Aspectos bioquímicos, moleculares e comportamentais da dependência de crack e cocaína em modelos animais: enfoque nos sistemas dopaminérgico e glutamatérgico

Abstract

Drug addiction is a social and health burden worldwide, and despite the extensive research in this field, there remains a lack of effective treatment for this condition. In the past few decades, crack cocaine (crack) addiction has increasingly become a major issue especially in developing countries. However, there is a lack of studies specifically for the addiction to this drug. In this study, we aimed to evaluate crack effects in memory and cognition and its molecular basis, using a mouse model of crack exposure. It was observed that 11 days of crack inhalation does not affect object recognition memory or reference spatial memory. However, mice exposed to this protocol exhibit working memory deficits and reduced social interaction. These alterations, along with a previously described reduction in dopamine levels in the prefrontal cortex (PFC) and increase in D2R receptor expression, in addition to the psychiatric symptoms exhibited by crack users, led us to investigate whether crack exposure in our model induce other molecular alterations observed in schizophrenia. We found that upon crack inhalation mice have shown increased D2S/D2L dopamine receptors expression ratio and decreased expression of NR1, NR2A and NR2B NMDA receptor subunits in the PFC, along with decreased social interaction and working memory deficits, and these alterations are also found in subjects with schizophrenia. Therefore, we showed that crack cocaine inhalation promotes behavioral alterations in mice resembling negative and cognitive symptoms of schizophrenia, likely underlined by similar molecular mechanisms. Studies have shown that glutamatergic signaling, especially through mGluR5, is involved in the development of cocaine addiction. Therefore, in a second part of this work, we investigated the effect of a negative allosteric modulator of mGluR5 in cocaine associated behaviors, and the possible role of spinophilin, a scaffold protein involved in mGluR5 signalling and regulation, in cocaine addiction. We observed that the knockout of spinophilin blocks the development of cocaine sensitization in the protocol used, revealing an important role of spinophilin in this process. In terms of rewarding aspects, neither spinophilin deletion nor mGluR5 blockade affected conditioned place preference to cocaine. However, it was observed that CTEP attenuated the activation of ERK, Akt and mTOR induced by cocaine. Additionally, gene expression of DARPP-32 and â-arrestin 2 was increased in response to the combination of cocaine and CTEP in wild type mice, suggesting a possible role of these proteins in the observed effects. Thus, both mGluR5 and spinophilin seem to be involved in cocaine responses, however, further studies are necessary to better characterize the therapeutic potential of CTEP in cocaine addiction.