title: Nicotine receptors mediating sensorimotor gating and its enhancement by systemic nicotine.
abstract: Prepulse inhibition (PPI) of startle occurs when intensity stimuli precede stronger startle-inducing stimuli by 10-1000 ms. PPI deficits are found in individuals with schizophrenia and other psychiatric disorders, and they correlate with other cognitive impairments. Animal research and clinical studies have demonstrated that both PPI and cognitive function can be enhanced by nicotine. PPI has been shown to be mediated, at least in part, by mesopontine cholinergic neurons that project to pontine startle neurons and activate muscarinic and potentially nicotine receptors (nAChRs). The subtypes and anatomical location of nAChRs involved in mediating and modulating PPI remain unresolved. We tested the hypothesis that nAChRs that are expressed by pontine startle neurons contribute to PPI. We also explored whether or not these pontine receptors are responsible for the nicotine enhancement of PPI. While systemic administration of nAChR antagonists had limited effects on PPI, PnC microinfusions of the non-α7nAChR preferring antagonist TMPH, but not of the α7nAChR antagonist MLA, into the PnC significantly reduced PPI. Electrophysiological recordings from startle-mediating PnC neurons confirmed that nicotine affects excitability of PnC neurons, which could be antagonized by TMPH, but not by MLA, indicating the expression of non-α7nAChR. In contrast, systemic nicotine enhancement of PPI was only reversed by systemic MLA and not by TMPH or local microinfusions of MLA into the PnC. In summary, our data indicate that non-α7nAChRs in the PnC contribute to PPI at stimulus intervals of 100 ms or less, whereas activation of α7nAChRs in other brain areas is responsible for the systemic nicotine enhancement of PPI. This is important knowledge for the correct interpretation of behavioral, preclinical, and clinical data as well as for developing drugs for the amelioration of PPI deficits and the enhancement of cognitive function.
authors.affiliation: Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario London, ON, Canada.
authors.forename: Farena
authors.initials: F
authors.lastname: Pinnock
authors.affiliation: Department of Psychology, University of Toronto Toronto, ON, Canada ; Hertie Institute for Clinical Brain Research, Eberhard-Karls-Universität Tübingen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bosch
authors.affiliation: Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario London, ON, Canada.
authors.forename: Tyler
authors.initials: T
authors.lastname: Brown
authors.affiliation: Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario London, ON, Canada.
authors.forename: Nadine
authors.initials: N
authors.lastname: Simons
authors.affiliation: Department of Psychology, University of Toronto Toronto, ON, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Yeomans
authors.affiliation: Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario London, ON, Canada.
authors.forename: Cleusa
authors.initials: C
authors.lastname: DeOliveira
authors.affiliation: Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario London, ON, Canada ; Department of Psychology, University of Toronto Toronto, ON, Canada.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schmid
keywords: alpha-7 nicotine receptor; nicotine receptor; prepulse inhibition; rat; schizophrenia; sensorimotor gating; sensory gating; startle