Behavioural, biochemical and molecular changes induced by chronic crack-cocaine inhalation in mice: The 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 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.
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.
Lorena B
LB
Areal
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.
Livia C M
LC
Rodrigues
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.
Filipe
F
Andrich
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.
Livia S
LS
Moraes
Department of Physiological Sciences, Health Sciences Center, Federal University of Espirito Santo, Av. Marechal Campos 1468 - Maruípe, Vitoria-ES 29.043-910, Brazil.
Maria A
MA
Cicilini
Laboratory of Forensic Science Service, Espirito Santo State Police, Av. Nossa Senhora. da Penha, 2290, Vitória-ES 29045-402, Brazil.
Josideia B
JB
Mendonça
Laboratory of Forensic Science Service, Espirito Santo State Police, Av. Nossa Senhora. da Penha, 2290, Vitória-ES 29045-402, Brazil.
Fabricio S
FS
Pelição
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.
Ester M
EM
Nakamura-Palacios
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.
Cristina
C
Martins-Silva
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. Electronic address: rita.pires@ufes.br.
Rita G W
RG
Pires
D000280:Administration, Inhalation; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D016578:Crack Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D004298:Dopamine / Q000235:genetics / Q000378:metabolism*; D063388:Endocannabinoids / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*
D016578:Crack Cocaine; D063388:Endocannabinoids; D004298:Dopamine
Crack-cocaine; Dopaminergic system; Drug addiction; Endocannabinoid system; Prefrontal cortex