Continuous exposure to the competitive N-methyl-D: -aspartate receptor antagonist, LY235959, facilitates escalation of cocaine consumption in Sprague-Dawley rats.
BACKGROUND
Chronic high dose consumption of cocaine is associated with significant negative effects to individual users and society. Nevertheless, the precise mechanisms that mediate increases in cocaine consumption in a drug-using individual are not fully understood.


OBJECTIVE
This study used a long access version of the drug self-administration procedure to determine whether escalation of cocaine consumption is mediated by increased activity through N-methyl-D: -aspartate (NMDA) receptors.


METHODS
Male Sprague-Dawley rats (n = 63) were first trained to self-administer cocaine (0.33 mg/infusion, i.v.) under a fixed-ratio 1 schedule of reinforcement. After training, some rats were implanted with subcutaneous osmotic minipumps filled with vehicle or the competitive NMDA receptor antagonist, LY235959, and subsequently allowed to self-administer cocaine in short (2 h) or long (6 h) access self-administration sessions.


RESULTS
Vehicle-treated rats escalated cocaine self-administration across 14 long-access self-administration sessions. Rats treated with LY235959 via osmotic minipump, but not twice daily injections, escalated cocaine self-administration at a greater rate and to a greater degree than vehicle-treated rats. In post-escalation cocaine dose-infusion tests, rats treated continuously with LY235959 self-administered more cocaine (0.08-1.32 mg/infusion) than vehicle-treated rats, regardless of access condition, shifting the dose-infusion curves upward. During extinction sessions, which were conducted after the escalation phase of the study, rats that had long (6 h) access to cocaine stopped responding sooner than rats that had short (2 h) access to cocaine, independent of LY235959 treatment.


CONCLUSIONS
These data are consistent with hypo-glutamatergic consequences of repeated cocaine exposure.
Allen
Richard M
RM
Department of Psychology, University of Colorado at Denver and Health Sciences Center, Downtown Denver Campus, CB# 173, P.O. Box 173364, Denver, CO 80217, USA. richard.allen@cudenver.edu
Dykstra
Linda A
LA
Carelli
Regina M
RM
D000704:Analysis of Variance; D000818:Animals; D016739:Behavior, Addictive; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005108:Extinction, Psychological / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D018377:Neurotransmitter Agents; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D012055:Reinforcement Schedule; D012646:Self Administration
D018765:Dopamine Uptake Inhibitors; D007546:Isoquinolines; D018377:Neurotransmitter Agents; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; C088643:LY 235959; D003042:Cocaine