Prepulse inhibition deficits of the startle reflex in neonatal ventral hippocampal-lesioned rats: reversal by glycine and a glycine transporter inhibitor.
BACKGROUND
Neonatal ventral hippocampal (NVH) lesions in rats induce behavioral abnormalities at adulthood thought to simulate some aspects of the positive, negative, and cognitive deficits classically observed in schizophrenic patients. Such lesions induce a postpubertal emergence of prepulse inhibition (PPI) deficits of the startle reflex reminiscent of the sensorimotor gating deficits observed in a majority of schizophrenic patients. To study the potential involvement of the glycinergic neurotransmission in such deficits, we investigated the capacity of glycine (an obligatory N-methyl-D-aspartate [NMDA] receptor co-agonist) and ORG 24598 (a selective glycine transporter 1 inhibitor) to reverse NVH lesion-induced PPI deficits in rats.


METHODS
Ibotenic acid was injected bilaterally into the ventral hippocampus of 7-day-old pups. Prepulse inhibition of the startle reflex was measured at adulthood.


RESULTS
Glycine (.8 and 1.6 g/kg IP) and ORG 24598 (10 mg/kg IP) fully and partially reversed lesion-induced PPI deficits, respectively.


CONCLUSIONS
These findings confirm that an impaired glutamatergic neurotransmission may be responsible for PPI deficits exhibited by NVH-lesioned rats and support the hypoglutamatergic hypothesis of schizophrenia. They also suggest that drugs acting either directly at the NMDA receptor glycine site or indirectly on the glycine transporter 1 could offer promising targets for the development of novel therapies for schizophrenia.
Le Pen
Gwenaëlle
G
INSERM-EMI, Centre Paul Broca (GLP), Paris, France
Kew
James
J
Alberati
Daniela
D
Borroni
Edilio
E
Heitz
Marie Paule
MP
Moreau
Jean-Luc
JL
D026921:Amino Acid Transport Systems, Neutral / Q000037:antagonists & inhibitors*; D000818:Animals; D000831:Animals, Newborn; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D050487:Glycine Plasma Membrane Transport Proteins; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007051:Ibotenic Acid; D007266:Inhibition, Psychological; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology*
D026921:Amino Acid Transport Systems, Neutral; D050487:Glycine Plasma Membrane Transport Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C493266:Slc6a9 protein, rat; C435781:org 24598; D007051:Ibotenic Acid; D018698:Glutamic Acid; D005998:Glycine