Endocrine and neurochemical effects of 3,4-methylenedioxymethamphetamine and its stereoisomers in rhesus monkeys.
3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative that elicits complex biological effects in humans. One plausible mechanism for this phenomenon is that racemic MDMA is composed of two stereoisomers that exhibit qualitatively different pharmacological effects. In support of this, studies have shown that R(-)-MDMA tends to have hallucinogen-like effects, whereas S(+)-MDMA tends to have psychomotor stimulant-like effects. However, relatively little is known about whether these stereoisomers engender different endocrine and neurochemical effects. In the present study, the endocrine and neurochemical effects of each stereoisomer and the racemate were assessed in four rhesus monkeys after intravenous delivery at doses (1-3 mg/kg) that approximated voluntary self-administration by rhesus monkeys and human recreational users. Specifically, fluorescence-based enzyme-linked immunosorbent assay was used to assess plasma prolactin concentrations, and in vivo microdialysis was used to assess extracellular dopamine and serotonin concentrations in the dorsal striatum. R(-)-MDMA, but not S(+)-MDMA, significantly increased plasma prolactin levels and the effects of S,R(+/-)-MDMA were intermediate to each of its component stereoisomers. Although S(+)-MDMA did not alter prolactin levels, it did significantly increase extracellular serotonin concentrations. In addition, S(+)-MDMA, but not R(-)-MDMA, significantly increased dopamine concentrations. Furthermore, as in the prolactin experiment, the effects of the racemate were intermediate to each of the stereoisomers. These studies demonstrate the stereoisomers of MDMA engender qualitatively different endocrine and neurochemical effects, strengthening the inference that differences in these stereoisomers might be the mechanism producing the complex biological effects of the racemic mixture of MDMA in humans.
Murnane
K S
KS
Division of Neuroscience, Yerkes National Primate Research Center, Atlanta, Georgia 30322, USA.
Fantegrossi
W E
WE
Godfrey
J R
JR
Banks
M L
ML
Howell
L L
LL
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D000697:Central Nervous System Stimulants / Q000737:chemistry / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D006213:Hallucinogens / Q000737:chemistry / Q000494:pharmacology*; D006719:Homovanillic Acid / Q000378:metabolism; D008253:Macaca mulatta; D017551:Microdialysis; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000737:chemistry / Q000494:pharmacology*; D011388:Prolactin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000697:Central Nervous System Stimulants; D006213:Hallucinogens; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D011388:Prolactin; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine; D006719:Homovanillic Acid
Exp Clin Psychopharmacol. 2008 Feb;16(1):1-12
18266547
Neuropsychopharmacology. 2004 Jul;29(7):1270-81
15039771
J Pharm Sci. 1986 Nov;75(11):1019-27
3820095
Psychopharmacology (Berl). 1997 Mar;130(1):2-13
9089844
Psychopharmacology (Berl). 2008 Jan;196(1):63-70
17899019
Psychopharmacology (Berl). 2007 Jan;189(4):471-82
16555062
J Pharmacol Exp Ther. 1994 Oct;271(1):143-8
7965707
Pharmacol Biochem Behav. 1988 Mar;29(3):443-9
2896360
Mol Pharmacol. 2003 Jun;63(6):1223-9
12761331
Psychopharmacology (Berl). 2003 Mar;166(3):202-11
12563544
Psychopharmacology (Berl). 2007 Jan;189(4):483-8
17063335
J Psychoactive Drugs. 1986 Oct-Dec;18(4):291-304
2880943
Behav Pharmacol. 1995 Apr;6(3):263-275
11224335
Psychopharmacology (Berl). 2002 Jun;161(4):356-64
12073162
Brain Res. 2009 Feb 3;1252:87-93
19059385
Neuroscience. 2008 Mar 27;152(3):773-84
18313226
Synapse. 2002 Jan;43(1):78-85
11746736
J Endocrinol. 1989 Dec;123(3):393-402
2607250
Psychopharmacology (Berl). 2009 Aug;205(3):467-74
19430765
J Pharmacol Exp Ther. 1997 Dec;283(3):1305-22
9400006
Bioorg Med Chem Lett. 2004 May 3;14(9):2367-70
15081042
Drug Alcohol Depend. 2006 May 20;82(3):276-81
16289931
Psychopharmacol Ser. 1988;4:161-75
3293041
Pharmacol Biochem Behav. 2007 Jan;86(1):45-54
17258302
Eur J Pharmacol. 1994 Nov 3;264(3):325-30
7698172
Brain Res. 2004 Aug 6;1016(2):240-6
15246860
Addiction. 2002 Dec;97(12):1531-6
12472637
Neuropsychopharmacology. 2004 May;29(5):833-46
14997175
Psychiatry Res. 1995 Sep 29;58(2):89-98
8570772
NIDA Res Monogr. 1978;(22):8-15
101890
Synapse. 2002 Apr;44(1):51-7
11842446
J Psychoactive Drugs. 1986 Oct-Dec;18(4):305-13
2880944
J Pharmacol Exp Ther. 2009 Nov;331(2):717-23
19684254
Psychopharmacology (Berl). 2007 Jan;189(4):407-24
16541247
Drug Alcohol Depend. 2006 Jan 4;81(1):27-36
15975736
J Pharmacol Exp Ther. 2002 Jun;301(3):1097-102
12023542
Neurosci Lett. 1994 Aug 15;177(1-2):111-5
7824160
Psychoneuroendocrinology. 2004 Feb;29(2):185-200
14604600
Psychoneuroendocrinology. 2005 Apr;30(3):273-83
15511601
Synapse. 2005 Dec 15;58(4):220-8
16206183
Neuropharmacology. 1990 Mar;29(3):269-75
1691459
Drug Alcohol Depend. 2003 Oct 24;72(1):33-44
14563541
J Pharmacol Exp Ther. 2008 Oct;327(1):38-44
18591215
Psychopharmacology (Berl). 2000 Feb;148(3):299-306
10755743
Psychopharmacology (Berl). 2002 Aug;162(4):396-405
12172693
Drugs. 1983 Apr;25(4):399-432
6133737
Life Sci. 1984 Apr 2;34(14):1325-31
6708733
J Neurochem. 2007 Jul;102(1):121-32
17564678
Pharmacol Rev. 2003 Sep;55(3):463-508
12869661