title: Role of 6-monoacetylmorphine in the acute release of striatal dopamine induced by intravenous heroin.
abstract: After injection, heroin is rapidly metabolized to 6-monoacetylmorphine (6-MAM) and further to morphine. As morphine has been shown to increase striatal dopamine, whereas 6-MAM has not been studied in this respect, we gave i.v. injections of 3 μmol 6-MAM, morphine or heroin to rats. Opioids were measured in blood, and dopamine and opioids in microdialysate from brain striatal extracellular fluid (ECF), by UPLC-MS/MS. After 6-MAM injection, 6-MAM ECF concentrations increased rapidly, and reached Cmax of 4.4 μM after 8 min. After heroin injection, 6-MAM increased rapidly in blood and reached Cmax of 6.4 μM in ECF after 8 min, while ECF Cmax for heroin was 1.2 μM after 2 min. T max for morphine in ECF was 29 and 24 min following 6-MAM and heroin administration, respectively, with corresponding Cmax levels of 1 and 2 μM. Dopamine levels peaked after 8 and 14 min following 6-MAM and heroin administration, respectively. The dopamine responses were equal, indicating no dopamine release by heroin per se. Furthermore, 6-MAM, and not morphine, appeared to mediate the early dopamine response, whereas morphine administration, giving rise to morphine ECF concentrations similar to those observed shortly after 6-MAM injection, did not increase ECF dopamine. 6-MAM appeared accordingly to be the substance responsible for the early increase in dopamine observed after heroin injection. As 6-MAM was formed rapidly from heroin in blood, and was the major substance reaching the brain after heroin administration, this also indicates that factors influencing blood 6-MAM concentrations might change the behavioural effects of heroin.
authors.affiliation: Department of Drug Abuse Research and Method Development, Division of Forensic Medicine and Drug Abuse Research,Norwegian Institute of Public Health,Pb. 4404, Nydalen, 0403 Oslo,Norway.
authors.forename: A
authors.initials: A
authors.lastname: Gottås
authors.affiliation: Department of Drug Abuse Research and Method Development, Division of Forensic Medicine and Drug Abuse Research,Norwegian Institute of Public Health,Pb. 4404, Nydalen, 0403 Oslo,Norway.
authors.forename: F
authors.initials: F
authors.lastname: Boix
authors.affiliation: Department of Drug Abuse Research and Method Development, Division of Forensic Medicine and Drug Abuse Research,Norwegian Institute of Public Health,Pb. 4404, Nydalen, 0403 Oslo,Norway.
authors.forename: E L
authors.initials: EL
authors.lastname: Øiestad
authors.affiliation: Department of Drug Abuse Research and Method Development, Division of Forensic Medicine and Drug Abuse Research,Norwegian Institute of Public Health,Pb. 4404, Nydalen, 0403 Oslo,Norway.
authors.forename: V
authors.initials: V
authors.lastname: Vindenes
authors.affiliation: Department of Drug Abuse Research and Method Development, Division of Forensic Medicine and Drug Abuse Research,Norwegian Institute of Public Health,Pb. 4404, Nydalen, 0403 Oslo,Norway.
authors.forename: J
authors.initials: J
authors.lastname: Mørland
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D019540:Area Under Curve; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D003932:Heroin / Q000008:administration & dosage* / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D017551:Microdialysis; D009020:Morphine / Q000494:pharmacology; D009022:Morphine Derivatives / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014851:Wakefulness / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D009022:Morphine Derivatives; D003932:Heroin; D009020:Morphine; C026979:6-O-monoacetylmorphine; D004298:Dopamine