Effects of maternal separation with early weaning on cocaine addictive behaviour and consequences on neuroplasticity

Abstract

Chronic exposure to stress, especially in early life, has been associated with the onset and the severity of several psychiatric disorders in adults. Moreover, early-life stress induces maladaptive long-lasting brain effects that increase the likelihood of developing substance use disorders or depression. It is known that early-life stress affects in different way women and men, however, this phenomenon is poorly explored. Understand the mechanistic connections among early-life stress and development of substance use disorders and depression, could help to develop new therapeutic targets against these public health problems. Here, we sought to investigate the effects of early-life stress in cocaine addiction behaviour and the molecular alterations induced by both factors, cocaine exposure and early stress. For this reason, we tested the impact of early-life stress induced by maternal separation with early weaning in CD1 male and female mice at different phases of cocaine self-administration. We also investigated in brain regions associated with stress, reward and impulsivity, the subsequent alterations on AMPA receptor subunit composition and other molecules associated with neuroplasticity process. Our results yield that maternal separation with early weaning has behavioural effects in males while females appear to be resilient to this kind of early-life stress. Additionally, maternally separated males express despair-like behaviour, higher cocaine intake, increased vulnerability to the acquisition of cocaine self-administration and incapacity to extinguish the cocaine self-administration behaviour. Molecular analyses of ventral tegmental area, nucleus accumbens and medial prefrontal cortex show sex-induced alterations in the composition of the AMPA receptor but also alterations after cocaine exposure. Maternal separation with early weaning and cocaine exposure also alters the expression of GluA1, GluA2, pCREB and CREB in these brain areas. Altogether, our results displayed changes in neuroplastic molecules that play a crucial role in depression and the regulation of the rewarding effects of cocaine, helping to elucidate the mechanisms involved in the progression from cocaine use to cocaine abuse in both women and men.