Differential effects of 5-HT1B/1D receptor antagonists in dorsal and median raphe innervated brain regions

被引:47
作者
Roberts, C
Belenguer, A
Middlemiss, DN
Routledge, C
机构
[1] SmithKline Beecham Pharmaceut, Dept Neurosci, Harlow CM19 5AW, Essex, England
[2] SmithKline Beecham Pharmaceut, Dept Separat Sci, Harlow CM19 5AW, Essex, England
关键词
microdialysis; (guinea pig); 5-HT1B/(1D) receptor antagonist;
D O I
10.1016/S0014-2999(98)00061-2
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The effect of SE-224289 (2,3,6,7-tetrahydro-1'-methyl-5-{2'-methyl-4'-[(5-methyl-1,2,4-oxadiazole-3-yl)biphenyl-4yl]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-methyl- 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-MT) 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, 3B-224289 had no effect on 5-HT levels in either region. In the dentate gyrus (median raphe innervated area), GR 127935 and 3B-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)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 administration of 5-HT in median raphe innervated areas. This, in turn, suggests that such compounds may be efficacious in the treatment of depression. (C) 1998 Elsevier Science B.V.
引用
收藏
页码:175 / 180
页数:6
相关论文
共 40 条
[1]  
ARBORELIUS L, 1995, N-S ARCH PHARMACOL, V352, P157
[2]   DIFFERENTIAL RESPONSIVENESS OF THE RAT DORSAL AND MEDIAN RAPHE 5-HT SYSTEMS TO 5-HT1-RECEPTOR AGONISTS AND PARA-CHLOROAMPHETAMINE [J].
BLIER, P ;
SERRANO, A ;
SCATTON, B .
SYNAPSE, 1990, 5 (02) :120-133
[3]  
BLIER P, 1990, J CLIN PSYCHIAT, V51, P14
[4]   Evidence for presynaptic location of inhibitory 5-HT1D beta-like autoreceptors in the guinea-pig brain cortex [J].
Buhlen, M ;
Fink, K ;
Boing, C ;
Gothert, M .
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 1996, 353 (03) :281-289
[5]   THE INHIBITORY EFFECT OF 8-OH-DPAT ON THE FIRING ACTIVITY OF DORSAL RAPHE SEROTONINERGIC NEURONS IN RATS IS ATTENUATED BY LESION OF THE FRONTAL-CORTEX [J].
CECI, A ;
BASCHIROTTO, A ;
BORSINI, F .
NEUROPHARMACOLOGY, 1994, 33 (05) :709-713
[6]   EVIDENCE THAT 5-HYDROXYTRYPTAMINE RELEASE IN RAT DORSAL RAPHE NUCLEUS IS CONTROLLED BY 5-HT1A, 5-HT1B AND 5-HT1D AUTORECEPTORS [J].
DAVIDSON, C ;
STAMFORD, JA .
BRITISH JOURNAL OF PHARMACOLOGY, 1995, 114 (06) :1107-1109
[7]   Serotonin efflux in the rat ventral lateral geniculate nucleus assessed by fast cyclic voltammetry is modulated by 5-HT1B and 5-HT1D autoreceptors [J].
Davidson, C ;
Stamford, JA .
NEUROPHARMACOLOGY, 1996, 35 (11) :1627-1634
[8]   IDENTITY OF INHIBITORY PRESYNAPTIC 5-HYDROXYTRYPTAMINE (5-HT) AUTORECEPTORS IN THE RAT-BRAIN CORTEX WITH 5-HT1B BINDING-SITES [J].
ENGEL, G ;
GOTHERT, M ;
HOYER, D ;
SCHLICKER, E ;
HILLENBRAND, K .
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 1986, 332 (01) :1-7
[9]   Role of 5-HT1A autoreceptors in the mechanism of action of serotoninergic antidepressant drugs: Recent findings from in vivo microdialysis studies [J].
Gardier, AM ;
Malagie, I ;
Trillat, AC ;
Jacquot, C ;
Artigas, F .
FUNDAMENTAL & CLINICAL PHARMACOLOGY, 1996, 10 (01) :16-27
[10]  
HARTIG R, 1996, TRENDS PHARMACOL SCI, V17, P103