Effects of haloperidol, clozapine, and quetiapine on sensorimotor gating in a genetic model of reduced NMDA receptor function.
BACKGROUND
Reduced N-methyl D-aspartate (NMDA) receptor function is hypothesized to contribute to the pathophysiology of schizophrenia. In order to model chronic and developmental NMDA receptor hypofunction, a mouse line was developed that expresses low levels of the NMDA R1 (NR1) subunit of the NMDA receptor. These mice show increased acoustic startle reactivity and deficits in prepulse inhibition (PPI) of acoustic startle.


OBJECTIVE
The present study tested the hypothesis that these altered acoustic startle responses in the NR1 hypomorphic (NR1-/-) mice would be affected by antipsychotic drug treatment.


METHODS
Mice were injected with drugs 30 min before assessment of acoustic startle responses with and without prepulse stimuli.


RESULTS
Haloperidol (0.5 or 1.0 mg/kg) did not reduce the increased startle reactivity in the NR1-/- mice, but did increase PPI in both the mutant and wild type mice. Clozapine (3 mg/kg) and quetiapine (20 mg/kg) reduced startle magnitude and increased PPI in both the wild type and mutant mice. The antidepressant drug imipramine (10 and 20 mg/kg) had minimal effects on startle amplitude in NR1-/- or wild type mice. However, for the 20-mg/kg dose of imipramine, a significant increase in PPI was observed in the wild type animals, but not in the mutant mice.


CONCLUSIONS
The results demonstrate that PPI can be increased in a mouse model of chronic NMDA receptor hypofunction by typical and atypical antipsychotic drugs. The similar effects of typical and atypical antipsychotic drugs to increase PPI in the wild type and mutant mice indicates that the assessment of behavior of the NR1 hypomorphic mice in the PPI paradigm offers no advantage over the wild type controls for identifying new clozapine-like drugs.
Duncan
Gary E
GE
Department of Psychiatry, CB# 7090, University of North Carolina School of Medicine, Chapel Hill, NC, 27599-7090, USA. gduncan@med.unc.edu
Moy
Sheryl S
SS
Lieberman
Jeffery A
JA
Koller
Beverly H
BH
D000161:Acoustic Stimulation; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology*; D003987:Dibenzothiazepines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006220:Haloperidol / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006633:Histamine Antagonists / Q000494:pharmacology; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D000069348:Quetiapine Fumarate; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000502:physiology*; D013216:Reflex, Startle / Q000187:drug effects* / Q000235:genetics*; D012727:Sex Characteristics
D000929:Antidepressive Agents, Tricyclic; D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D006633:Histamine Antagonists; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D000069348:Quetiapine Fumarate; D003024:Clozapine; D006220:Haloperidol; D007099:Imipramine