5-HT1B receptors and serotonin function : microdialysis studies in rats and knockout mice

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. The 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. A 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. NAS-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. The 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. Concluding, 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.