benzofurans and Amnesia

Topics: Amnesia; Animals; Benzofurans; Biological Products; Cholinergic Antagonists; Male; Maze Learning; Mice; Neuroprotective Agents; Oxidative Stress; Scopolamine

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

Topics: Amnesia; Animals; Antipsychotic Agents; Behavior, Animal; Benzofurans; Benzylamines; Cognition Disorders; Cyclopentanes; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Male; Models, Animal; Phencyclidine; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D3; Receptors, Dopamine D4; Reflex; Reflex, Startle; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Serotonin Receptor Agonists

The effects of the administration of metoclopramide, cisapride and SR-17 on memory processes were evaluated in the mouse passive avoidance test. The administration of dicyclomine (0.1-3 mg kg-1 i.p.), immediately after termination of the training session, produced a dose-dependent amnesic effect. Metoclopramide (1-5 mg kg-1 i.p.), cisapride (0.5-2 mg kg-1 i.p.) and SR-17 (1-10 mg kg-1 i.p.), administered 20 min before the training session, prevented dicyclomine-induced amnesia. In the same experimental conditions piracetam (30 mg kg-1 i.p.), physostigmine (0.2 mg kg-1 i.p.) and CGP 35348 (100 mg kg-1 i.p.) prevented dicyclomine amnesia. At the highest effective doses, none of the drugs impaired motor coordination, as revealed by the rota-rod test, nor did they modify spontaneous motility, as revealed by the Animex test. These results suggest that metoclopramide, cisapride and SR-17 play an important role in the modulation of memory processes. On these bases, these compounds could be useful in the treatment of cognitive deficits.

Topics: Amnesia; Animals; Avoidance Learning; Behavior, Animal; Benzofurans; Bridged Bicyclo Compounds; Cisapride; Dicyclomine; Dopamine Antagonists; Dose-Response Relationship, Drug; Male; Memory; Metoclopramide; Mice; Motor Activity; Muscarinic Antagonists; Piperidines; Serotonin Antagonists; Serotonin Receptor Agonists