title: Continuous intracerebroventricular infusion of the competitive NMDA receptor antagonist, LY235959, facilitates escalation of cocaine self-administration and increases break point for cocaine in Sprague-Dawley rats.
abstract: Although escalation of consumption is an important characteristic of cocaine dependence, the neurobiological mechanisms that mediate this phenomenon have not been fully described. In this study, we used male, Sprague-Dawley rats to measure the effects of acute and continuous intracerebroventricular (ICV) administration of the competitive NMDA receptor antagonist, LY235959, on cocaine self-administration behavior under various schedules of reinforcement and access conditions. Single ICV infusions of LY235959 (0.03-0.3 microg/5 microl) produced dose-dependent and statistically significant decreases in the number of cocaine infusions earned under a progressive ratio schedule of reinforcement. In a second experiment, vehicle or LY235959 (0.2-0.3 microg/day) was continuously administered ICV to rats via surgically-implanted subcutaneous osmotic minipump/intracranial cannula assemblies. Both vehicle- and LY235959-treated rats significantly escalated cocaine self-administration over the 10 long access sessions; however, rats treated with LY235959 escalated cocaine self-administration faster and to a greater degree than vehicle-treated rats. There was a statistically significant increase in cocaine infusions earned under the PR schedule in LY235959-treated rats, but not vehicle-treated rats, after 10 long access cocaine self-administration sessions. These data support the hypothesis that escalation of cocaine consumption is mediated by hypo-glutamatergic tone in the central nervous system and this facilitation of escalation is associated with an increase in motivation to respond for cocaine.
authors: Department of Psychology, University of Colorado at Denver and Health Sciences Center, Downtown Denver Campus, CO 80217, United States. richard.allen@cudenver.edu
authors: Richard M
authors: RM
authors: Allen
authors: Kristina A
authors: KA
authors: Uban
authors: Elizabeth M
authors: EM
authors: Atwood
authors: David S
authors: DS
authors: Albeck
authors: Dorothy J
authors: DJ
authors: Yamamoto
mesh_terms: D000818:Animals; D002406:Catheterization, Peripheral; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000523:psychology*; D003216:Conditioning, Operant / Q000187:drug effects; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D007276:Injections, Intraventricular; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D012646:Self Administration
chemical_list: D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D016194:Receptors, N-Methyl-D-Aspartate; C088643:LY 235959; D003042:Cocaine
references: J Pharmacol Exp Ther. 2005 Oct;315(1):449-57
references: 16024734
references: Eur J Neurosci. 2001 Dec;14(11):1843-55
references: 11860480
references: Psychopharmacology (Berl). 2001 Mar;154(3):292-300
references: 11351936
references: Nat Neurosci. 2003 Jul;6(7):743-9
references: 12778052
references: Neuroscience. 2003;117(2):461-75
references: 12614686
references: Neuroreport. 2003 Dec 2;14(17):2229-32
references: 14625453
references: J Neurosci Methods. 1996 May;66(1):1-11
references: 8794935
references: Psychopharmacology (Berl). 2003 Feb;165(4):337-45
references: 12459930
references: J Neural Transm Gen Sect. 1991;85(2):131-43
references: 1834088
references: J Neurosci. 2005 Jul 6;25(27):6389-93
references: 16000629
references: Neuropsychopharmacology. 2005 Aug;30(8):1455-63
references: 15702135
references: J Pharmacol Exp Ther. 2001 Jul;298(1):288-97
references: 11408554
references: Life Sci. 1989;45(7):599-606
references: 2671566
references: J Pharmacol Exp Ther. 2006 Sep;318(3):1300-6
references: 16772537
references: J Neurosci. 2001 Sep 1;21(17):6588-96
references: 11517248
references: Brain Res. 1995 Mar 6;673(2):242-50
references: 7606438
references: Behav Pharmacol. 1993 Dec;4(6):652-659
references: 11224234
references: Psychopharmacology (Berl). 2004 Apr;172(4):450-4
references: 14647962
references: Brain Res. 2001 Mar 9;894(1):150-3
references: 11245826
references: J Pharmacol Exp Ther. 1995 Apr;273(1):445-54
references: 7714800
references: Neuroscience. 2002;109(2):267-74
references: 11801363
references: Psychopharmacology (Berl). 2007 Apr;191(2):341-51
references: 17225167
references: Psychopharmacology (Berl). 2004 Apr;173(1-2):124-31
references: 14712340
references: Neurochem Res. 2001 May;26(5):559-65
references: 11513485
references: Psychopharmacology (Berl). 1993;111(3):332-8
references: 7870971
references: Neuropsychopharmacology. 2000 Sep;23(3):335-44
references: 10942857
references: Synapse. 1998 Dec;30(4):393-401
references: 9826231
references: Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11631-6
references: 10500228
references: Nat Neurosci. 2002 Jul;5(7):625-6
references: 12055635
references: Nat Neurosci. 2001 Dec;4(12):1217-23
references: 11694884
references: Pain. 1996 Dec;68(2-3):229-37
references: 9121809
references: Behav Pharmacol. 1995 Aug;6(5 And 6):568-576
references: 11224364
references: Psychopharmacology (Berl). 2005 May;179(3):644-51
references: 15650844
references: Science. 1998 Oct 9;282(5387):298-300
references: 9765157
references: J Pharmacol Exp Ther. 2000 Jul;294(1):239-47
references: 10871318