title: Neonatal NMDA receptor antagonist treatments have no effects on prepulse inhibition of postnatal day 25 Sprague-Dawley rats.
abstract: Glutamate activation of the NMDA receptor is essential for neuronal differentiation, migration, and survival. Treatment with NMDA receptor antagonists, such as ketamine (KET) or phencyclidine (PCP), can trigger apoptosis in neonatal rats. However, L-carnitine (LC) treatment appears to prevent glutamate-induced toxicity in the developing CNS. Previously, we described altered preweaning behaviors (i.e., abnormal home cage, slant board and forelimb hang behaviors) resulting from neonatal PCP and KET treatment. Those adverse effects of KET were somewhat ameliorated by LC [Boctor SY, Wang C, Ferguson SA. Neonatal PCP is more potent than ketamine at modifying preweaning behaviors of Sprague-Dawley rats. Toxicol Sci 2008;106:172-9]. Here, a portion of those subjects were evaluated for prepulse inhibition (PPI) of the acoustic startle response at postnatal day (PND) 25 since previous reports described PCP-induced effects on this response. Rats were subcutaneously treated with: saline; 10 mg/kg PCP (1x/day) on PNDs 7, 9 and 11; 20 mg/kg KET (6 injections every 2h on PND 7); or a similar regimen of ketamine and 250 mg/kg LC on PND 7, with a single injection of 250 mg/kg LC on PNDs 8-11 (KLC). Male and female rats were assessed using a standard PPI paradigm with prepulses of 68, 78 and 82 dB. Body weight was decreased 17-21% and whole brain weight was decreased 10% in PCP-treated rats. Specifically, cerebellar weight was significantly less in PCP-treated rats relative to control. Despite the magnitude of those PCP-induced changes, startle response in normal pulse only trials and percent of PPI in PCP-, KET-, and KLC-treated groups were comparable to controls. Average latency to maximum startle was 2.6 ms less in females than males (p<0.007); there were no other significant sex effects. The lack of neonatal PCP treatment on later PPI is similar to that reported by Rasmussen et al. [Rasmussen BA, O'Neil J, Manaye KF, Perry DC, Tizabi Y. Long-term effects of developmental PCP administration on sensorimotor gating in male and female rats. Psychopharmacology (Berl) 2007; 190: 43-9.], and indicates that neonatal PCP-induced effects on PPI [Wang C, McInnis J, Ross-Sanchez M, Shinnick-Gallagher P, Wiley JL, Johnson KM. Long-term behavioral and neurodegenerative effects of perinatal phencyclidine administration: implications for schizophrenia. Neuroscience 2001; 107: 535-50.] appear difficult to replicate.
authors.affiliation: Department of Interdisciplinary Biomedical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States. Sherin.Boctor@fda.hhs.gov
authors.forename: Sherin Y
authors.initials: SY
authors.lastname: Boctor
authors.forename: Sherry A
authors.initials: SA
authors.lastname: Ferguson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D002331:Carnitine / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects; D005260:Female; D007266:Inhibition, Psychological; D007649:Ketamine / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010622:Phencyclidine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D049590:Postpartum Period; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013216:Reflex, Startle / Q000187:drug effects; D012727:Sex Characteristics
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D010622:Phencyclidine; D002331:Carnitine