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.

Lurasidone is a novel antipsychotic drug with potent binding affinity for dopamine D2 and serotonin (5-hydroxytryptamine, 5-HT)2A, 5-HT7, and 5-HT1A receptors. Previous pharmacological studies have revealed that lurasidone exhibits a preferable profile (potent antipsychotic activity and lower incidence of catalepsy) to other antipsychotic drugs, although the contribution of receptor subtypes to this profile remains unclear.To compare target engagements of lurasidone with those of an atypical antipsychotic, olanzapine, we performed evaluation of dopamine D2/D3 and serotonin 5-HT2A receptor occupancy in vivo by positron emission tomography (PET) with conscious common marmosets.We measured brain receptor occupancies in conscious common marmosets after oral administrations of lurasidone or olanzapine by PET with [11C]raclopride and [11C]R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine methanol (MDL 100907) for D2/D3 and 5-HT2A receptors, respectively.Increases in brain D2/D3 receptor occupancies of both lurasidone and olanzapine, which reached >80 % at maximum, were observed in the striatum with significant correlations to plasma drug levels. However, lurasidone showed lower 5-HT2A receptor occupancy in the frontal cortex within the same dose range, while olanzapine showed broadly comparable 5-HT2A and D2/D3 receptor occupancies.Compared with olanzapine, lurasidone preferentially binds to D2/D3 receptors rather than 5-HT2A receptors in common marmosets. These results suggest that the contribution of in vivo 5-HT2A receptor blocking activity to the pharmacological profile of lurasidone might differ from olanzapine in terms of the low risk of extrapyramidal syndrome and efficacy against negative symptoms.