Reversal of isolation-rearing-induced PPI deficits by an alpha7 nicotinic receptor agonist

• Published in: Psychopharmacology 2005-10, Vol.182 (2), p.214-219
• Main Authors: Cilia, Jackie, Cluderay, Jane E, Robbins, Melanie J, Reavill, Charlie, Southam, Eric, Kew, James N C, Jones, Declan N C
• Format: Article
• Language: English
• Subjects: Aconitine - analogs & derivatives; Aconitine - metabolism; alpha7 Nicotinic Acetylcholine Receptor; Animals; Bungarotoxins - metabolism; Male; Nicotinic Agonists - pharmacology; Rats; Receptors, Nicotinic - genetics; Receptors, Nicotinic - physiology; Reflex, Startle - drug effects; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; Social Isolation
• ISSN: 0033-3158

The alpha7 subtype of the nicotinic receptor plays an important role in auditory sensory gating. Schizophrenics show deficient sensory gating and abnormalities in the number and regulation of nicotinic receptors. Prepulse inhibition (PPI) deficits exhibited by isolation-reared rats are thought to model the sensorimotor gating deficits seen in schizophrenia. To examine the role of nicotinic alpha7 receptors in the isolation-rearing rat model, we tested whether the selective alpha7 receptor agonist (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide) (compound A) could reverse isolation-rearing-induced PPI deficits, and investigated alpha7 receptor RNA expression in the hippocampus, prefrontal cortex, cerebellum, nucleus accumbens and thalamus, and alpha7 receptor protein expression in the hippocampus of isolation- and group-reared rats. Rats reared in isolation or groups of five from weaning were tested in the PPI paradigm under conditions of variable inter-stimulus interval (ISI) (pulse = 110 dB/50 ms; prepulse = 75 dB/30 ms; ISI = 30, 100 and 300 ms) 30 min following administration of compound A (3.2-10 mg/kg i.p.). Alpha7 receptor expression was measured by TaqMan RT-PCR (total RNA) and autoradiography (protein). Isolation-rearing-induced PPI deficits were attenuated by both doses of compound A at 100-ms ISI and by 10 mg/kg at 300-ms ISI. Expression of alpha7 receptor RNA and protein was unaltered in isolation-reared rats. Although altered alpha7 receptor expression may not underlie the phenotype of isolation-reared rats, the activation of these receptors may be of benefit in re-establishing efficient gating function.