ADOLESCENT BRAIN ON COCAINE:�SHORT- AND LONG-TERM MOLECULAR CHANGES�FOLLOWING REPEATED PSYCHOSTIMULANT EXPOSURE
Creators: name: GIANNOTTI, GIUSEPPE
Publisher: name: Universit� degli Studi di Milano
Year: 2016

description: Drug addiction is a chronic, relapsing brain disorder that relies on the substantial shift from a controlled drug use to compulsive drug seeking despite negative consequences. Among the growing and broad field of illicit drugs, so far cocaine still represents the most used psychostimulant. Although drug addiction can be considered an adult brain disorder, drug use peaks during adolescence. During this period the brain undergoes profound structural and molecular changes, making the adolescent brain more vulnerable to the pharmacological effects brought about by drugs of abuse and, perhaps, may set the stage to initiate drug use or relapse to drugs of abuse later in life. Accordingly, to understand the molecular mechanisms underlying drug use in adults is necessary to investigate the drug-induced molecular changes in the adolescent brain. We focused our molecular analyses on the medial prefrontal cortex (mPFC), a brain region that is still developing during adolescence and may result more sensitive to the pharmacologic effects of cocaine. We found that repeated exposure to cocaine during adolescence induces a maladaptive neuroplasticity after either short- and long-term withdrawal. In particular, we found that short-term withdrawal from developmental exposure to cocaine alters the physiological response of the glutamatergic system to a challenging situation, thus generating a hyper-reactive glutamatergic synapse. Moreover, three days of withdrawal are sufficient to induce a pro-depressive behavior that, perhaps, may reflect the cocaine-induced alteration of the stress-related system in the mPFC. One of the major clinical issues of drug addiction is the relapse even after long periods of abstinence. Accordingly, we investigated whether long-term withdrawal from developmental exposure to cocaine may have altered markers of neuroplasticity in the mPFC. Interestingly, we found an increase BDNF expression, its high-affinity receptor TrkB and the associated signaling pathway. On the other hand, we found reduced expression of GluA1 subunit of AMPA receptors, suggesting, perhaps, an indirect effect of BDNF on the glutamatergic system through the up-regulation of ARC expression. Further, we found that long-term withdrawal from developmental exposure to cocaine increases FGF-2 expression in the mPFC, as observed for BDNF. Taking into account that adolescence is a vulnerable period to initiate drug use, we investigated whether a single injection of cocaine is sufficient to produce a maladaptive molecular background that may contribute to develop maladaptive behaviors. Interestingly, we found that a single injection to cocaine is sufficient to up-regulate FGF-2 expression in the mPFC seven days later while its expression returns to baseline after the second challenge. However, a different modulation of the neurotrophin was observed in hippocampus. In particular, a single injection of cocaine reduces FGF-2 expression, as well as ARC, seven days later, suggesting, at least in part, a reduced neuronal activity. Altogether, these results further highlight the adolescence as a period of high vulnerability to the pharmacological effects brought about by cocaine in the mPFC after a single injection rather than repeated exposure to the psychostimulant. Further, these results add important preclinical evidence to the short- or long-term action of cocaine following exposure during adolescence.