Name: Lorena Bianchine Areal de AzevedoType: MSc dissertationPublication date: 17/07/2014Advisor:

Namesort descending Role
Rita Gomes Wanderley Pires Advisor *

Examining board:

Namesort descending Role
Ana Paula Santana de Vasconcellos Bittencourt Internal Examiner *
Cristina Martins e Silva Co advisor *
Fabiola Mara Ribeiro External Examiner *
Rita Gomes Wanderley Pires Advisor *

Summary: Crack cocaine addiction is a major social and health problem. This drug has higher abuse potential compared to other forms of cocaine, and it’s more related to criminality and impaired control over behavior. This study aimed to evaluate behavioral, biochemical and molecular changes in a chronic crack cocaine inhalation model, focusing on dopaminergic and endocannabinoid systems in prefrontal cortex. It has been suggested an involvement of these systems in cocaine addiction, but this interaction in the prefrontal cortex, the main region involved in behavioral control, remains unclear. Male C57 BL/6 mice were divided into control or crack cocaine group. Mice from crack cocaine group were submitted to two inhalation sessions of crack cocaine a day, for an eleven days period. Locomotor activity was assessed after the exposure and mice from crack cocaine group exhibit hyperlocomotion in all sessions, however, there was no difference over the inhalation days. Moreover, these animals exhibit a particular behavior that was called “escape jumping”, consisting in repetitive jumps in the corner of the open field, and the frequency of this jumps increased statistically with a time effect. GC-MS of blood collected right after the last inhalation session for quantification of cocaine and its metabolites, revealed that methylecgonidine (MEG) concentration was much higher than cocaine itself in mice exposed to crack cocaine. MEG is an exclusive crack cocaine metabolite and it was shown that this metabolite had greater neurotoxic potential then cocaine itself, and an additive neurotoxicity when associated to cocaine. Gene expression analyses by real time PCR revealed that ∆FosB mRNA levels, a key molecule in the establishment of addiction, were increased in the prefrontal cortex of mice submitted to crack cocaine exposure. Concerning the genes from dopaminergic and endocannabinoid systems, it was observed that chronic crack cocaine inhalation promoted upregulation of dopamine receptors and tyrosine hydroxylase, while most genes related to endocannabinoid system, CB1 receptor and cannabinoid degradation enzymes, were downregulated. Also, dopamine and its metabolites, dopac and hva levels assessed by HPLC were reduced in prefrontal cortex of mice exposed to crack cocaine inhalation for eleven days. Taking together our data, the regimen of drug exposure and data found in literature, it is possible to suggest that after eleven days of crack cocaine exposure mice developed neuroadaptations in order to reduce reinforcement mechanisms, and that dopaminergic and endocannabinoid systems might be mediators of this process. Since our data shows alterations produced by crack cocaine exposure that were never described previously in cocaine hydrochloride models, and considering the much higher levels of MEG than cocaine found, we could raise the possibility that those alterations might be mediated by MEG and not only by cocaine.Access to document

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