5-HT1B receptors and serotonin function : microdialysis studies in rats and knockout mice
Year: 2002
Type: dissertation
Abstract: The serotonergic system is an important target in the treatment of psychiatric disorders. Selective serotonin reuptake inhibitors (SSRIs) are widely used in the treatment of depression and anxiety disorders, but a clinical problem is the delayed therapeutic effect. This delayed onset of action suggests that adaptive changes may occur. Previous pre-clinical studies have indicated a role of 5-HT autoreceptors in the effects of SSRIs. Moreover, dysfunction of 5-HT1B receptors has been associated with aggression, impulsivity, alcoholism and drug abuse. More insight in the functional role of 5-HT1B receptors contributes to our understanding of this receptor in psychiatric disorders. \nThe studies described in this thesis investigated the role of 5-HT1B receptors in serotonin (5-HT) function in rats and in genetically modified mice lacking 5-HT1B receptors. The central serotonergic system is complex as 5-HT exerts its function through fourteen different receptor subtypes. In the mammalian brain, 5-HT1B receptors are expressed either as inhibitory 5-HT autoreceptors or as 5-HT1B heteroreceptors. The 5-HT1B autoreceptors are localized on serotonergic nerve terminals controlling 5-HT release. The 5-HT1B heteroreceptors are present on non-serotonergic neurons, suggesting that these receptors modulate other neurotransmitters and are involved in a variety of functions. \nA limitation in research on 5-HT1B receptors has been the relative restricted selectivity of 5-HT1B receptor antagonists. Therefore, the generation of 5-HT1B knockout (KO) mice has provided an interesting model to study 5-HT1B receptors. Activation of 5-HT1B autoreceptors reduces the release of 5-HT. Thus in the absence of 5-HT1B autoreceptors, increased extracellular 5-HT levels and an increased response to SSRIs may be expected. In the hippocampus of 5-HT1B KO mice an increased 5-HT response after systemic administration of the SSRI paroxetine was found. To further examine the contribution of terminal autoreceptors on 5-HT levels, and to circumvent possible effects of raphe 5-HT autoreceptors, a SSRI was locally administered into the brain structures of interest by reversed microdialysis. Augmented 5-HT levels following local SSRI administration were found in the hippocampus and prefrontal cortex, but not in the striatum of mice lacking 5-HT1B receptors. In wildtype mice, stimulation of 5-HT1B receptors with CP-93,129, a 5-HT1B receptor agonist, reduced 5-HT output, also in the striatum, indicating that these autoreceptors are functionally present in this genotype. \nNAS-181, a new rodent 5-HT1B receptor antagonist, was used to block 5-HT1B receptors. NAS-181 was found to be a potent 5-HT1B receptor antagonist in rat frontal cortex. The effects of a SSRI on extracellular 5-HT in the prefrontal cortex in mice and rats were augmented by 5-HT1B receptor blockade with NAS-181. The studies in mice and rats described in this thesis clearly show that 5-HT1B autoreceptors limit the acute effects of local administration of a SSRI in the hippocampus and frontal cortex. The results obtained in mice indicate some evidence for compensatory changes in 5-HT1B KO mice, supporting the importance of 5-HT1B receptors in 5-HT neurotransmission. The main advantage of a knockout model is its selectivity. In addition, the 5-HT1B receptor antagonist NAS-181 can be a valuable pharmacological tool to study 5-HT1B receptors in rodents. \nThe role of 5-HT1B heteroreceptors in dopamine release was studied in mice dorsal striatum. Local administration of the 5-HT1B receptor agonist CP-93,129 increased DA outflow in 5-HT1B KO mice to the same extent as wildtype mice, indicating that the DA effect this compound can not be attributed to stimulation of 5-HT1B receptors. The previous reported role of 5-HT1B heteroreceptors in striatal dopamine release could not be confirmed in mice lacking 5-HT1B receptors.\nConcluding, 5-HT1B autoreceptors limit the acute effects of 5-HT reuptake inhibition in hippocampus and frontal cortex, but not in the striatum. These findings support the idea that blockade of 5-HT1B autoreceptors may be a potential interesting augmentation strategy for treatment with SSRIs. In contrast to the well-established role of 5-HT1B autoreceptors, relative little is known about 5-HT1B heteroreceptors. Our study could not confirm a role 5-HT1B heteroreceptors in striatal dopamine release. The 5-HT1B KO mice may be an interesting to further study the functional role of 5-HT1B heteroreceptors.
Author: Lotte de Groote
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2138829566