title: Stimulants as specific inducers of dopamine-independent σ agonist self-administration in rats.
abstract: A previous study showed that cocaine self-administration induced dopamine-independent reinforcing effects of σ agonists mediated by their selective actions at σ1 receptors (σ1Rs), which are intracellularly mobile chaperone proteins implicated in abuse-related effects of stimulants. The present study assessed whether the induction was specific to self-administration of cocaine. Rats were trained to self-administer the dopamine releaser, d-methamphetamine (0.01-0.32 mg/kg per injection), the μ-opioid receptor agonist, heroin (0.001-0.032 mg/kg per injection), and the noncompetitive N-methyl-d-aspartate receptor/channel antagonist ketamine (0.032-1.0 mg/kg per injection). As with cocaine, self-administration of d-methamphetamine induced reinforcing effects of the selective σ1R agonists PRE-084 [2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate hydrochloride] and (+)-pentazocine (0.032-1.0 mg/kg per injection, each). In contrast, neither self-administration of heroin nor ketamine induced PRE-084 or (+)-pentazocine (0.032-10 mg/kg per injection, each) self-administration. Although the σ1R agonists did not maintain responding in subjects with histories of heroin or ketamine self-administration, substitution for those drugs was obtained with appropriate agonists (e.g., remifentanil, 0.1-3.2 µg/kg per injection, for heroin and (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ((+)-MK 801; dizocilpine), 0.32-10.0 µg/kg per injection, for ketamine). The σR antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine dihydrobromide (BD 1008; 1.0-10 mg/kg) dose-dependently blocked PRE-084 self-administration but was inactive against d-methamphetamine, heroin, and ketamine. In contrast, PRE-084 self-administration was affected neither by the dopamine receptor antagonist (+)-butaclamol (10-100 μg/kg) nor by the opioid antagonist (-)-naltrexone (1.0-10 mg/kg), whereas these antagonists were active against d-methamphetamine and heroin self-administration, respectively. The results indicate that experience specifically with indirect-acting dopamine agonists induces reinforcing effects of previously inactive σ1R agonists. It is further suggested that induced σ1R reinforcing mechanisms may play an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for its treatment.
authors.affiliation: Psychobiology Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (T.H., G.T., T.A.K., J.L.K.); and Behavioral Biology Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (P.L.S.).
authors.forename: Takato
authors.initials: T
authors.lastname: Hiranita
authors.forename: Paul L
authors.initials: PL
authors.lastname: Soto
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Tanda
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Kopajtic
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Katz
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D004298:Dopamine / Q000502:physiology; D018491:Dopamine Agonists / Q000008:administration & dosage*; D006168:Guinea Pigs; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects* / Q000502:physiology; D017480:Receptors, sigma / Q000819:agonists* / Q000502:physiology; D012055:Reinforcement Schedule; D012646:Self Administration
chemical_list: D000701:Analgesics, Opioid; D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists; D017480:Receptors, sigma; D004298:Dopamine
references.citation: J Pharmacol Exp Ther. 1992 Apr;261(1):311-7
references.pmid: 1560376
references.citation: J Pharmacol Exp Ther. 2003 Jan;304(1):364-9
references.pmid: 12490613
references.citation: Drugs. 2004;64(14):1547-73
references.pmid: 15233592
references.citation: Psychopharmacology (Berl). 2004 Aug;175(1):68-75
references.pmid: 15029471
references.citation: Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12304-8
references.pmid: 8618890
references.citation: Neuron. 2002 Apr 25;34(3):399-410
