Attenuation of cocaine self-administration in squirrel monkeys following repeated administration of the mGluR5 antagonist MPEP: comparison with dizocilpine.
BACKGROUND
The mGluR5 antagonist MPEP has effects that suggest potential as a pharmacotherapy for cocaine addiction. MPEP can attenuate self-administration of cocaine in animals; however, studies usually involved only acute treatment with MPEP and a single dose of self-administered cocaine. Cocaine addicts use varied amounts of cocaine over long periods of time, and an effective pharmacotherapy would almost certainly require more chronic treatment.


OBJECTIVE
The present study (1) compared the effects of repeated treatment with MPEP or the NMDA receptor antagonist dizocilpine on the reinforcing effects of a range of doses of cocaine and (2) determined the pharmacological specificity of the effects of the drugs in attenuating cocaine self-administration compared to food-reinforced behavior. An effective pharmacotherapy should selectively reduce cocaine self-administration.


METHODS
Groups of monkeys responded under a fixed-ratio schedule of i.v. cocaine self-administration or food-pellet delivery. The effects of daily treatment with MPEP and dizocilpine were determined under both the schedule of i.v. cocaine injection and food delivery.


RESULTS
Treatment with MPEP and dizocilpine significantly reduced cocaine self-administration, producing rightward and downward shifts in the ascending limb of the cocaine dose-response function. MPEP and dizocilpine selectively and significantly attenuated self-administration of a low reinforcing dose of cocaine compared to food without evidence of tolerance.


CONCLUSIONS
Both MPEP and dizocilpine functioned as partially surmountable antagonists of the reinforcing effects of cocaine. The similar effects of the two drugs raises the possibility that MPEP attenuated the reinforcing effects of cocaine, at least in part, via mGluR5-mediated inhibition of NMDA receptor activity.
Platt
Donna M
DM
New England Primate Research Center, Harvard Medical School, One Pine Hill Drive, P.O. Box 9102, Southborough, MA 01772-9102, USA. donna_platt@hms.harvard.edu
Rowlett
James K
JK
Spealman
Roger D
RD
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors; D012055:Reinforcement Schedule; D012453:Saimiri; D012646:Self Administration
D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016291:Dizocilpine Maleate; C121465:6-methyl-2-(phenylethynyl)pyridine; D003042:Cocaine