F15063, a compound with D2/D3 antagonist, 5-HT 1A agonist and D4 partial agonist properties. III. Activity in models of cognition and negative symptoms.
OBJECTIVE
The D(2)/D(3) receptor antagonist, D(4) receptor partial agonist, and high efficacy 5-HT(1A) 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.


METHODS
F15063, given i.p., was assessed in models of behavioural deficits induced by interference with the NMDA/glutamatergic (phencyclidine: PCP) or cholinergic (scopolamine) systems.


RESULTS
Through 5-HT(1A) activation, F15063 partially alleviated (MED: 0.04 mg kg(-1)) 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(-1), F15063 reduced interaction by itself. F15063 (0.16 mg kg(-1)) selectively re-established PCP-impaired 'cognitive flexibility' in a reversal learning task, suggesting potential against adaptability deficits. F15063 (0.04-0.63 mg kg(-1)) 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 D(4) partial agonism, as it was blocked by the D(4) antagonist L745,870. Finally, F15063 up to 40 mg kg(-1) did not disrupt basal prepulse inhibition of startle reflex in rats, a marker of sensorimotor gating.


CONCLUSIONS
The balance of D(2)/D(3), D(4) and 5-HT(1A) receptor interactions of F15063 yields a promising profile of activity in models of cognitive deficits and negative symptoms of schizophrenia.
Depoortère
R
R
Division of Neurobiology 2, Centre de Recherche Pierre Fabre, Castres, France. ronan.depoortere@pierre-fabre.com
Auclair
A L
AL
Bardin
L
L
Bruins Slot
L
L
Kleven
M S
MS
Colpaert
F
F
Vacher
B
B
Newman-Tancredi
A
A
D000647:Amnesia / Q000503:physiopathology / Q000517:prevention & control; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001572:Benzofurans / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D003072:Cognition Disorders / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D003517:Cyclopentanes / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D008297:Male; D023421:Models, Animal; D010622:Phencyclidine; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors; D050638:Receptors, Dopamine D4 / Q000819:agonists; D012018:Reflex / Q000187:drug effects; D013216:Reflex, Startle / Q000187:drug effects; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D014150:Antipsychotic Agents; D001572:Benzofurans; D001596:Benzylamines; D003517:Cyclopentanes; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C518313:N-((2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)ethyl)-3-(cyclopent-1-enyl)benzylamine; D050637:Receptors, Dopamine D3; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D017366:Serotonin Receptor Agonists; D050638:Receptors, Dopamine D4; D010622:Phencyclidine