Abstract | RATIONALE: OBJECTIVES: We report the in vivo characterization of the novel 5-HT(1A/1B) autoreceptor antagonist/5-HT transporter inhibitor (6-[(1-{2-[(2-methyl-5-quinolinyl)oxy]ethyl}-4-piperidinyl)methyl]-2H-1,4-benzoxazin-3(4H)-one), SB-649915-B. MATERIALS AND METHODS: Ex vivo binding was used to ascertain 5-HT(1A) receptor and serotonin transporter occupancy. 8-OH-DPAT-induced hyperlocomotion and SKF-99101-induced elevation of seizure threshold were used as markers of central blockade of 5-HT(1A) and 5-HT(1B) receptors, respectively. In vivo electrophysiology in the rat dorsal raphe and microdialysis in freely moving guinea pigs and rats were used to evaluate the functional outcome of SB-649915-B. RESULTS: SB-649915-B (1-10 mg/kg p.o.) produced a dose-related inhibition of 5-HT(1A) receptor radioligand binding and inhibited ex vivo [(3)H]5-HT uptake in both guinea pig and rat cortex. SB-649915-B (0.1-10 mg/kg p.o.) reversed both 8-OH-DPAT-induced hyperlocomotor activity and SKF-99101-induced elevation of seizure threshold in the rat, demonstrating in vivo blockade of both 5-HT(1A) and 5-HT(1B) receptors, respectively. SB-649915-B (0.1-3 mg/kg i.v.) produced no change in raphe 5-HT neuronal cell firing per se but attenuated the inhibitory effect of 8-OH-DPAT. Acute administration of SB-649915-B resulted in increases (approximately two- to threefold) in extracellular 5-HT in the cortex of rats and the dentate gyrus and cortex of guinea pigs. CONCLUSIONS:
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Authors | Zoë A Hughes, Kathryn R Starr, Claire M Scott, Michael J Newson, Trevor Sharp, Jeannette M Watson, Jim J Hagan, Lee A Dawson |
Journal | Psychopharmacology
(Psychopharmacology (Berl))
Vol. 192
Issue 1
Pg. 121-33
(May 2007)
ISSN: 0033-3158 [Print] Germany |
PMID | 17265079
(Publication Type: Journal Article)
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Chemical References |
- Benzoxazines
- Piperidines
- Quinolines
- SB-649915
- Serotonin 5-HT1 Receptor Antagonists
- Serotonin Plasma Membrane Transport Proteins
- Serotonin Uptake Inhibitors
- Serotonin
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Topics |
- Animals
- Benzoxazines
(pharmacology)
- Dentate Gyrus
(drug effects, metabolism)
- Dose-Response Relationship, Drug
- Electrophysiology
- Electroshock
- Guinea Pigs
- Locomotion
(drug effects)
- Male
- Microdialysis
- Mood Disorders
(drug therapy)
- Neurons
(drug effects)
- Piperidines
(pharmacology)
- Prefrontal Cortex
(drug effects, metabolism)
- Quinolines
(pharmacology)
- Radioligand Assay
- Raphe Nuclei
- Rats
- Rats, Sprague-Dawley
- Seizures
- Serotonin
(metabolism)
- Serotonin 5-HT1 Receptor Antagonists
- Serotonin Plasma Membrane Transport Proteins
(drug effects, metabolism)
- Selective Serotonin Reuptake Inhibitors
(pharmacology)
- Species Specificity
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