Co-administration of 5-HT6 receptor antagonists with clozapine, risperidone, and a 5-HT2A receptor antagonist: effects on prepulse inhibition in rats

Psychopharmacology (Berl). 2014 Jan;231(1):269-81. doi: 10.1007/s00213-013-3234-2. Epub 2013 Aug 18.

Abstract

Rationale: Some novel antipsychotics manifest antagonistic activity at serotonin-6 receptors; however, little is known about the role of 5-HT6 receptors in ameliorating sensory gating deficits.

Objective: We evaluated the effects of the combined administration of the 5-HT6 receptor antagonist SB 271046 with clozapine and haloperidol, as well as the co-administration of SB 271046 or SB 399885 with risperidone and the 5-HT2A antagonist M100907, to overcome the deficits induced by MK-801 in the prepulse inhibition (PPI) test.

Results: MK-801 (0.1 mg/kg) produced reliable PPI deficits. Administration of SB 271046 (6 and 9 mg/kg), SB 399885 (3 and 6 mg/kg), clozapine (2.5 mg/kg), haloperidol (0.1 and 0.2 mg/kg), risperidone (0.25-1 mg/kg), and M100907 (0.5 and 1 mg/kg) did not affect the MK-801-induced deficits, but the administration of clozapine (5 mg/kg) did reverse the effects of MK-801. In MK-801-treated rats, the co-administration of inactive doses of clozapine (2.5 mg/kg) and SB 271046 (6 mg/kg) reversed the PPI impairments compared to animals that were administered inactive doses of either clozapine or SB 271046 alone. Co-administration of risperidone (1 mg/kg) or M100907 (0.5 mg/kg) with SB 271046 (6 mg/kg) or SB 399885 (3 mg/kg) also attenuated the MK-801-induced PPI deficits. In contrast, joint administration of haloperidol and SB 271046 had no effect on the PPI deficit.

Conclusion: The present results suggest that the 5-HT6 receptors may play adjunctive roles in antipsychotic drug action, and that the combination of 5-HT2A and 5-HT6 antagonism may represent an important element in the pharmacological profile of antipsychotic drugs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology*
  • Clozapine / pharmacology*
  • Data Interpretation, Statistical
  • Dizocilpine Maleate / pharmacology
  • Dopamine Antagonists / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Excitatory Amino Acid Antagonists / pharmacology
  • Fluorobenzenes / pharmacology
  • Haloperidol / pharmacology
  • Male
  • Piperazines / pharmacology
  • Piperidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Serotonin / drug effects*
  • Reflex, Startle / drug effects*
  • Risperidone / pharmacology*
  • Serotonin 5-HT2 Receptor Antagonists / pharmacology*
  • Serotonin Antagonists / pharmacology*
  • Sulfonamides / pharmacology
  • Thiophenes / pharmacology

Substances

  • Antipsychotic Agents
  • Dopamine Antagonists
  • Excitatory Amino Acid Antagonists
  • Fluorobenzenes
  • Piperazines
  • Piperidines
  • Receptors, Serotonin
  • SB 399885
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Antagonists
  • Sulfonamides
  • Thiophenes
  • serotonin 6 receptor
  • Dizocilpine Maleate
  • volinanserin
  • Clozapine
  • Haloperidol
  • SB 271046
  • Risperidone