Acute neurochemical and behavioral effects of stereoisomers of 4-methylaminorex in relation to brain drug concentrations.
4-Methylaminorex is a stimulant drug of abuse that exists as four stereoisomers: cis-4R,5S, cis-4S,5R, trans-4S,5S, and trans-4R,5R. These isomers have previously been shown to differ markedly in various respects. In the present study we assessed the effects of the isomers of 4-methylaminorex (2.5, 5.0, and 10 mg/kg i.p.) on extracellular dopamine and 5-hydroxytryptamine (5-HT) levels in the nucleus accumbens, as well as behavior in the rats simultaneously. The relative concentrations of the isomers in the brain were also measured. The samples were collected by in vivo microdialysis and then analyzed for neurotransmitters with high-performance liquid chromatography/electrochemical detection and for cis- and trans-4-methylaminorex with gas chromatography/mass spectrometry. The behavioral effects of the isomers were assessed from videotapes recorded during the microdialysis experiments. All isomers elevated the extracellular levels of both dopamine and 5-HT, with the exception of trans-4R,5R. The rank order of potency for elevating dopamine was trans-4S,5S > cis-4S,5R approximately cis-4R,5S > trans-4R,5R, and for elevating 5-HT cis-4S,5R > trans-4S,5S approximately cis-4R,5S > trans-4R,5R. Analysis of the behavioral data, together with the neurochemical data, suggests that behavioral effects of the isomers of 4-methylaminorex are related to drug-induced dopamine release and, in the case of higher doses of the most efficacious isomers, to 5-HT as well. The brain concentrations of the isomers did not reflect their neurochemical efficacy, which implies that their differences are pharmacodynamic rather than pharmacokinetic.
Kankaanpää
Aino
A
Drug Research Unit, Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland. aino.kankaanpaa@ktl.fi
Ellermaa
Satu
S
Meririnne
Esa
E
Hirsjärvi
Paula
P
Seppälä
Timo
T
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010080:Oxazoles / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D013237:Stereoisomerism; D013566:Sympathomimetics / Q000737:chemistry / Q000494:pharmacology*
D010080:Oxazoles; D013566:Sympathomimetics; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; C000081:4-methylaminorex; D004298:Dopamine; D006719:Homovanillic Acid