Activation of α7 nicotinic receptors improves phencyclidine-induced deficits in cognitive tasks in rats: implications for therapy of cognitive dysfunction in schizophrenia.
BACKGROUND
Nicotinic α7 acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia.


OBJECTIVE
To investigate whether the deficits induced by sub-chronic phencyclidine (PCP) in reversal learning and novel object recognition could be attenuated by the selective α7 nAChR full agonist, PNU-282987.


METHODS
Adult female hooded-Lister rats received sub-chronic PCP (2mg/kg) or vehicle i.p. twice daily for 7days, followed by 7 days washout. In cohort 1, PCP-treated rats then received PNU-282987 (5, 10, 20mg/kg; s.c.) or vehicle and were tested in the reversal-learning task. In cohort 2, PCP-treated rats received PNU-282987 (10mg/kg; s.c.) or saline for 15days and were tested in the novel object recognition test on day 1 and on day 15, to test for tolerance.


RESULTS
Sub-chronic PCP produced significant deficits in both cognitive tasks (P<0.01-0.001). PNU-282987 attenuated the PCP-induced deficits in reversal learning at 10mg/kg (P<0.01) and 20mg/kg (P<0.001), and in novel object recognition at 10mg/kg on day 1 (P<0.01) and on day 15 (P<0.001).


CONCLUSIONS
These data show that PNU-282987 has efficacy to reverse PCP-induced deficits in two paradigms of relevance to schizophrenia. Results further suggest that 15-day once daily dosing of PNU-282987 (10mg/kg s.c.) does not cause tolerance in the rat. This study suggests that activation of α7 nAChRs, may represent a suitable strategy for improving cognitive deficits of relevance to schizophrenia.
McLean
Samantha L
SL
Bradford School of Pharmacy, The University of Bradford, Bradford, West Yorkshire, BD7 1DP, UK. j.c.neill@bradford.ac.uk
Grayson
Ben
B
Idris
Nagi F
NF
Lesage
Anne S
AS
Pemberton
Darrel J
DJ
Mackie
Claire
C
Neill
Jo C
JC
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D006207:Half-Life; D007858:Learning / Q000187:drug effects; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010622:Phencyclidine / Q000633:toxicity*; D011897:Random Allocation; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012193:Reversal Learning / Q000187:drug effects; D012559:Schizophrenia / Q000503:physiopathology*; D013618:Tachyphylaxis; D064569:alpha7 Nicotinic Acetylcholine Receptor
D001549:Benzamides; D001643:Bridged Bicyclo Compounds; C579165:Chrna7 protein, rat; D018691:Excitatory Amino Acid Antagonists; D018722:Nicotinic Agonists; C498513:PNU-282987; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D010622:Phencyclidine