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F15063, a compound with D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties. III. Activity in models of cognition and negative symptoms. PDF

Depoortère R, Auclair AL, Bardin L, Bruins Slot L, Kleven MS, Colpaert F, Vacher B, Newman-Tancredi A.
Br J Pharmacol. 2007 May;151(2):266-77. Epub 2007 Mar 20.

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BACKGROUND AND PURPOSE: The D2/D3 receptor antagonist, D4 receptor partial agonist, and high efficacy 5-HT1A receptor agonist F15063 was shown to be highly efficacious and potent in rodent models of activity against positive symptoms of schizophrenia. However F15063 induced neither catalepsy nor the 'serotonin syndrome'. Here, we evaluated its profile in rat models predictive of efficacy against negative symptoms/cognitive deficits of schizophrenia. EXPERIMENTAL APPROACH: F15063, given i.p., was assessed in models of behavioural deficits induced by interference with the NMDA/glutamatergic (phencyclidine: PCP) or cholinergic (scopolamine) systems. KEY RESULTS: Through 5-HT1A activation, F15063 partially alleviated (MED: 0.04 mg/kg) PCP-induced social interaction deficit between two adult rats, without effect by itself, underlining its potential to combat negative symptoms. At doses above 0.16 mg/kg, F15063 reduced interaction by itself. F15063 (0.16 mg/kg) selectively re-established PCP-impaired 'cognitive flexibility' in a reversal learning task, suggesting potential against adaptability deficits. F15063 (0.04-0.63 mg/kg) also reversed scopolamine-induced amnesia in a juvenile-adult rat social recognition test, indicative of a pro-cholinergic influence. Activity in this latter test is consistent with its D4 partial agonism, as it was blocked by the D4 antagonist L745,870. Finally, F15063 up to 40 mg/kg did not disrupt basal prepulse inhibition of startle reflex in rats, a marker of sensorimotor gating. CONCLUSIONS AND IMPLICATIONS: The balance of D2/D3, D4 and 5-HT1A receptor interactions of F15063 yields a promising profile of activity in models of cognitive deficits and negative symptoms of schizophrenia.