Behavioral, biochemical and molecular changes induced by chronic crack cocaine inhalation in mice: role of dopaminergic and endocannabinoid systems in the prefrontal cortex.

Crack-cocaine addiction has increasingly become a public health problem worldwide, especially in developing countries. However, no studies have focused on neurobiological mechanisms underlying the severe addiction produced by this drug, which seems to differ from powder cocaine in many aspects. This study investigated behavioral, biochemical and molecular changes in mice inhaling crack-cocaine, focusing on dopaminergic and endocannabinoid systems in the prefrontal cortex. Mice were submitted to two inhalation sessions of crack-cocaine a day (crack-cocaine group) during eleven days, meanwhile control group had no access to the drug. We found that crack-cocaine group exhibited hyperlocomotion and a peculiar jumping behavior (“escape jumping”). Blood collected right after the last inhalation session revealed that the anhydroecgonine methyl ester (AEME), a specific metabolite of cocaine pyrolysis, was much more concentrated than cocaine itself in the crack-cocaine group. Most genes related to endocannabinoid system, CB1 receptor and cannabinoid degradation enzymes, were downregulated after eleven-day crack-cocaine exposition. These changes may have decreased dopamine and its metabolites levels, which in turns may be related with the extreme upregulation of dopamine receptors and tyrosine hydroxylase observed in the prefrontal cortex of these animals. Our data suggest that after eleven days of crack-cocaine exposure, neuroadaptive changes towards dowregulation of reinforcing mechanisms may have taken place as a result of neurochemical changes observed on dopaminergic and endocannabinoid systems. Successive changes like these have never been described in cocaine hydrochloride models before, probably because AEME is only produced by cocaine pyrolysis and this metabolite may underlie the more aggressive pattern of addiction induced by crack-cocaine.
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