Ketamine inhibits serotonin uptake in vivo

Martin, Louis L.; Bouchal, R. L.; Smith, David J.

doi:10.1016/0028-3908(82)90149-6

Cited by 56 publications

(20 citation statements)

References 19 publications

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“…Whether these effects are due to a direct action of ketamine on 5-HT receptors is not clear and needs further investigation. Nevertheless, there are also conflicting data on the effects of ketamine on 5-HT receptors, because even at very high concentrations (1 mM) ketamine only slightly altered [ 3 H]5-HT or [ 3 H]spiroperidol binding to 5-HT 1 or 5-HT 2 receptors, respectively (Martin et al, 1982). It is thus possible that ketamine may interact with serotonin uptake as opposed to directly binding to serotonin receptors.…”

Section: E Monoaminergic Receptors and Transportersmentioning

confidence: 99%

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

et al. 2018

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Ketamine, a racemic mixture consisting of ()- and ()-ketamine, has been in clinical use since 1970. Although best characterized for its dissociative anesthetic properties, ketamine also exerts analgesic, anti-inflammatory, and antidepressant actions. We provide a comprehensive review of these therapeutic uses, emphasizing drug dose, route of administration, and the time course of these effects. Dissociative, psychotomimetic, cognitive, and peripheral side effects associated with short-term or prolonged exposure, as well as recreational ketamine use, are also discussed. We further describe ketamine's pharmacokinetics, including its rapid and extensive metabolism to norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK) metabolites. Whereas the anesthetic and analgesic properties of ketamine are generally attributed to direct ketamine-induced inhibition of -methyl-D-aspartate receptors, other putative lower-affinity pharmacological targets of ketamine include, but are not limited to, γ-amynobutyric acid (GABA), dopamine, serotonin, sigma, opioid, and cholinergic receptors, as well as voltage-gated sodium and hyperpolarization-activated cyclic nucleotide-gated channels. We examine the evidence supporting the relevance of these targets of ketamine and its metabolites to the clinical effects of the drug. Ketamine metabolites may have broader clinical relevance than was previously considered, given that HNK metabolites have antidepressant efficacy in preclinical studies. Overall, pharmacological target deconvolution of ketamine and its metabolites will provide insight critical to the development of new pharmacotherapies that possess the desirable clinical effects of ketamine, but limit undesirable side effects.

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Section: E Monoaminergic Receptors and Transportersmentioning

confidence: 99%

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

et al. 2018

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“…Ketamine administered at greater doses has been found to reduce [ 11 C]raclopride binding in monkey striatum (Tsukada et al 2000), whereas several studies in humans at lower doses have found no change in [ 11 C]raclopride striatal binding (Aalto et al 2002; Kegeles et al 2002). In addition, ketamine can inhibit serotonin uptake and increase the levels of serotonin in the rat brain (Martin et al 1982). Thus, ketamine may have some effect on radioligand binding in these PET studies.…”

Section: Discussionmentioning

confidence: 99%

Occupancy of dopamine D2 and D3 and serotonin 5-HT1A receptors by the novel antipsychotic drug candidate, cariprazine (RGH-188), in monkey brain measured using positron emission tomography

et al. 2011

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Rationale Cariprazine is a novel antipsychotic drug candidate that exhibits high selectivity and affinity to dopamine D3 and D2 receptors and moderate affinity to serotonin 5-HT1A receptors. Targeting receptors other than D2 may provide a therapeutic benefit for both positive and negative symptoms associated with schizophrenia. Positron emission tomography (PET) can be used as a tool in drug development to assess the in vivo distribution and pharmacological properties of a drug. Objectives The objective of this study was to determine dopamine D2/D3 and serotonin 5-HT1A receptor occupancy in monkey brain after the administration of cariprazine. Methods We examined three monkeys using the following PET radioligands: [11C]MNPA (an agonist at D2 and D3 receptors), [11C]raclopride (an antagonist at D2 and D3 receptors), and [11C]WAY-100635 (an antagonist at 5-HT1A receptors). During each experimental day, the first PET measurement was a baseline study, the second after a low dose of cariprazine, and the third after the administration of a high dose. Results We found that cariprazine occupied D2/D3 receptors in a dose-dependent and saturable manner, with the lowest dose occupying ~5% of receptors and the highest dose showing more than 90% occupancy. 5-HT1A receptor occupancy was considerably lower compared with D2/D3 occupancy at the same doses, with a maximal value of ~30% for the raphe nuclei. Conclusions We conclude that cariprazine binds preferentially to dopamine D2/D3 rather than to serotonin 5-HT1A receptors in monkey brain. These findings can be used to guide the selection of cariprazine dosing in humans.

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“…Although ketamine appears to play a role in opioid potentiation (Finck and Ngai, 1982; Smith et al, 1987; Pacheco et al, 2014), antinociceptive effects mediated by opioid receptors may vary based on receptor subtype (Mikkelsen et al, 1999; Pacheco et al, 2014). Inhibition of serotonin reuptake is another suggested as a mechanism by which ketamine may confer analgesic effects (Martin et al, 1982), and ketamine’s block of large-conductance K Ca channels (BK channels) preferentially suppresses spinal microglia hyperactivation after nerve injury and may explain its potent effects on neuropathic pain (Hayashi et al, 2011). More recently, a novel mechanism for activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors by the (R,S)-ketamine metabolite (2S,6S;2R,6R)-hydroxynorketamine has been implicated in the rapid, antidepressant-like properties observed with ketamine (Zanos et al, 2016).…”

Section: Proposed Mechanisms Of Actionsmentioning

confidence: 99%

Ketamine: 50 Years of Modulating the Mind

Vlisides

2016

Front. Hum. Neurosci.

272

212

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Ketamine was introduced into clinical practice in the 1960s and continues to be both clinically useful and scientifically fascinating. With considerably diverse molecular targets and neurophysiological properties, ketamine’s effects on the central nervous system remain incompletely understood. Investigators have leveraged the unique characteristics of ketamine to explore the invariant, fundamental mechanisms of anesthetic action. Emerging evidence indicates that ketamine-mediated anesthesia may occur via disruption of corticocortical information transfer in a frontal-to-parietal (“top down”) distribution. This proposed mechanism of general anesthesia has since been demonstrated with anesthetics in other pharmacological classes as well. Ketamine remains invaluable to the fields of anesthesiology and critical care medicine, in large part due to its ability to maintain cardiorespiratory stability while providing effective sedation and analgesia. Furthermore, there may be an emerging role for ketamine in treatment of refractory depression and Post-Traumatic Stress Disorder. In this article, we review the history of ketamine, its pharmacology, putative mechanisms of action and current clinical applications.

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Ketamine inhibits serotonin uptake in vivo

Cited by 56 publications

References 19 publications

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

Occupancy of dopamine D2 and D3 and serotonin 5-HT1A receptors by the novel antipsychotic drug candidate, cariprazine (RGH-188), in monkey brain measured using positron emission tomography

Ketamine: 50 Years of Modulating the Mind

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