Areal Lorena B, Rodrigues Livia C M, Andrich Filipe, Moraes Livia S, Cicilini Maria A, Mendonça Josideia B, Pelição Fabricio S, Nakamura-Palacios Ester M, Martins-Silva Cristina, Pires Rita G W
Department of Physiological Sciences, Health Sciences Center, Federal University of Espirito Santo, Av. Marechal Campos 1468 - Maruípe, Vitoria-ES 29.043-910, Brazil; Laboratory of Molecular and Behavioral Neurobiology, Health Sciences Center, Federal University of Espirito Santo, Av. Marechal Campos 1468 - Maruípe, Vitoria-ES 29.043-910, Brazil.
Department of Physiological Sciences, Health Sciences Center, Federal University of Espirito Santo, Av. Marechal Campos 1468 - Maruípe, Vitoria-ES 29.043-910, Brazil; Laboratory of Cognitive Sciences and Neuropsychopharmacology, Health Sciences Center, Federal University of Espirito Santo, Av. Marechal Campos 1468 - Maruípe, Vitoria-ES 29.043-910, Brazil.
Behav Brain Res. 2015 Sep 1;290:8-16. doi: 10.1016/j.bbr.2015.04.036. Epub 2015 May 1.
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 behavioural, 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 11 days, meanwhile the control group had no access to the drug. We found that the crack-cocaine group exhibited hyperlocomotion and a peculiar jumping behaviour ("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 the endocannabinoid system, CB1 receptor and cannabinoid degradation enzymes were downregulated after 11-day crack-cocaine exposition. These changes may have decreased dopamine and its metabolites levels, which in turn 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 11 days of crack-cocaine exposure, neuroadaptive changes towards downregulation 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.
强效可卡因成瘾在全球范围内日益成为一个公共卫生问题，在发展中国家尤为如此。然而，尚无研究聚焦于该药物所致严重成瘾背后的神经生物学机制，这种机制在许多方面似乎与粉末可卡因不同。本研究调查了吸入强效可卡因的小鼠的行为、生化和分子变化，重点关注前额叶皮质中的多巴胺能和内源性大麻素系统。在11天内，小鼠每天接受两次强效可卡因吸入（强效可卡因组），同时对照组不接触该药物。我们发现，强效可卡因组表现出运动亢进和一种特殊的跳跃行为（“逃避跳跃”）。在最后一次吸入后立即采集的血液显示，强效可卡因组中可卡因热解的特定代谢产物脱水芽子碱甲酯（AEME）的浓度远高于可卡因本身。在接触11天强效可卡因后，大多数与内源性大麻素系统、CB1受体和大麻素降解酶相关的基因表达下调。这些变化可能降低了多巴胺及其代谢产物的水平，进而可能与在这些动物前额叶皮质中观察到的多巴胺受体和酪氨酸羟化酶的极度上调有关。我们的数据表明，在接触11天强效可卡因后，由于在多巴胺能和内源性大麻素系统中观察到的神经化学变化，可能发生了强化机制下调的神经适应性变化。此前在盐酸可卡因模型中从未描述过这样的连续变化，可能是因为AEME仅由可卡因热解产生，且这种代谢产物可能是强效可卡因所致更具侵袭性的成瘾模式的基础。
