Antipsychotic-like effects of the N-methyl-D-aspartate receptor modulator neboglamine: an immunohistochemical and behavioural study in the rat.
Neboglamine is a functional modulator of the glycine site on the N-methyl-d-aspartate (NMDA) receptor. Dysfunction of this receptor has been associated with negative and cognitive symptoms in schizophrenia. Thus, we tested the hypothesis that neboglamine behaves as a potential antipsychotic. We compared the effects of neboglamine, D-serine, clozapine, and haloperidol on the expression of Fos-like immunoreactivity (FLI), a marker of neuronal activation, in rat forebrain. We also studied the effects of these agents on phencyclidine (PCP)-induced behaviour in rats, a model predictive of potential antipsychotic activity. Neboglamine, like haloperidol and clozapine, significantly increased the number of FLI-positive cells in the prefrontal cortex, nucleus accumbens, and lateral septal nucleus (3.2-, 4.8-, and 4.5-fold over control, respectively). Haloperidol dramatically increased FLI (390-fold over control) in the dorsolateral striatum, a brain region in which neboglamine and clozapine had no effect. The pattern of FLI induced by neboglamine closely matched that of d-serine, an endogenous agonist at the glycine site of NMDA receptors. Consistent with this finding, neboglamine restored NMDA-mediated neurotransmitter release in frontal cortex punches exposed to the NMDA antagonist PCP. In the behavioural model, all test compounds significantly inhibited PCP-induced hyperlocomotion. Unlike haloperidol and clozapine, neither neboglamine nor D-serine affected the basal levels of locomotor activity. Moreover, oral neboglamine dose-dependently inhibited both the hyperlocomotion and the frequency of rearing behaviour induced by PCP. These results, while confirming that the NMDA glycine site is a feasible target for activating the frontostriatal system, support the clinical evaluation of neboglamine as a treatment for schizophrenia.
Chiusaroli
Riccardo
R
Department of Pharmacology & Toxicology, Rottapharm S.p.A., Via Valosa di Sopra 9, 20052 Monza (MB), Italy.
Garofalo
Paolo
P
Espinoza
Stefano
S
Neri
Elisa
E
Caselli
Gianfranco
G
Lanza
Marco
M
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D003024:Clozapine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006213:Hallucinogens / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010421:Pentanoic Acids / Q000494:pharmacology*; D010622:Phencyclidine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018009:Receptors, Glycine / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D012694:Serine / Q000378:metabolism
D014150:Antipsychotic Agents; D006213:Hallucinogens; D010421:Pentanoic Acids; D016760:Proto-Oncogene Proteins c-fos; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; C105010:neboglamine; D012694:Serine; D010622:Phencyclidine; D003024:Clozapine; D006220:Haloperidol