8-OH-DPAT disruption of prepulse inhibition in rats: reversal with (+)WAY 100,135 and localization of site of action.
Recent studies have implicated central serotonergic systems in the modulation of prepulse inhibition (PPI), an operational measure of sensorimotor gating, which has been used to identify gating deficits in psychiatric disorders, such as schizophrenia, Huntington's disease, and obsessive compulsive disorder. Both serotonin (5-HT) releasers and agonists at 5-HT1A, 5-HT1B, and 5-HT2 receptors reduce PPI in the rat. The present experiments demonstrate that the disruption of PPI in rats induced by the systemic administration of the 5-HT1A agonist, 8-OH-DPAT (8-hydroxy-2(di-n-propylamino)tetralin; 0.2 mg/kg), can be attenuated by the novel, selective 5-HT1A antagonist (+)WAY 100,135, (20.0 mg/kg), N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenyl-propa namide. Further experiments addressing the central site of action of 8-OH-DPAT revealed that the microinjection of 8-OH-DPAT (5.0 micrograms/0.5 microliter) into either the median raphe nucleus (MR) or dorsal raphe nucleus (DR) disrupts PPI. The reduction in PPI produced by intra-raphe microinjections of 8-OH-DPAT was prevented by a systemic injection of (+)WAY 100,135. These results support the hypothesis that somatodendritic 5-HT1A autoreceptors within the midbrain raphe subserve the PPI-disruptive effects of systemically administered 8-OH-DPAT. The decrement in PPI after intra-raphe infusions of a high dose of 8-OH-DPAT, however, was substantially less than the decrement in PPI after systemic administration of the drug. Hence, sites in addition to the somatodendritic autoreceptors may also play an important role in 8-OH-DPAT-induced disruption of PPI.(ABSTRACT TRUNCATED AT 250 WORDS)
Sipes
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TA
Department of Neuroscience, University of California at San Diego, La Jolla 92093-0804, USA.
Geyer
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MA
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008845:Microinjections; D010879:Piperazines / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*
D010879:Piperazines; D012702:Serotonin Antagonists; C081293:WAY 100135; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin