Differential effects of 5-HT1B/1D receptor antagonists in dorsal and median raphe innervated brain regions.
The effect of SB-224289 (2,3,6.7-tetrahydro-1'-methyl-5-¿2'-methyl-4'-[(5-methyl-1,2,4-oxadiazol e-3-yl)biphenyl-4-yl]carbonyl¿Furo[2,3-F]-indole-3-spiro-4'-piperidine oxalate) (4 mg/kg i.p., 5-HT1B receptor antagonist), GR 127935 (N-[4-methoxy-3-(4-methyl-1-piperizinyl)phenyl]-2'-methyl-4'-(5-me thyl-1,2,4-oxadiazole-3-yl)[1,1'-biphenyl]-carboxamide) (0.3 mg/kg i.p., 5-HT1B/1D receptor antagonist), and paroxetine (10 mg/kg p.o.) were investigated on extracellular 5-hydroxytryptamine (5-HT) levels in the frontal cortex, striatum and dentate gyrus of the freely moving guinea-pig with microdialysis. In the frontal cortex and striatum (dorsal raphe innervated areas), GR 127935 evoked a significant decrease in extracellular 5-HT, reaching minima of 41+/-12% and 32+/-6% of basal, respectively. This decrease may be explained by antagonism of inhibitory 5-HT1B/1D receptors on raphe cell bodies, leading to a local increase in 5-HT, which, in turn, stimulated 5-HT1A receptors to decrease cell firing, and hence 5-HT release from terminals. In contrast, SB-224289 had no effect on 5-HT levels in either region. In the dentate gyrus (median raphe innervated area), GR 127935 and SB-224289 significantly increased extracellular 5-HT, reaching maxima of 146+/-11% and 151+/-19% of basal, respectively. The ability of both compounds to increase 5-HT levels in the dentate gyrus suggests a lack of 5-HT1B/1D receptors in the median raphe nucleus. Paroxetine produced a small but non-significant increase in extracellular 5-HT in the frontal cortex, and a small decrease in the dentate gyrus. The lack of effect of paroxetine in terminal areas may be due to the limiting effects of cell body 5-HT autoreceptors. In summary, the above data demonstrate that 5-HT1B/1D receptor antagonists increase 5-HT levels in the dentate gyrus, implying that acute administration of 5-HT1B/1D receptor antagonists will achieve a similar effect to chronic selective serotonin re-uptake inhibitor treatment in median raphe innervated areas. This, in turn, suggests that such compounds may be efficacious in the treatment of depression.
Roberts
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SmithKline Beecham Pharmaceuticals, Department of of Neuroscience, New Frontiers Science Park, Harlow, Essex, UK. claire_roberts-1@sbphrd.com@inet
Belenguer
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Middlemiss
D N
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Routledge
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C
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D001921:Brain / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D018891:Dentate Gyrus / Q000187:drug effects / Q000502:physiology; D004563:Electrochemistry; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D008297:Male; D017551:Microdialysis; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D017374:Paroxetine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010881:Piperidones / Q000494:pharmacology; D011903:Raphe Nuclei / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology
D018687:Antidepressive Agents, Second-Generation; D010069:Oxadiazoles; D010879:Piperazines; D010881:Piperidones; C108518:SB 22489G; D012702:Serotonin Antagonists; D013141:Spiro Compounds; C090701:GR 127935; D017374:Paroxetine