Reduced 5-HT_1A- and GABA_BReceptor Function in Dorsal Raphé Neurons Upon Chronic Fluoxetine Treatment of Socially Stressed Rats

Abstract

Cornelisse LN, Van der Harst JE, Lodder JC, Baarendse PJ, Timmerman AJ, Mansvelder HD, Spruijt BM, Brussaard AB. Reduced 5-HT 1A -and GABA B receptor function in dorsal raphé neurons upon chronic fluoxetine treatment of socially stressed rats. J Neurophysiol 98: 196 -204, 2007. First published April 25, 2007; doi:10.1152/jn.00109.2007. Autoinhibitory serotonin 1A receptors (5-HT 1A ) in dorsal raphé nucleus (DRN) have been implicated in chronic depression and in actions of selective serotonin reuptake inhibitors (SSRI). Due to experimental limitations, it was never studied at single-cell level whether changes in 5-HT 1A receptor functionality occur in depression and during SSRI treatment. Here we address this question in a social stress paradigm in rats that mimics anhedonia, a core symptom of depression. We used whole cell patch-clamp recordings of 5-HT-and baclophen-induced G-proteincoupled inwardly rectifying potassium (GIRK) currents as a measure of 5-HT 1A -and GABA B receptor functionality. 5-HT 1A -and GABA B receptor-mediated GIRK-currents were not affected in socially stressed rats, suggesting that there was no abnormal (auto)inhibition in the DRN on social stress. However, chronic fluoxetine treatment of socially stressed rats restored anticipatory behavior and reduced the responsiveness of 5-HT 1A receptor-mediated GIRK currents. Because GABA B receptor-induced GIRK responses were also suppressed, fluoxetine does not appear to desensitize 5-HT 1A receptors but rather one of the downstream components shared with GABA B receptors. This fluoxetine effect on GIRK currents was also present in healthy animals and was independent of the animal's "depressed" state. Thus our data show that symptoms of depression after social stress are not paralleled by changes in 5-HT 1A receptor signaling in DRN neurons, but SSRI treatment can alleviate these behavioral symptoms while acting strongly on the 5-HT 1A receptor signaling pathway. 1995;Pejchal et al. 2002;Shen et al. 2002;Subhash et al. 2000). Although it remains unclear by which mechanism SSRIs exert their antidepressant action, there is a clear relation between reduced 5-HT1 A receptor function and increased 5-HT levels in DRN innervated forebrain areas after SSRI treatment in rodents. If SSRIs are acutely applied, locally enhanced 5-HT levels in the DRN inhibit serotonernergic neurons through activation of the 5-HT1 A autoreceptor. This results in decreased 5-HT release in the projection areas (Artigas et al. 1996b). However, after chronic SSRI treatment, 5-HT1 A receptors are desensitized, and firing of DRN cells is restored resulting in increased 5-HT levels in the frontal cortex (Artigas et al. 1996b;Bel and Artigas 1993). Co-application of 5-HT1 A receptor antagonists appears to prevent the initial decrease of 5-HT release in the forebrain during SSRI treatment and may accelerate antidepressant responses in patients (Artigas et al. 1996b;Blier et al. 1998).These studies suggest a role for DRN 5-HT1 A autoreceptors in etiology of depression as well as in ...

Differential Role of Galanin Receptors in the Regulation of Depression-Like Behavior and Monoamine/Stress-Related Genes at the Cell Body Level

“…The present data indicate that the mechanisms underlying the impairment of coping mechanisms by galanin, although partially related to disturbances in 5-HT neurotransmission, cannot be directly related to changes in 5-HT 1A autoreceptor functions. In agreement, a recent paper has shown that the effects of chronic fluoxetine treatment in socially stressed rats is not associated with downregulation of the 5-HT 1A receptor function in the DR neurons (Cornelisse et al, 2007).…”

Phytochemicals as Antidepressants: The Involvement of Serotonin Receptor Function, Stress Resistance and Neurogenesis

“…In addition, many studies suggest that increases in adult neurogenesis after the SSRI administration require the activation of 5-HT 1A receptors (Santarelli et al, 2003), which is consistent with the results that 5-HT 1A receptor antagonists or knockout mice decrease or lack cell proliferation in the dentate gyrus, respectively (Radley and Jacobs, 2002;Santarelli et al, 2003). Furthermore, it has been reported that the antidepressant effect of SSRIs are mediated by 5-HT 1A receptors (Tatarczynska et al, 2002;Hirano et al, 2002) by changing the receptor-medicated Gprotein-coupled inwardly rectifying potassium (GIRK) currents (Cornelisse et al, 2007). Therefore, 5-HT 1A is definitely involved in depression as well as the action of antidepressants.…”

Transcriptional regulation of the 5-HT1Areceptor: implications for mental illness

“…Several possible mechanisms have been implicated in 5-HT 1A autoreceptor desensitization [42] including uncoupling from G-proteins [41,[47][48][49][50], receptor internalization [51], G-protein inactivation [52] and reduction in 5-HT 1A autoreceptors [38,53]. In addition, coupling to the GIRK is reduced upon chronic fluoxetine treatment [54], one mechanism that may disinhibit raphe firing and allow for enhanced 5-HT neurotransmission. However, these mechanisms of rapid desensitization do not account for the chronic treatment required for antidepressant effects, and are also rapidly reversible [51].…”