Amphetamine-induced disruption of prepulse inhibition in mice with reduced NMDA receptor function.
Genetically altered mice with reductions in the NR1 subunit of the N-methyl-d-aspartate (NMDA) receptor have been proposed as a model for the intrinsic NMDA hypofunction hypothesized for schizophrenia. The following study investigated whether NR1-deficient mice have enhanced susceptibility for the effects of amphetamine, similar to the exaggerated responsivity to dopamine agonists observed in many schizophrenia patients. NR1-/- mice and wild-type controls were tested for the effects of amphetamine (2-10 mg/kg) on prepulse inhibition of acoustic startle responses. The results showed that mice with reduced NMDA receptor function demonstrated consistent deficits in prepulse inhibition (PPI), as well as higher startle response amplitudes. In comparison to normal controls, the NR1-/- mice were more sensitive to the disruptive effects of amphetamine on PPI, but not to the drug effects on startle magnitude without a prepulse stimulus. Wild-type mice only showed decreased PPI at the highest dose of amphetamine tested (10 mg/kg) and demonstrated small increases in PPI at lower amphetamine doses (2 and 6 mg/kg). The NR1-/- mice did not show enhanced PPI in response to amphetamine at low doses, with reductions in PPI apparent at doses of 4-10 mg/kg. Overall, these findings suggest that the NR1-/- mouse may provide a model for enhanced sensitivity to dopamine agonist-induced disruption of PPI.
Moy
Sheryl S
SS
Department of Psychiatry, and Neurodevelopmental Disorders Research Center, University of North Carolina at Chapel Hill, NC 27599, USA. ssmoy@med.unc.edu
Perez
Antonio
A
Koller
Beverly H
BH
Duncan
Gary E
GE
D000661:Amphetamine / Q000494:pharmacology*; D019969:Amphetamine-Related Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects* / Q000235:genetics; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000187:drug effects* / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D013216:Reflex, Startle / Q000187:drug effects / Q000235:genetics; D012727:Sex Characteristics
D015259:Dopamine Agents; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D000661:Amphetamine