N-acetylaspartylglutamate (NAAG) inhibits intravenous cocaine self-administration and cocaine-enhanced brain-stimulation reward in rats.
Pharmacological activation of group II metabotropic glutamate (mGlu2 and mGlu3) receptors inhibits reward-seeking behavior and/or rewarding efficacy induced by drugs (cocaine, nicotine) or natural rewards (food, sucrose). In the present study, we investigated whether elevation of brain N-acetylaspartylglutamate (NAAG), an endogenous group II mGlu receptor agonist, by the NAAG peptidase inhibitor 2-PMPA attenuates cocaine's rewarding effects, as assessed by intravenous cocaine self-administration and intracranial electrical brain-stimulation reward (BSR) in rats. Systemic administration of 2-PMPA (10, 30, 100 mg/kg, i.p.) or intranasal administration of NAAG (100, 300 microg/10 microl/nostril) significantly inhibited intravenous cocaine self-administration under progressive-ratio (PR), but not under fixed-ratio 2 (FR2), reinforcement conditions. In addition, 2-PMPA (1, 10, 30 mg/kg, i.p) or NAAG (50, 100 microg/10 microl/nostril) significantly inhibited cocaine-enhanced BSR, but not basal BSR. Pretreatment with LY341495 (1 mg/kg, i.p.), a selective mGlu2/3 receptor antagonist, prevented the inhibitory effects produced by 2-PMPA or NAAG in both the self-administration and BSR paradigms. In vivo microdialysis demonstrated that 2-PMPA (10, 30, 100 mg/kg) dose-dependently attenuated cocaine-enhanced extracellular dopamine (DA) in the nucleus accumbens (NAc). 2-PMPA alone inhibited basal NAc DA release, an effect that was prevented by LY341495. These findings suggest that systemic administration of 2-PMPA or intranasal administration of NAAG inhibits cocaine's rewarding efficacy and cocaine-enhanced NAc DA - likely by activation of presynaptic mGlu2/3 receptors in the NAc. These data suggest a potential utility for 2-PMPA or NAAG in the treatment of cocaine addiction.
Xi
Zheng-Xiong
ZX
Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA. zxi@intra.nida.nih.gov
Kiyatkin
Michael
M
Li
Xia
X
Peng
Xiao-Qing
XQ
Wiggins
Armina
A
Spiller
Krista
K
Li
Jie
J
Gardner
Eliot L
EL
D000818:Animals; D016739:Behavior, Addictive / Q000503:physiopathology / Q000523:psychology / Q000628:therapy*; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods*; D007275:Injections, Intravenous / Q000379:methods; D008297:Male; D017551:Microdialysis; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D012055:Reinforcement Schedule; D012201:Reward; D012646:Self Administration
C402107:2-(phosphonomethyl)pentanedioic acid; D018765:Dopamine Uptake Inhibitors; D018696:Neuroprotective Agents; D009943:Organophosphorus Compounds; D003042:Cocaine