Differential effects of 5-HT 1B/1D receptor antagonists in dorsal and median raphe innervated brain regions

Abstract

The effect of SB-224289 (2,3,6,7-tetrahydro-1′-methyl-5-{2′-methyl-4′-[(5-methyl-1,2,4-oxadiazole-3-yl)biphenyl-4-yl]carbonyl}Furo[2,3-F]-indole-3-spiro-4′-piperidine oxalate) (4 mg/kg i.p., 5-HT 1B receptor antagonist), GR 127935 (N-[4-methoxy-3-(4-methyl-1-piperizinyl)phenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazole-3-yl)[1,1′-biphenyl]-carboxamide) (0.3 mg/kg i.p., 5-HT 1B/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-HT 1B/1D receptors on raphe cell bodies, leading to a local increase in 5-HT, which, in turn, stimulated 5-HT 1A 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-HT 1B/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-HT 1B/1D receptor antagonists increase 5-HT levels in the dentate gyrus, implying that acute administration of 5-HT 1B/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.