Inactivation of the 5-HT(7) receptor partially blocks phencyclidine-induced disruption of prepulse inhibition

Biol Psychiatry. 2008 Jan 1;63(1):98-105. doi: 10.1016/j.biopsych.2006.12.011. Epub 2007 May 24.

Abstract

Background: Studies have implicated the serotonin (5-HT)(7) receptor in physiological and pathophysiological phenomena, including thermoregulation, central control of micturition and locomotion, regulation of circadian rhythm, sleep, and depression. Further, several antidepressant and antipsychotic drugs have high affinity for the 5-HT(7) receptor.

Methods: We examined the role of 5-HT(7) receptors in a rodent analogue of sensorimotor gating deficits in schizophrenia: phencyclidine (PCP)-induced disruption of prepulse inhibition (PPI) of acoustic startle. We used mice lacking the 5-HT(7) receptor due to a targeted inactivation of this receptor gene and the selective 5-HT(7) receptor antagonist SB-269970.

Results: SB-269970 did not affect either baseline PPI or PCP-disrupted PPI. There was no difference between 5-HT(7)(+/+) and 5-HT(7)(-/-) mice in startle reactivity or PPI regardless of prepulse intensity (74-82 dB), interstimulus interval (25-500 msec), or pulse intensity (90-120 dB). Nevertheless, disruption of PPI produced by PCP (10 mg/kg) in wild-type mice was reduced in 5-HT(7)(-/-) mice, although it was not affected by the 5-HT(7) antagonist SB-269970. By contrast, the PPI-disruptive effects of apomorphine (5 mg/kg) and amphetamine (7.5 mg/kg) were comparable in both genotypes.

Conclusions: The results indicate a partial role for the 5-HT(7) receptor in the glutamatergic PPI model of sensorimotor gating deficits in schizophrenia that is sensitive to atypical antipsychotics and no involvement of this receptor in the dopaminergic PPI model that is sensitive to typical antipsychotics. Thus, the 5-HT(7)(-/-) mice may provide a useful tool to study the role of 5-HT(7) receptor in the action of atypical antipsychotic drugs and schizophrenia.

Publication types

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

MeSH terms

  • Acoustic Stimulation / methods
  • Amphetamine / pharmacology
  • Analysis of Variance
  • Animals
  • Apomorphine / pharmacology
  • Behavior, Animal / drug effects
  • Dopamine Agonists / pharmacology
  • Dopamine Uptake Inhibitors / pharmacology
  • Dose-Response Relationship, Radiation
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neural Inhibition / drug effects*
  • Phencyclidine / pharmacology*
  • Phenols / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Serotonin / deficiency
  • Receptors, Serotonin / physiology*
  • Reflex, Startle / drug effects*
  • Serotonin Antagonists / pharmacology
  • Sulfonamides / pharmacology

Substances

  • Dopamine Agonists
  • Dopamine Uptake Inhibitors
  • Excitatory Amino Acid Antagonists
  • Phenols
  • Receptors, Serotonin
  • SB 269970
  • Serotonin Antagonists
  • Sulfonamides
  • Amphetamine
  • Phencyclidine
  • Apomorphine