SSR181507, a putative atypical antipsychotic with dopamine D2 antagonist and 5-HT1A agonist activities: improvement of social interaction deficits induced by phencyclidine in rats.
Social behaviour is frequently impaired in schizophrenic patients, and current antipsychotics appear poorly effective in alleviating this deficit. SSR181507 is a selective dopamine D2 receptor antagonist and 5-HT1A receptor agonist [Neuropsychopharmacology 28 (2003) 2064] with an atypical antipsychotic profile and additional antidepressant/anxiolytic activities [Neuropsychopharmacology 28 (2003) 1889]. Here, we sought to assess the efficacy of SSR181507, and of reference antipsychotics and antidepressant/anxiolytics, to counteract phencyclidine (PCP)-induced social interaction deficit in rats. Pairs of unfamiliar rats were placed for 10 min each day into a dimly lit arena, during four consecutive days. On the test day (5th day), each pair was placed into the arena 30 min after i.p. treatment with PCP (or vehicle) and a challenge compound or vehicle (same for both rats, i.p. or s.c.). The time spent in social interaction was scored during 10 min. PCP (1 mg/kg) decreased social interaction time by about 35%. This effect was fully antagonized by pre-treatment with SSR181507 (1 mg/kg). In contrast, neither haloperidol (0.05 and 0.1 mg/kg) nor clozapine (0.3 and 1 mg/kg) antagonized this PCP-induced deficit. The selective 5-HT1A receptor agonist 8-OH-DPAT (0.025 and 0.05 mg/kg s.c.), but not the anxiolytic diazepam (0.75 and 1.5 mg/kg), also improved social interaction impairment in PCP-treated rats: this would indicate that the 5-HT1A receptor agonist properties of SSR181507 are responsible for the reversal of PCP-induced social deficit. These data suggest that, in addition to its atypical antipsychotic profile and antidepressant/anxiolytic activities, SSR181507 has a potential therapeutic activity in another key feature of schizophrenia poorly controlled by current antipsychotics, namely deterioration in social functioning.
Boulay
D
D
CNS Department, Sanofi-Synthelabo Recherche, Discovery Research, 31 Ave P. Vaillant-Couturier, 92220 Bagneux, France. denis.boulay@sanofi-synthelabo.com
Depoortère
R
R
Louis
C
C
Perrault
G
G
Griebel
G
G
Soubrié
P
P
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D007398:Interpersonal Relations; D008297:Male; D010622:Phencyclidine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000502:physiology; D058825:Serotonin 5-HT1 Receptor Agonists; D012919:Social Behavior; D014326:Tropanes / Q000494:pharmacology*
C480819:(3-exo)-8-benzoyl-N-(((2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine monohydrochloride; D014150:Antipsychotic Agents; D004146:Dioxanes; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D058825:Serotonin 5-HT1 Receptor Agonists; D014326:Tropanes; D044282:Receptor, Serotonin, 5-HT1A; D010622:Phencyclidine