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.
Bradford School of Pharmacy, The University of Bradford, Bradford, West Yorkshire, BD7 1DP, UK.
Nagi
N
Idris
Jo
J
Neill
Ben
B
Grayson
Benny
B
Bang-Andersen
Louise M
LM
Witten
Lise Tøttrup
LT
Brennum
Jørn
J
Arnt
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