BRAIN MICRODIALYSIS IN KNOCKOUT MICE: DRAWBACKS AND ADVANTAGES TO STUDY THE ROLE OF 5-HT_1A AND 5-HT_1B AUTORECEPTORS IN THE MECHANISM OF ACTION OF ANTIDEPRESSANTS

From anesthetized rats in the 90s to conscious wild-type or knockout mice today, intracerebral in vivo microdialysis provided important information about the brain mechanism of action of psychotropic drugs such as antidepressants. The principle of microdialysis technique is based on the balance between the release of neurotransmitters (e.g., serotonin 5-HT, norepinephrine, dopamine) and re-uptake by selective transporters (e.g., SERT for 5-HT). Complementary to electrophysiology, this technique reflects presynaptic monoamines release and intrasynaptic events corresponding to ≈ 80% of whole brain tissue content. It has been proposed that the inhibitory role of 5-HT_1A and 5-HT_1B serotonergic receptor sub-types that limit somatodendritic and nerve terminal 5-HT release, respectively, plays a key role in the mechanism of action of Selective Serotonin Reuptake Inhibitors (SSRI). This hypothesis is based partially on results of microdialysis experiments performed in naïve, non stressed Rodents. Examples from our own experience and from relevant publications from key investigators in this field will illustrate this statement. The present chapter will first remind the principle and methodology of the microdialysis technique when performed in mice. We will also underline the crucial need of developing animal models displaying behavioral, neurochemical and brain morphological phenotypes reminiscent of depression and anxiety in Human. Recently developed genetic mouse models have been generated to independently manipulate 5-HT_1A autoreceptor and heteroreceptor populations and microdialysis helped to clarify the role of the presynaptic component, i.e., by measuring extracellular levels of neurotransmitters in serotonergic nerve terminal regions and raphe nuclei. The last two paragraphs will summarize main advantages and drawbacks of using microdialysis in mice through recent examples obtained in knockouts or alternatives such as infusion of a small-interfering RNA (siRNA) suppressing receptor functions in the mouse brain. Finally, by using drug infusion through the probe, correlation of microdialysis changes with behavioural data can be obtained, e.g., with the antidepressant-like activity.

Keywords: Serotonin (5-HT), serotonin-1A/1B (5-HT1A/5-HT1B) receptors, serotonin transporter (SERT), depression, antidepressant drugs, selective serotonin reuptake inhibitors (SSRIs), animal models, knockout mice, microdialysis, small-interfering RNA (siRNA).