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


OBJECTIVE
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.


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
Psychiatry CEDD, GlaxoSmithKline, Third Avenue, Harlow, CM19 5AW, UK. Jackie.2.Cilia@gsk.com
Jackie
J
Cilia
Jane E
JE
Cluderay
Melanie J
MJ
Robbins
Charlie
C
Reavill
Eric
E
Southam
James N C
JN
Kew
Declan N C
DN
Jones
D000157:Aconitine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D002038:Bungarotoxins / Q000378:metabolism; D008297:Male; D018722:Nicotinic Agonists / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011978:Receptors, Nicotinic / Q000235:genetics / Q000502:physiology*; D013216:Reflex, Startle / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012934:Social Isolation; D064569:alpha7 Nicotinic Acetylcholine Receptor
D002038:Bungarotoxins; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C054634:methyllycaconitine; D000157:Aconitine