title: Effects of novel antipsychotics with mixed D(2) antagonist/5-HT(1A) agonist properties on PCP-induced social interaction deficits in the rat.
abstract: Considerable interest has arisen in identifying antipsychotic agents with improved efficacy against negative symptoms, such as social withdrawal. In rats, a social interaction deficit can be induced by the NMDA antagonist phencyclidine (PCP). Here, we examined the effects of antipsychotics, reported to exert dual 5-HT(1A)/D(2) actions, on PCP-induced social interaction deficits. Drugs were administered daily for 3 days in combination with either vehicle or PCP (2.5mg/kg, SC) and social interaction was measured on the last day of drug treatment. Pairs of unfamiliar rats receiving the same treatment were placed in a large open field for 10 min and the number of social behaviors were scored. The results indicate that: (1) PCP significantly reduced social interaction by over 50% compared with vehicle-treated controls; (2) haloperidol (0.0025-0.16 mg/kg, SC) and clozapine (0.04-10mg/kg, IP) did not reverse PCP-induced social interaction deficits; (3) the substituted benzamide remoxipride reversed PCP-induced deficits at 0.63 and 2.5mg/kg (4) the 5-HT(1A) agonist 8-OH-DPAT was inactive (at 0.01-0.63 mg/kg, SC); (5) among compounds reported to exert dual 5-HT(1A)/D(2) actions, SSR181507 (at 0.16 mg/kg, SC) and aripiprazole (at 0.04 and 0.16 mg/kg, IP), but not ziprasidone (0.04-2.5mg/kg, IP), SLV313 (0.0025-0.16 mg/kg, SC) or bifeprunox (0.01-0.63 mg/kg, IP), significantly reversed PCP-induced social interaction deficits; and (6) the 5-HT(1A) receptor antagonist WAY100635 blocked the effects of SSR181507 and aripiprazole. These findings indicate that the balance of activity at 5-HT(1A) and D(2) receptors profoundly influences the activity of antipsychotics in this model of social withdrawal, and their potential benefit on at least some of the negative symptoms of schizophrenia.
authors: Department of Cellular and Molecular Biology, Centre de Recherche Pierre Fabre, 17, Avenue Jean Moulin, F 81106 Castres Cedex, France. liesbeth.bruins.slot@pierre-fabre.com
authors: Liesbeth A
authors: LA
authors: Bruins Slot
authors: Mark S
authors: MS
authors: Kleven
authors: Adrian
authors: A
authors: Newman-Tancredi
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D003024:Clozapine / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D007398:Interpersonal Relations; D008297:Male; D010622:Phencyclidine / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects*; D017330:Remoxipride / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology; D014326:Tropanes / Q000494:pharmacology
chemical_list: 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; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D011725:Pyridines; D015363:Quinolones; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013844:Thiazoles; D014326:Tropanes; D017330:Remoxipride; D044282:Receptor, Serotonin, 5-HT1A; C092292:ziprasidone; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000068180:Aripiprazole; D010622:Phencyclidine; D003024:Clozapine; D006220:Haloperidol