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Effect of acute administration of the 5‐HT 1A receptor ligand, lesopitron, on rat cortical 5‐HT and dopamine turnover
Author(s) -
Ballarín M.,
Carceller A.,
Guitart X.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb17006.x
Subject(s) - buspirone , homovanillic acid , autoreceptor , anxiolytic , microdialysis , chemistry , dopaminergic , medicine , endocrinology , dopamine , pharmacology , striatum , serotonin , receptor
1 The involvement of presynaptic 5‐hydroxytryptamine 1A (5‐HT 1A ) autoreceptors in the anxiolytic‐like properties of lesopitron (E‐4424) (2‐{4‐[4‐(4‐chloro‐1‐pyrazolyl)butyl]‐1‐piperazinyl}pyrimidine) was studied. Brain microdialysis was used to examine the effect of the drug on the release of 5‐hydroxytryptamine (5‐HT) and its metabolite 5‐hydroxyindoleacetic acid (5‐HIAA) in the frontal cortex of awake, freely moving rats. Moreover, extracellular cortical 3,4‐dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were also studied to assess the possible participation of dopaminergic systems. 2 Lesopitron administered at a dose which induces anxiolytic behaviour in rats (30 μg kg −1 , i.p.) markedly reduced 5‐HT levels (to 45% of the basal value) in cortical perfusates, having no effect on 5‐HIAA, DOPAC and HVA. The effects of lesopitron were compared with those produced by the anxiolytic, and structurally related compound, buspirone. 3 Buspirone administered at a dose inducing anxiolytic‐like effects in rats (5 mg kg −1 , i.p.) produced a marked decrease in cortical 5‐HT levels (to 20% of the basal value), but in contrast to lesopitron, buspirone produced a pronounced increase in cortical DOPAC (to 300% of the basal value) and HVA (to 400% of the basal value) levels. Buspirone administered at a low dose (30 μg kg −1 , i.p.) was unable to affect cortical 5‐HT levels. 4 To test the hypothesis that the 5‐HT decreasing effect of lesopitron could be due to 5‐HT 1A autoreceptor (somatodendritic)‐mediated inhibition of 5‐HT neurotransmission, lesopitron was administered locally into the raphe nuclei. Intraraphe administration of 10 μ m lesopitron caused a decrease in cortical 5‐HT levels (the effect being of the same order as that obtained after systemic injection), with no effect on 5‐HIAA, DOPAC and HVA. Raphe 5‐HT extracellular levels were not modified after intraraphe administration of lesopitron, indicating the absence of 5‐HT reuptake blocking properties. 5 We concluded that lesopitron, at an anxiolytic dose produced a marked inhibition of 5‐HT release in the frontal cortex of awake, freely moving rats. This effect was observed after systemic administration as well as after intraraphe administration of the drug, suggesting an agonistic action at raphe 5‐HT 1A autoreceptors controlling 5‐HT release in the projecting areas. In contrast to buspirone, lesopitron treatment had no effect on cortical DOPAC or HVA levels.