Sertindole improves sub-chronic PCP-induced reversal learning and episodic memory deficits in rodents: involvement of 5-HT(6) and 5-HT (2A) receptor mechanisms.
OBJECTIVE
This study examined the efficacy of sertindole in comparison with a selective 5-HT(6) and a 5-HT(2A) receptor antagonist to reverse sub-chronic phencyclidine (PCP)-induced cognitive deficits in female rats.


METHODS
In the first test, adult female hooded Lister rats were trained to perform an operant reversal learning task to 90% criterion. After training, rats were treated with PCP at 2 mg/kg (i.p.) or vehicle twice daily for 7 days, followed by 7 days washout. For the second test, novel object recognition (NOR), a separate batch of rats, had the same sub-chronic PCP dosing regime and washout period. In reversal learning, rats were treated acutely with sertindole, the selective 5-HT(2A) receptor antagonist M100.907 or the selective 5-HT(6) receptor antagonist SB-742457.


RESULTS
The PCP-induced selective reversal learning deficit was significantly improved by sertindole, M100.907 and SB-742457. Sertindole also significantly improved the sub-chronic PCP-induced deficit in NOR, a test of episodic memory following a 1 min and 1 h inter-trial interval. In vivo binding studies showed that the dose-response relationship for sertindole in this study most closely correlates with affinity for 5-HT(6) receptor in vivo binding in striatum, although contribution from binding to 5-HT(2A) receptors in vivo in cortex may also provide an important mechanism.


CONCLUSIONS
The efficacies of selective 5-HT(2A) and 5-HT(6) receptor antagonists suggest potential mechanisms mediating the effects of sertindole, which has high affinity for these 5-HT receptor subtypes. The sertindole-induced improvement in cognitive function in this animal model suggests relevance for the management of cognitive deficit symptoms in schizophrenia.
Idris
Nagi
N
Bradford School of Pharmacy, The University of Bradford, Bradford, West Yorkshire, BD7 1DP, UK.
Neill
Jo
J
Grayson
Ben
B
Bang-Andersen
Benny
B
Witten
Louise M
LM
Brennum
Lise Tøttrup
LT
Arnt
Jørn
J
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005464:Fluorobenzenes / Q000494:pharmacology; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy; D010622:Phencyclidine / Q000633:toxicity*; D010880:Piperidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D012193:Reversal Learning / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology; D013450:Sulfones / Q000494:pharmacology
C548140:3-benzenesulfonyl-8-piperazin-1-ylquinoline; D014150:Antipsychotic Agents; D005464:Fluorobenzenes; D007093:Imidazoles; D007211:Indoles; D010880:Piperidines; D011804:Quinolines; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D013450:Sulfones; C097216:serotonin 6 receptor; C079049:volinanserin; C066304:sertindole; D010622:Phencyclidine