Inactivation of the 5-HT(7) receptor partially blocks phencyclidine-induced disruption of prepulse inhibition.
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.
Semenova
Svetlana
S
Department of Psychiatry, University of California, San Diego, USA.
Geyer
Mark A
MA
Sutcliffe
J Gregor
JG
Markou
Athina
A
Hedlund
Peter B
PB
D000161:Acoustic Stimulation / Q000379:methods; D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D018491:Dopamine Agonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000187:drug effects*; D010622:Phencyclidine / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000172:deficiency / Q000502:physiology*; D013216:Reflex, Startle / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D018691:Excitatory Amino Acid Antagonists; D010636:Phenols; D011985:Receptors, Serotonin; C404922:SB 269970; D012702:Serotonin Antagonists; D013449:Sulfonamides; D000661:Amphetamine; D010622:Phencyclidine; D001058:Apomorphine