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.
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.
Allen
Richard M
RM
Department of Psychology, University of Colorado at Denver and Health Sciences Center, Downtown Denver Campus, CO 80217, United States. richard.allen@cudenver.edu
Uban
Kristina A
KA
Atwood
Elizabeth M
EM
Albeck
David S
DS
Yamamoto
Dorothy J
DJ
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
D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D016194:Receptors, N-Methyl-D-Aspartate; C088643:LY 235959; D003042:Cocaine
J Pharmacol Exp Ther. 2005 Oct;315(1):449-57
16024734
Eur J Neurosci. 2001 Dec;14(11):1843-55
11860480
Psychopharmacology (Berl). 2001 Mar;154(3):292-300
11351936
Nat Neurosci. 2003 Jul;6(7):743-9
12778052
Neuroscience. 2003;117(2):461-75
12614686
Neuroreport. 2003 Dec 2;14(17):2229-32
14625453
J Neurosci Methods. 1996 May;66(1):1-11
8794935
Psychopharmacology (Berl). 2003 Feb;165(4):337-45
12459930
J Neural Transm Gen Sect. 1991;85(2):131-43
1834088
J Neurosci. 2005 Jul 6;25(27):6389-93
16000629
Neuropsychopharmacology. 2005 Aug;30(8):1455-63
15702135
J Pharmacol Exp Ther. 2001 Jul;298(1):288-97
11408554
Life Sci. 1989;45(7):599-606
2671566
J Pharmacol Exp Ther. 2006 Sep;318(3):1300-6
16772537
J Neurosci. 2001 Sep 1;21(17):6588-96
11517248
Brain Res. 1995 Mar 6;673(2):242-50
7606438
Behav Pharmacol. 1993 Dec;4(6):652-659
11224234
Psychopharmacology (Berl). 2004 Apr;172(4):450-4
14647962
Brain Res. 2001 Mar 9;894(1):150-3
11245826
J Pharmacol Exp Ther. 1995 Apr;273(1):445-54
7714800
Neuroscience. 2002;109(2):267-74
11801363
Psychopharmacology (Berl). 2007 Apr;191(2):341-51
17225167
Psychopharmacology (Berl). 2004 Apr;173(1-2):124-31
14712340
Neurochem Res. 2001 May;26(5):559-65
11513485
Psychopharmacology (Berl). 1993;111(3):332-8
7870971
Neuropsychopharmacology. 2000 Sep;23(3):335-44
10942857
Synapse. 1998 Dec;30(4):393-401
9826231
Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11631-6
10500228
Nat Neurosci. 2002 Jul;5(7):625-6
12055635
Nat Neurosci. 2001 Dec;4(12):1217-23
11694884
Pain. 1996 Dec;68(2-3):229-37
9121809
Behav Pharmacol. 1995 Aug;6(5 And 6):568-576
11224364
Psychopharmacology (Berl). 2005 May;179(3):644-51
15650844
Science. 1998 Oct 9;282(5387):298-300
9765157
J Pharmacol Exp Ther. 2000 Jul;294(1):239-47
10871318