show Abstracthide AbstractSubstance use disorders are more prevalent in schizophrenia, worsening its course and prognosis. Here, we used a double-hit rat model, combining maternal immune activation (MIA) and peripubertal stress (PUS), to study cocaine addiction and the underlying neurobehavioral alterations. We injected lipopolysaccharide (LPS) or saline on gestational days 15 and 16 to pregnant rats. Their male offspring were then subjected to unpredictable stress during adolescence. When rats reached adulthood, we studied their cocaine addiction-like behavior, impulsivity and conditioning processes, and several aspects of brain structure and function by MRI, PET and RNAseq. MIA facilitated the acquisition of cocaine self-administration but PUS reduced cocaine intake, an effect that was reversed by MIA. MIA increased motivation for cocaine and revearsed the effects of PUS during extended access. Incubation of seeking was unaffected. Neither hit alone nor their combination impacted pavlovian or instrumental learning or impulsiveness. At the brain level, PUS reduced hippocampal volume and hyperactivated the dorsal subiculum. When combined, both hits altered the structure and function of the dorsal striatum increasing its volume and interferring with glutamatergic dynamics. MIA alone had no effect on the gene expression of the nucleus accumbens but, when combined with PUS, modulated specific genes that could account for the decreased cocaine intake. PUS had a profund effect on the dorsal striatal transcriptome however, this was obliterated when PUS occurred in animals with MIA. These results describe a complex interplay between MIA and stress on neurodevelopment and in the susceptibility to develop cocaine addiction. Overall design: Gene expression profiles of the nucleus accumbens and dorsolateral striatum of male Sprague-Dawley rats after prenatal immune activation induced by LPS administration and peripubertal unpredictable stress. We analysed 24 samples (3 per group) corresponding to experimental groups (including saline-exposed and/or non-stressed controls).