A possible mechanism of the nucleus accumbens and ventral pallidum 5-HT1B receptors underlying the antidepressant action of ketamine: a PET study with macaques

Abstract

Ketamine is a unique anesthetic reagent known to produce various psychotic symptoms. Ketamine has recently been reported to elicit a long-lasting antidepressant effect in patients with major depression. Although recent studies provide insight into the molecular mechanisms of the effects of ketamine, the antidepressant mechanism has not been fully elucidated. To understand the involvement of the brain serotonergic system in the actions of ketamine, we performed a positron emission tomography (PET) study on non-human primates. Four rhesus monkeys underwent PET studies with two serotonin (5-HT)-related PET radioligands, [11C]AZ10419369 and [11C]DASB, which are highly selective for the 5-HT1B receptor and serotonin transporter (SERT), respectively. Voxel-based analysis using standardized brain images revealed that ketamine administration significantly increased 5-HT1B receptor binding in the nucleus accumbens and ventral pallidum, whereas it significantly reduced SERT binding in these brain regions. Fenfluramine, a 5-HT releaser, significantly decreased 5-HT1B receptor binding, but no additional effect was observed when it was administered with ketamine. Furthermore, pretreatment with 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), a potent antagonist of the glutamate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor, blocked the action of ketamine on the 5-HT1B receptor but not SERT binding. This indicates the involvement of AMPA receptor activation in ketamine-induced alterations of 5-HT1B receptor binding. Because NBQX is known to block the antidepressant effect of ketamine in rodents, alterations in the serotonergic neurotransmission, particularly upregulation of postsynaptic 5-HT1B receptors in the nucleus accumbens and ventral pallidum may be critically involved in the antidepressant action of ketamine.

Serotonin transporter occupancy by escitalopram and citalopram in the non-human primate brain: a [11C]MADAM PET study

“…isoflurane, have been shown to decrease cortical extracellular serotonin concentration (Mukaida et al 2007) and to increase [ 3 H]escitalopram binding in rats (Elfving et al 2003). Moreover, in a paradigm more similar to the current study, sub-anaesthetic doses of ketamine have recently been shown to decrease [ 11 C]DASB binding by up to 30 % in NHPs (Yamamoto et al 2013;Yamanaka et al 2014). In the current and previous SERT occupancy studies (Batis et al 2012;Cosgrove et al 2010), ketamine was used to induce anaesthesia and baseline PET measurements may therefore be more affected by ketamine than the post-SSRI measurements.…”

A Lack of Serotonin 1B Autoreceptors Results in Decreased Anxiety and Depression-Related Behaviors

“…Given the various underlying serotonergic mechanisms, it is interesting that a lack of 5-HT 1B autoreceptors was sufficient to generate antidepressant and anxiolytic responses. Taken together with studies showing dysregulation of 5-HT 1B Rs in mood disorders in humans (Murrough et al, 2011a,b) and the potential involvement of 5-HT 1B Rs in antidepressant responses (Tiger et al, 2014;Yamanaka et al, 2014), our results suggest the potential benefit of strategies aimed at targeting 5-HT 1B autoreceptor signaling for the treatment of anxiety and depression. …”

Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs

“…Furthermore, ketamine does not produce antidepressant effects in 5-HT deprived animals [128], suggesting that 5-HT tone is required for ketamine's antidepressant activity. Additional targets of ketamine, such as sigma receptors [129], monoamine transporters [130], and 5-HT 1B receptors [131], as well as pharmacological activities of ketamine's metabolites, might collectively contribute to its antidepressant effect. Thus, additional research is needed to elucidate ketamine's mechanism of action.…”