title: Anhydroecgonine methyl ester, a cocaine pyrolysis product, may contribute to cocaine behavioral sensitization.
abstract: Crack cocaine has a high potential to induce cocaine addiction and its smoke contains cocaine's pyrolysis product anhydroecgonine methyl ester (AEME), a partial agonist at M1- and M3-muscarinic acetylcholine receptor and an antagonist at the remaining subtypes. No reports have assessed AEME's role in addiction. Adult male Wistar rats were intraperitoneally administered with saline, 3mg/kg AEME, 15mg/kg cocaine, or a cocaine-AEME combination on every other day during a period of 9 days. After a 7-days withdrawal period, a challenge injection of the respective drugs was performed on the 17th day. The locomotor activity was evaluated on days 1, 3, 5, 7, 9 and 17, as well as dopamine levels (9th day) and dopaminergic receptors proteins (D1R and D2R on the 17th day) in the caudate-putamen (CPu) and nucleus accumbens (NAc). AEME was not able to induce the expression of behavioral sensitization, but it substantially potentiates cocaine-effects, with cocaine-AEME combination presenting higher expression than cocaine alone. An increase in the dopamine levels in the CPu in all non-saline groups was observed, with the highest levels in the cocaine-AEME group. There was a decrease in D1R protein level in this brain region only for cocaine and cocaine-AEME groups. In the NAc, an increase in the dopamine levels was only observed for cocaine and cocaine-AEME groups, with no changes in both D1R and D2R protein levels. These behavioral and neurochemical data indicate that AEME alone does not elicit behavioral sensitization but it significantly potentiates cocaine effects when co-administered, resulting in dopamine increase in CPu and NAc, brain regions where dopamine release is mediated by cholinergic activity.
authors.affiliation: Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 580, Bl. 13B, 05508-000, São Paulo, SP, Brazil; Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo, Rua São Nicolau, 210, 1° andar, 09913-030, Diadema, SP, Brazil.
authors.forename: Raphael Caio Tamborelli
authors.initials: RC
authors.lastname: Garcia
authors.affiliation: Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 580, Bl. 13B, 05508-000, São Paulo, SP, Brazil; Department of Food and Drugs, School of Pharmaceutical Sciences, Federal University of Alfenas, Rua Gabriel Monteiro da Silva, 700, 37130-000, Alfenas, MG, Brazil.
authors.forename: Larissa Helena
authors.initials: LH
authors.lastname: Torres
authors.affiliation: Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 580, Bl. 13B, 05508-000, São Paulo, SP, Brazil.
authors.forename: Natália Trigo
authors.initials: NT
authors.lastname: Balestrin
authors.affiliation: Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 580, Bl. 13B, 05508-000, São Paulo, SP, Brazil.
authors.forename: Tatiana Costa
authors.initials: TC
authors.lastname: Andrioli
authors.affiliation: Department of Pathology, School of Veterinary Medicine, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva, 87, 05508-270, São Paulo, SP, Brazil.
authors.forename: Jorge Camilo
authors.initials: JC
authors.lastname: Flório
authors.affiliation: Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 580, Bl. 13B, 05508-000, São Paulo, SP, Brazil; Poison Control Centre of São Paulo, Municipal Health Secretary of São Paulo, Rua Santa Isabel, 181, 01221-010, São Paulo, SP, Brazil.
authors.forename: Carolina Dizioli Rodrigues
authors.initials: CD
authors.lastname: de Oliveira
authors.affiliation: Criminalistic Institute of São Paulo, Rua Moncorvo Filho, 410, 05507-060, São Paulo, SP, Brazil.
authors.forename: José Luiz
authors.initials: JL
authors.lastname: da Costa
authors.affiliation: Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 580, Bl. 13B, 05508-000, São Paulo, SP, Brazil.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Yonamine
authors.affiliation: Laboratory of Pharmacology, Butantan Institute, Av. Vital Brasil, 1500, 05503-900, São Paulo, SP, Brazil.
authors.forename: Maria Regina Lopes
authors.initials: MR
authors.lastname: Sandoval
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, Prédio 1, 05508-900, São Paulo, SP, Brazil.
authors.forename: Rosana
authors.initials: R
authors.lastname: Camarini
authors.affiliation: Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 580, Bl. 13B, 05508-000, São Paulo, SP, Brazil. Electronic address: tmarcour@usp.br.
authors.forename: Tania
authors.initials: T
authors.lastname: Marcourakis
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004357:Drug Synergism; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000378:metabolism
chemical_list: D011954:Receptors, Dopamine; C068464:anhydroecgonine methyl ester; D003042:Cocaine; D004298:Dopamine
keywords: Anhydroecgonine methyl ester; Behavioral sensitization; Crack cocaine; Dopamine; Muscarinic acetylcholine receptor