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: Liesbeth A Bruins Slot, Mark S Kleven, Adrian Newman-Tancredi
• Journal: Neuropharmacology (Neuropharmacology) Vol. 49 Issue 7 Pg. 996-1006 (Dec 2005) ISSN: 0028-3908 [Print] England
• PMID: 16009387 (Publication Type: Journal Article)

Chemical References

• (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
• Antipsychotic Agents
• Dioxanes
• Dopamine Antagonists
• Dopamine D2 Receptor Antagonists
• Excitatory Amino Acid Antagonists
• Piperazines
• Pyridines
• Quinolones
• Serotonin Antagonists
• Serotonin Receptor Agonists
• Thiazoles
• Tropanes
• Remoxipride
• Receptor, Serotonin, 5-HT1A
• ziprasidone
• N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
• 8-Hydroxy-2-(di-n-propylamino)tetralin
• Aripiprazole
• Phencyclidine
• Clozapine
• Haloperidol

Topics

• 8-Hydroxy-2-(di-n-propylamino)tetralin (pharmacology)
• Animals
• Antipsychotic Agents (pharmacology)
• Aripiprazole
• Clozapine (pharmacology)
• Dioxanes (pharmacology)
• Dopamine Antagonists (pharmacology)
• Dopamine D2 Receptor Antagonists
• Excitatory Amino Acid Antagonists (pharmacology)
• Haloperidol (pharmacology)
• Interpersonal Relations
• Male
• Phencyclidine (pharmacology)
• Piperazines (pharmacology)
• Pyridines (pharmacology)
• Quinolones (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptor, Serotonin, 5-HT1A (drug effects)
• Remoxipride (pharmacology)
• Serotonin Antagonists (pharmacology)
• Serotonin Receptor Agonists (pharmacology)
• Thiazoles (pharmacology)
• Tropanes (pharmacology)