references.pmid: 11988171
references.citation: Neuropsychopharmacology. 2007 Sep;32(9):1967-73
references.pmid: 17268407
references.citation: Neuropharmacology. 1998 Jun;37(6):793-802
references.pmid: 9707293
references.citation: Cell. 2007 Nov 2;131(3):596-610
references.pmid: 17981125
references.citation: Curr Opin Psychiatry. 2005 May;18(3):265-70
references.pmid: 16639150
references.citation: J Pharmacol Exp Ther. 2007 Jan;320(1):202-10
references.pmid: 17050780
references.citation: Eur J Pharmacol. 1988 Jan 27;146(1):113-20
references.pmid: 2895008
references.citation: PLoS One. 2013 Apr 18;8(4):e61245
references.pmid: 23637801
references.citation: J Pharmacol Exp Ther. 2011 Nov;339(2):662-77
references.pmid: 21859929
references.citation: J Pharmacol Exp Ther. 2010 Mar;332(3):1054-63
references.pmid: 19940104
references.citation: Neuropsychopharmacology. 2005 Aug;30(8):1443-54
references.pmid: 15770241
references.citation: Neuropsychopharmacology. 2013 Mar;38(4):605-15
references.pmid: 23187725
references.citation: Neuropsychopharmacology. 1996 Jun;14(6):375-424
references.pmid: 8726752
references.citation: J Pharmacol Exp Ther. 1978 Feb;204(2):481-6
references.pmid: 413904
references.citation: Behav Pharmacol. 1990;1(4):355-363
references.pmid: 11175420
references.citation: Eur J Pharmacol. 1999 Apr 16;370(3):225-32
references.pmid: 10334496
references.citation: J Pharmacol Exp Ther. 2007 Nov;323(2):599-605
references.pmid: 17675585
references.citation: J Pharmacol Exp Ther. 2006 Jun;317(3):1088-96
references.pmid: 16478825
references.citation: J Pharmacol Exp Ther. 1991 May;257(2):706-13
references.pmid: 1674533
references.citation: Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18676-81
references.pmid: 20956312
references.citation: Biol Psychiatry. 2011 Feb 1;69(3):208-17
references.pmid: 20950794
references.citation: J Pharmacol Exp Ther. 2005 Aug;314(2):770-9
references.pmid: 15879001
references.citation: Behav Pharmacol. 2009 Sep;20(5-6):492-504
references.pmid: 19696656
references.citation: Expert Rev Clin Pharmacol. 2009 Jul;2(4):351-8
references.pmid: 22112179
references.citation: J Pharmacol Exp Ther. 2010 Feb;332(2):515-24
references.pmid: 19892920
references.citation: Pharmaceuticals (Basel). 2011;4(6):880-914
references.pmid: 21904468
references.citation: Eur J Pharmacol. 2001 May 11;419(2-3):163-74
references.pmid: 11426838
references.citation: Neuropsychopharmacology. 2002 Apr;26(4):444-55
references.pmid: 11927169
references.citation: Psychopharmacology (Berl). 2000 May;150(1):61-6
references.pmid: 10867977
references.citation: Am J Psychiatry. 2005 Aug;162(8):1432-40
references.pmid: 16055764
references.citation: Science. 2009 Feb 13;323(5916):934-7
references.pmid: 19213917
references.citation: J Pharmacol Exp Ther. 2008 Oct;327(1):187-95
references.pmid: 18591217
references.citation: J Pharmacol Exp Ther. 2009 May;329(2):677-86
references.pmid: 19228996
references.citation: Proc Natl Acad Sci U S A. 1983 Nov;80(21):6703-7
references.pmid: 6314335
references.citation: J Neurosci. 2012 Aug 15;32(33):11187-200
references.pmid: 22895704
references.citation: Nature. 1996 Jul 18;382(6588):255-7
references.pmid: 8717040
references.citation: Neuroreport. 2000 Sep 11;11(13):2885-8
references.pmid: 11006959
references.citation: J Pharmacol Exp Ther. 1989 Nov;251(2):455-60
references.pmid: 2553919
references.citation: Pharmacol Ther. 2009 Nov;124(2):195-206
references.pmid: 19619582
references.citation: Science. 1997 Jun 27;276(5321):2048-50
references.pmid: 9197269
references.citation: Eur J Pharmacol. 1999 Apr 29;371(2-3):123-35
references.pmid: 10357249
references.citation: Behav Pharmacol. 2011 Sep;22(5-6):525-30
references.pmid: 21808192
references.citation: Life Sci. 1989;44(21):1547-54
references.pmid: 2471910
references.citation: Eur J Pharmacol. 1996 Sep 12;311(2-3):233-40
references.pmid: 8891604
references.citation: J Pharmacol Exp Ther. 2005 Jul;314(1):310-9
references.pmid: 15833897