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.
Highlights
A neuroimaging study using positron emission tomography (PET) showed that 5-HT1B receptor binding in the ventral striatum including the nucleus accumbens and ventral pallidum is reduced in patients with major depressive disorder compared with healthy controls.[20]
In the case of [11C]AZ10419369, we investigated the effect of ketamine in combination with fenfluramine, a 5-HT releaser, because [11C]AZ10419369 binding to 5-HT1B receptors is reported to be affected by 5-HT release.[21,22]
We obtained the following results, which strongly suggest a critical role for the 5-HT1B receptor in the Acb, ventral GP and midline nucleus reuniens of the thalamus (Tha-Re): (i) ketamine administration significantly increased 5-HT1B receptor binding in three brain regions, the Acb, ventral GP and Tha-Re, where serotonin transporter (SERT) binding was significantly decreased and (ii) pretreatment with NBQX blocked the ketamine-induced increases in 5-HT1B receptor binding in the Acb, ventral GP and Tha-Re but not in the lateral geniculate nucleus (LGN) and occipital cortex (Occ), whereas it did not affect ketamine-induced decreases in SERT binding
Summary
Ketamine (2-chlorphenyl-2-methylamino-cyclohexanone), a noncompetitive antagonist of the N-methyl-D-aspartic acid (NMDA) glutamate receptor, is known to induce anesthesia, analgesia, hallucinations and a dissociative state.[1,2,3,4] In addition, ketamine has recently been demonstrated to have an antidepressant action in patients suffering from treatment-resistant major depressive disorder; onset occurs within 2 h and the duration of the effect is several days following a single administration.[5,6] Because existing antidepressants—such as selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors and tricyclic antidepressants—take several weeks to reach their full therapeutic effect, ketamine is a possible attractive novel treatment for depression. A neuroimaging study using positron emission tomography (PET) showed that 5-HT1B receptor binding in the ventral striatum including the nucleus accumbens and ventral pallidum is reduced in patients with major depressive disorder compared with healthy controls.[20]. Before the PET scan, the saphenous vein in one of the legs was cannulated for infusion of drugs or the PET radioligand Vital signs such as electrocardiography and oxygen saturation were continuously monitored performed a PET imaging study using nonhuman primates and two PET radioligands [11C]AZ10419369 and 11C-labeled N,Ndimethyl-2-(2-amino-4-cyanophenylthio)benzylamine ([11C]DASB), which are highly selective for the 5-HT1B receptor and SERT, respectively. A 30-min transmission scan with a 68Ga-68Ge line source was performed for attenuation correction of pretreatment with NBQX blocked the action of ketamine on the binding of [11C]AZ10419369 and [11C]DASB to the 5-HT1B receptor and SERT, respectively. The emission images were corrected for attenuation
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