Effects of selective inhibition of N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) on mice in learning and memory tasks.
The purpose of the present study was to examine the effects of 2-(phosphonomethyl)-pentanedioic acid (2-PMPA), a selective inhibitor of N-acetylated-alpha-linked-acidic dipeptidase (NAALADase, glutamate carboxypeptidase II), an enzyme catalyzing the cleavage of glutamate from the neuropeptide N-acetyl-aspartyl-glutamate (NAAG), on memory processes in mice. Long-term memory was evaluated in step-through passive avoidance task while alternation behavior, as a measure involving spatial working memory, was assessed in Y-maze task. Additionally, horizontal activity was evaluated by means of electronically monitored locomotor activity system. The mice were treated with either 2-PMPA (50, 100 and 150 mg/kg i.p.) or N-methyl-d-aspartate (NMDA) receptor antagonist, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine hydrogen maleate (MK-801) at doses of: 0.05, 0.1, 0.15 and 0.2 mg/kg i.p., as a comparator. In the passive avoidance task, the drugs were administered once before or immediately after training, and before retention test. 2-PMPA at the doses used did not affect retention of passive avoidance; however, it increased the latency to enter the dark box during the training day. In the Y-maze task, 2-PMPA (150 mg/kg i.p.) impaired spontaneous alternation and reduced locomotion while the lower dose of 100 mg/kg was ineffective. In the locomotor activity test, 2-PMPA (100 and 150 mg/kg i.p.) did not significantly affect horizontal activity. MK-801 (0.2 mg/kg i.p.) injected before training reduced retention in the passive avoidance task. In the Y-maze task, MK-801 (0.1 mg/kg i.p.) impaired alternation behavior and considerably increased locomotion in the Y-maze and locomotor activity test. These results indicate that NAALADase inhibition may impair alternation behavior.
Lukawski
Krzysztof
K
Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland. lukaw@mp.pl
Kamiński
Rafał M
RM
Czuczwar
Stanisław J
SJ
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D004151:Dipeptides / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000494:pharmacology*
C402107:2-(phosphonomethyl)pentanedioic acid; D004151:Dipeptides; D009943:Organophosphorus Compounds; C027172:isospaglumic acid; D016291:Dizocilpine Maleate; D043425:Glutamate Carboxypeptidase II