Prepulse Inhibition Deficits in the Neonatal Quinpirole Model of Schizophrenia: Epigenetic Evidence and Sex Differences
Neonatal quinpirole (QUIN; dopamine D2/D3 agonist) administered from postnatal days (P)1-21 results in an increase of dopamine D2 receptor sensitivity, similar to schizophrenia and is now an established rodent model of schizophrenia. The day after birth, male and female Sprague-Dawley rats were given a daily 1 mg/kg injection of either QUIN or saline from P1-21. One subset of these animals were behaviorally tested on PPI, referred to as first generation (F0). A different subset of animals were allowed to reach adult age (P60) and female and male QUIN-treated pairs from separate litters were bred. Their offspring were also used as subjects (F1 generation). Prepulse inhibition (PPI) is a measure of sensorimotor gating reduced in individuals diagnosed with schizophrenia. Trial types were defined as prepulse trials (73, 76, 82dB), startle stimuli trials (120 dB), or no stimulus (70 dB white noise; no prepulse or pulse). Animals were tested for six consecutive days and given an ip saline injection 10 min before testing, followed by testing for another six consecutive days and given an ip nicotine (0.5 mg/kg free base) or saline injection 10 min before testing. PPI testing for F0 generation animals occurred between P35-46, and testing for F1 generation animals occurred between P44-55. In one subset of generation F1 animals, rats were ip injected with a 0.1 mg/kg dose of quinpirole and immediately observed for 60 min and the number of yawns were recorded at P60. Yawning is a behavioral event mediated by the dopamine D2 receptor. Results revealed that neonatal QUIN resulted in PPI deficits throughout the six days of testing in the F0 generation regardless of the prepulse stimulus, but females demonstrated a less robust PPI deficit as compared to males. Nicotine given during the final 6 days of testing partially alleviated the PPI deficits in both males and females. The F1 generation also demonstrated PPI deficits, but the impairment was only in males and dissipated by day 6. Nicotine did not affect PPI in these animals. Finally, F1 generation rats demonstrated a robust increase in yawning compared to controls, demonstrating an increase in D2 receptor sensitivity. Brain tissue is being analyzed for changes in the dopamine D2 receptor signaling pathway.
Gill, Wesley D.; Wherry, J. D.; Burgess, Katherine C.; and Brown, Russell W.. 2016. Prepulse Inhibition Deficits in the Neonatal Quinpirole Model of Schizophrenia: Epigenetic Evidence and Sex Differences. Poster presentation. Society for Neuroscience Conference, Washington, DC. http://www.abstractsonline.com/pp8/#!/4071/presentation/24232