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Received for publication September 1, 2004.
Revised October 18, 2004.
Accepted for publication October 18, 2004.
7 Nicotinic Acetylcholine Receptor
Agonist PNU-282987 Enhances GABAergic Synaptic Activity
in Brain Slices and Restores Auditory Gating Deficits in
Anesthetized Rats
Schizophrenic patients are thought to have an impaired
ability to process sensory information. This deficit
leads to disrupted auditory gating measured
electrophysiologically as a reduced suppression of the
second of paired auditory-evoked responses (P50), and is
proposed to be associated with decreased function and/or
expression of the homomeric 
7 nicotinic acetylcholine
receptor (nAChR). Here we provide evidence that N-[(3R)-
1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide
hydrochloride (PNU-282987), a novel selective agonist of
the 7 nAChR, evoked whole cell currents from cultured
rat hippocampal neurons that were sensitive to the
selective 7 nAChR antagonist methyllycaconitine (MLA),
and enhanced GABAergic synaptic activity when applied to
hippocampal slices. Amphetamine-induced sensory gating
deficit, determined by auditory evoked potentials in
hippocampal CA3 region, was restored by systemic
administration of PNU-282987 in chloral hydrate
anaesthetized rats. Auditory gating of rat reticular
thalamic neurons was also disrupted by amphetamine,
however PNU-282987 normalized gating deficit only in a
subset of tested neurons (6 out of 11). Furthermore,
PNU-282987 improved the inherent hippocampal gating
deficit occurring in a subpopulation of anaesthetized
rats, and enhanced amphetamine-induced hippocampal theta
oscillation. We propose, that the 7 nAChR agonist PNU-
282987, via modulating/enhancing hippocampal GABAergic
neurotransmission, improves auditory gating and enhances
hippocampal oscillatory activity. These results provide
further support for the concept that drugs that
selectively activate 7 nAChRs may offer a novel,
potential pharmacotherapy in treatment of schizophrenia.
Key words:
EEG, auditory gating, hippocampus, nicotinic receptors, schizophrenia, theta
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