Augmentation of SSRI Effects on Serotonin by 5-HT2C Antagonists: Mechanistic Studies

Abstract

The treatment of depression may be improved by using an augmentation approach involving selective serotonin reuptake inhibitors (SSRIs) in combination with compounds that focus on antagonism of inhibitory serotonin receptors. Using microdialysis coupled to HPLC, it has recently been shown that the systemic co-administration of 5-HT 2C antagonists with SSRIs augmented the acute effect of SSRIs on extracellular 5-HT. In this paper, we have investigated the mechanism through which this augmentation occurs. The increase in extracellular 5-HT was not observed when both compounds were locally infused. However, varying the route of administration for both compounds differentially revealed that an augmentation took place when the 5-HT 2C antagonist was locally infused into ventral hippocampus and the SSRI given systemically, but not when systemic 5-HT 2C antagonist was co-administered with the local infusion of citalopram. This suggests that the release of extracellular serotonin in ventral hippocampus may be controlled by (an)other brain area(s). As 5-HT 2C receptors are not considered to be autoreceptors, this would implicate that other neurotransmitter systems are involved in this process. To investigate which neurotransmitter systems were involved in the interaction, systemic citalopram was challenged with several glutamatergic, GABA-ergic, noradrenergic, and dopaminergic compounds to determine their effects on serotonin release in ventral hippocampus. It was determined that the involvement of glutamate, norepinephrine, and dopamine in the augmentation did not seem likely, whereas evidence implicated a role for the GABA-ergic system in the augmentation.

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

“…However, either 5-HT2C-R gene knockout or systemic treatment with the selective 5-HT2C-R antagonists SB 242084 or RS 102221 has been shown to both potentiate the antidepressant-related effects of SRIs in the tail suspension test and augment the increases in cortical and hippocampal ECF serotonin levels produced by SRI treatment (Cremers et al, 2004(Cremers et al, , 2007. On the other hand, systemic treatment with the novel 5-HT2C-R agonists WAY 163909, RO 600175 also exert antidepressant-like effects in a range of rodent assays (Cryan and Lucki, 2000;Martin et al, 1998;Rosenzweig-Lipson et al, 2007).…”

Neurokinin1 Antagonists Potentiate Antidepressant Properties of Serotonin Reuptake Inhibitors, Yet Blunt Their Anxiogenic Actions: A Neurochemical, Electrophysiological, and Behavioral Characterization

“…This would enhance their responsiveness to SSRIs, by analogy to GABA B antagonists (Millan, 2006;Cremers et al, 2007). Glutamatergic terminals targeting serotonergic DRN neurones also bear NK 1 receptors (Liu et al, 2002;Valentino et al, 2003), and their stimulation by intraraphe perfusion of substance P enhances local release of 5-HT via recruitment of AMPA receptors (Guiard et al, 2007).…”

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

“…[85][86][87] In addition, blockade of ventrotegmental-and locus ceruleus-localized 5-HT 2C sites disinhibits dopaminergic and adrenergic pathways, respectively, and 5-HT 2C antagonists elicit robust antidepressant and anxiolytic actions in a broad range of paradigms. 40,85,86,88 -90 Blockade of 5-HT 2C sites may, further, enhance sexual function and improve restorative slow wave sleep, 42,85,91 and antagonism of hypothalamic 5-HT 2C receptors facilitatory to the hypothalamo-pituitary-adrenocortical (HPA) axis abrogates its overstimulation by stress.…”

“…[141][142][143] Indeed, GABA B antagonists enhance the influence of SSRIs on serotonergic transmission in the frontal cortex. 87,144,145 …”