Is slow-onset long-acting monoamine transport blockade to cocaine as methadone is to heroin? Implication for anti-addiction medications.
The success of methadone in treating opiate addiction has suggested that long-acting agonist therapies may be similarly useful for treating cocaine addiction. Here, we examined this hypothesis, using the slow-onset long-acting monoamine reuptake inhibitor 31,345, a trans-aminotetralin analog, in a variety of addiction-related animal models, and compared it with methadone's effects on heroin's actions in the same animal models. Systemic administration of 31,345 produced long-lasting enhancement of electrical brain-stimulation reward (BSR) and extracellular nucleus accumbens (NAc) dopamine (DA). Pretreatment with 31,345 augmented cocaine-enhanced BSR, prolonged cocaine-enhanced NAc DA, and produced a long-term (24-48  h) reduction in cocaine self-administration rate without obvious extinction pattern, suggesting an additive effect of 31,345 with cocaine. In contrast, methadone pretreatment not only dose-dependently inhibited heroin self-administration with an extinction pattern but also dose-dependently inhibited heroin-enhanced BSR and NAc DA, suggesting functional antagonism by methadone of heroin's actions. In addition, 31,345 appears to possess significant abuse liability, as it produces dose-dependent enhancement of BSR and NAc DA, maintains a low rate of self-administration behavior, and dose-dependently reinstates drug-seeking behavior. In contrast, methadone only partially maintains self-administration with an extinction pattern, and fails to induce reinstatement of drug-seeking behavior. These findings suggest that 31,345 is a cocaine-like slow-onset long-acting monoamine transporter inhibitor that may act as an agonist therapy for cocaine addiction. However, its pattern of action appears to be significantly different from that of methadone. Ideal agonist substitutes for cocaine should fully emulate methadone's actions, that is, functionally antagonizing cocaine's action while blocking monoamine transporters to augment synaptic DA.
Peng
Xiao-Qing
XQ
Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, Baltimore, MD 21224, USA.
Xi
Zheng-Xiong
ZX
Li
Xia
X
Spiller
Krista
K
Li
Jie
J
Chun
Lauren
L
Wu
Kuo-Ming
KM
Froimowitz
Mark
M
Gardner
Eliot L
EL
D000818:Animals; D001921:Brain / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D005108:Extinction, Psychological / Q000187:drug effects; D003932:Heroin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D008691:Methadone / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000378:metabolism; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000037:antagonists & inhibitors*; D051381:Rats; D020318:Rats, Long-Evans; D012646:Self Administration; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000494:pharmacology*
C556220:(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)dimethylammonium; D003692:Delayed-Action Preparations; D050480:Plasma Membrane Neurotransmitter Transport Proteins; D013764:Tetrahydronaphthalenes; D003932:Heroin; D003042:Cocaine; D008691:Methadone; D004298:Dopamine
J Pharmacol Exp Ther. 2001 Jul;298(1):1-6
11408518
Addict Behav. 2007 Oct;32(10):2140-50
17360126
Neuropsychopharmacology. 2006 Jul;31(7):1393-405
16205781
Neurosci Biobehav Rev. 1999 May;23(5):717-41
10392662
J Neurosci. 2005 Feb 23;25(8):1889-93
15728828
Mol Pharmacol. 1998 Mar;53(3):377-84
9495801
J Biol Chem. 2001 Aug 3;276(31):29012-8
11395483
J Neurochem. 2010 Jan;112(2):564-76
19895667
Psychopharmacology (Berl). 2009 Dec;207(2):281-9
19756525
Drug Alcohol Depend. 1995 May;38(2):95-137
7671769
Br J Psychiatry. 2008 Jul;193(1):65-72
18700222
Addiction. 2005 Oct;100(10):1496-509
16185211
Neuropsychopharmacology. 2004 Jul;29(7):1312-20
15039768
Mol Pharmacol. 2002 Feb;61(2):436-45
11809869
Arch Intern Med. 1966 Oct;118(4):304-9
4162686
Trends Pharmacol Sci. 1996 Jul;17(7):260-4
8756185
Am J Addict. 2000 Fall;9(4):285-313
11155784
Pharmacol Biochem Behav. 1992 Mar;41(3):489-96
1584830
Behav Pharmacol. 1990;1(4):355-363
11175420
Alcohol Alcohol. 2002 Sep-Oct;37(5):485-94
12217944
JAMA. 1965 Aug 23;193:646-50
14321530
Biochem Biophys Res Commun. 2002 Feb 8;290(5):1545-50
11820798
J Biol Chem. 2007 Dec 7;282(49):35842-54
17923483
Psychopharmacology (Berl). 1977 Oct 20;54(2):109-12
412203
Mol Pharmacol. 2002 Dec;62(6):1464-70
12435815
Mol Pharmacol. 2007 May;71(5):1222-32
17267664
J Med Chem. 1996 Nov 22;39(24):4689-91
8941381
J Neurosci. 2003 Apr 15;23(8):3498-505
12716959
Curr Opin Neurobiol. 1996 Apr;6(2):243-51
8725967
Science. 1997 Oct 3;278(5335):66-70
9311929
J Med Chem. 2000 Dec 28;43(26):4981-92
11150168
J Biol Chem. 2003 Jun 13;278(24):22168-74
12682063
Mol Pharmacol. 2001 Jan;59(1):113-21
11125031
J Pharmacol Exp Ther. 2003 Nov;307(2):729-36
12975490
Clin Psychol Rev. 2010 Mar;30(2):155-66
19926374
Neuropharmacology. 2006 Oct;51(5):993-1003
16901516
Eur J Pharmacol. 2004 Feb 23;486(3):251-7
14985046
J Med Chem. 1984 Nov;27(11):1508-15
6492080
Med Res Rev. 2002 Sep;22(5):429-64
12210554
NIDA Res Monogr. 1992;120:13-25
1501682
J Med Chem. 2007 Jan 25;50(2):219-32
17228864
Mol Pharmacol. 2008 Mar;73(3):813-23
17978168
J Neurochem. 1999 Feb;72(2):585-93
9930730
Addict Behav. 2004 Sep;29(7):1439-64
15345275
Psychopharmacology (Berl). 2002 May;161(2):202-12
11981600
Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6850-5
10823899
Curr Top Med Chem. 2006;6(17):1825-43
17017960
Psychopharmacology (Berl). 2008 Mar;196(4):533-42
17985117
Eur J Neurosci. 2005 Jun;21(12):3427-38
16026480
Psychopharmacology (Berl). 2002 Oct;163(3-4):265-82
12373428
Clin Pharmacokinet. 1986 Mar-Apr;11(2):144-53
3514044
Mol Neurobiol. 1995 Aug-Dec;11(1-3):1-19
8561954
Biochem Pharmacol. 2008 Jan 1;75(1):2-16
17897630
Mol Pharmacol. 2006 Aug;70(2):542-8
16684900
Neuropharmacology. 2004;47 Suppl 1:80-91
15464127
Arch Gen Psychiatry. 1995 Jun;52(6):456-63
7771915
AAPS J. 2006 Mar 24;8(1):E196-203
16584128
Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9333-8
16754872
Ann N Y Acad Sci. 2000;909:186-216
10911931
J Neurochem. 2007 Apr;101(2):377-88
17250655
Neurosci Biobehav Rev. 2004 Jan;27(8):739-49
15019424
Neurosci Lett. 1987 Aug 31;79(3):315-20
2958724