Kappa Opioid Receptors Reduce Serotonin Uptake and Escitalopram Efficacy in the Mouse Substantia Nigra Pars Reticulata

Abstract

The serotonin and kappa opioid receptor (KOR) systems are strongly implicated in disorders of negative affect, such as anxiety and depression. KORs expressed on axon terminals inhibit the release of neurotransmitters, including serotonin. The substantia nigra pars reticulata (SNr) is involved in regulating affective behaviors. It receives the densest serotonergic innervation in the brain and has high KOR expression; however, the influence of KORs on serotonin transmission in this region is yet to be explored. Here, we used ex vivo fast-scan cyclic voltammetry (FSCV) to investigate the effects of a KOR agonist, U50, 488 (U50), and a selective serotonin reuptake inhibitor, escitalopram, on serotonin release and reuptake in the SNr. U50 alone reduced serotonin release and uptake, and escitalopram alone augmented serotonin release and slowed reuptake, while pretreatment with U50 blunted both the release and uptake effects of escitalopram. Here, we show that the KOR influences serotonin signaling in the SNr in multiple ways and short-term activation of the KOR alters serotonin responses to escitalopram. These interactions between KORs and serotonin may contribute to the complexity in the responses to treatments for disorders of negative affect. Ultimately, the KOR system may prove to be a promising pharmacological target, alongside traditional antidepressant treatments.

Microdosing ketamine in Drosophila does not block serotonin reuptake, but causes complex behavioral changes mediated by glutamate and serotonin receptors

“…The effects of ketamine on the serotonin system have been studied in small mammals and humans, but how microdoses affect this system is ambiguous (West et al., 2023). For instance, some literature suggests that microdosing ketamine relies on SERT inhibition to increase serotonin concentrations after 24 h (Kraus et al., 2019; Li, 2020; Pham et al., 2017; Spies et al., 2018), while other studies suggest that immediate responses (≤24 h) may rely more on serotonin (5‐HT 1A,2A,2C ) receptor activation to increase serotonin concentrations (Kraus et al., 2019).…”

“…Formally, ketamine is classified as a non‐competitive, NMDA antagonist that blocks glutamate receptors (Kraus et al., 2019; Li, 2020). However, it also activates opioid receptors (Kraus et al., 2019; West et al., 2023), and binds to a variety of receptors and transporters in the brain, including serotonin (5‐hydroxytryptophan, 5‐HT) and dopamine (Bowman et al., 2020; Kraus et al., 2019; Li, 2020). Ketamine activates serotonin receptors, especially the 5‐HT 1 and 5‐HT 2 subtypes, which increase serotonin concentrations in the brain (Kraus et al., 2019).…”

Microdosing ketamine inDrosophiladoes not inhibit SERT like SSRIs, but causes behavioral changes mediated by glutamate and serotonin receptors

“…The effects of ketamine on the serotonin system have been studied in small mammals and humans, but how microdoses affect this system is ambiguous (West et al, 2023). For instance, some literature suggests microdosing ketamine relies on SERT inhibition to increase serotonin concentrations after 24 hours (Kraus et al, 2019; Li, 2020; Pham et al, 2017; Spies et al, 2018), while other studies suggest that immediate responses (≤ 24 hours) may rely more on serotonin (5-HT 1A,2A,2C ) receptor activation to increase serotonin concentrations.…”

“…Formally, ketamine is classified as a noncompetitive NMDA antagonist that blocks glutamate receptors (Kraus et al, 2019; Li, 2020). However, it also activates opioid receptors (Kraus et al, 2019; West et al, 2023), and binds to a variety of receptors and transporters in the brain, including serotonin (5-hydroxytryptophan, 5-HT) and dopamine (Bowman et al, 2020; Kraus et al, 2019; Li, 2020). Ketamine activates serotonin receptors, especially the 5-HT 1 and 5-HT 2 subtypes, which increase serotonin concentrations in the brain (Spies et al, 2018).…”

In and Out Beauty and Sensitive Skin, a Psychophysiological Exploration: Myth or Reality?

“…Among neuropeptides, kappa opioid receptor (KOR) has been extensively linked to numerous conditions such as anxiety, and depression [4]. Within the central nervous system, KOR plays a role in appropriate stress, which lead to negatives emotions, and discomfort in models related to pain and stress [5]. Opioid system is also present and functional in human skin.…”