Long-term effects of neurotoxic NMDA receptor antagonism and muscarinic activation on auditory gating and nicotinic receptor regulation in rats: Implications for models of schizophrenia.

摘要

N-methyl-d-aspartate (NMDA) receptor antagonists have been used to model schizophrenia, as measured by impairment in pre-pulse inhibition (PPI) of the acoustic startle response. The usefulness of this model, however, is limited by interaction of the NMDA and cholinergic systems. To determine the distribution and regulation by nicotine of the alpha7 receptor, osmotic mini-pumps delivering saline or 6mg/kg/day nicotine were implanted in male rats for 14 days. Upregulation by nicotine was found in 26 of 52 regions examined, including cortical, hippocampal and thalamic areas. To determine the long-term effects of developmental phencyclidine (PCP) treatment on auditory gating, male and female Sprague Dawley rats were injected with PCP (10 mg/kg s.c.) on postnatal days (PN) 7, 9 & 11. The groups were later divided and some of the animals received a single dose of PCP (10mg/kg s.c) on PN 45. There were no significant effects of adolescent only treatment. One week after the PN 45 treatment, animals that had been treated as neonates and as adolescents (PCP/PCP) were significantly impaired in PPI in both sexes. These groups also had significant increases in acoustic startle response (ASR) three weeks post-treatment, which subsequently declined. PPI ability in both sexes recovered over time; adolescent only treated females showed significant overcompensation. To determine the effects of NMDA receptor antagonism with muscarinic activation on auditory gating and nicotinic receptor regulation, adult female Sprague-Dawley rats were given MK-801 (5mg/kg) with pilocarpine (5mg/kg) followed by another dose of pilocarpine (5mg/kg) one hour later. The drug regimen was repeated 4 and 8 days later. Ten and 17 days after the last neurotoxic treatment, rats were significantly impaired in PPI. Some of the treated rats were administered nicotine (0.5mg (free base)/kg) twice daily from day 10 to 24 (Tx/Nic). Twenty-two days after the last neurotoxic treatment Tx/Nic rats showed a nicotine-inducible impairment in PPI. Homogenate binding studies showed that nicotine but not neurotoxic treatment caused upregulation of high-affinity nicotinic receptors in the cortex. Upregulation by nicotine or neurotoxic treatment of the alpha7 receptor was found in the hippocampus, an effect that was mitigated by combined administration of the treatments.