateral amygdala (BLA) and dentate gyrus (DG). Preclinical research suggests that D3 receptor (D3R) antagonists may be a promising means to attenuate cocaine reward and relapse. As D3R regulates the activity of the Akt/mTOR and MEK/ERK[sub.1/2] pathways, we assessed the effects of SB-277011-A, a D3R antagonist, on the activity of these kinases during the reinstatement of cocaine-induced conditioned place preference (CPP) induced by psychological (restraint) and physiological (tail pinch) stress. Both stimuli reactivated an extinguished cocaine-CPP, but only restrained animals decreased their locomotor activity during reinstatement. Cocaine-seeking behavior reactivation was correlated with decreased p-Akt, p-mTOR, and p-ERK[sub.1/2] activation in both nuclei of restrained animals. While a D3R blockade prevented stress-induced CPP reinstatement and plasma corticosterone enhancement, SB-277011-A distinctly modulated Akt, mTOR, and ERK[sub.1/2] activation depending on the stressor and the dose used. Our data support the involvement of corticosterone in the SB-277011-A effects in restrained animals. Additionally, the ratios p-mTOR/mTOR and/or p-ERK[sub.1/2] /ERK[sub.1/2] in the BLA during stress-induced relapse seem to be related to the locomotor activity of animals receiving 48 mg/kg of the antagonist. Hence, our study indicates the D3R antagonist’s efficacy to prevent stress-induced relapses in drug use through distinct modulation of Akt/mTOR and MEK/ERK[sub.1/2] pathways in memory-processing nuclei.