Tatsuhiro Kobashi

Phencyclidine-Induced Cognitive Deficits in Mice Are Improved by Subsequent Subchronic Administration of the Novel Selective α7 Nicotinic Receptor Agonist SSR180711

BACKGROUND Accumulating evidence suggests that alpha7 nicotinic receptor (alpha7 nAChR) agonists could be potential therapeutic drugs for cognitive deficits in schizophrenia. The present study was undertaken to examine the effects of the novel selective alpha7 nAChR agonist SSR180711 on cognitive deficits in mice after repeated administration of the N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). METHODS Saline or PCP (10 mg/kg/day for 10 days) was administered to mice. Subsequently, vehicle, SSR180711 (.3 or 3.0 mg/kg/day), SSR180711 (3.0 mg/kg/day) + the selective alpha7 nAChR antagonist methyllycaconitine (MLA; 3.0 mg/kg/day), or MLA (3.0 mg/kg/day) was administered IP for 2 consecutive weeks. Twenty-four hours after the final administration, a novel object recognition test was performed. RESULTS The PCP-induced cognitive deficits were significantly improved by subsequent subchronic (2-week) administration of SSR180711 (3.0 mg/kg). The effects of SSR180711 (3.0 mg/kg) were significantly antagonized by co-administration of MLA (3.0 mg/kg). Furthermore, Western blot analysis and immunohistochemistry revealed that levels of alpha7 nAChRs in the frontal cortex and hippocampus of the PCP (10 mg/kg/day for 10 days)-treated mice were significantly lower than those of saline-treated mice. CONCLUSIONS These findings suggest that repeated PCP administration significantly decreased the density of alpha7 nAChRs in the brain and that the alpha7 nAChR agonist SSR180711 could ameliorate cognitive deficits in mice after repeated administration of PCP. Therefore, alpha7 nAChR agonists including SSR180711 are potential therapeutic drugs for treating cognitive deficits in schizophrenic patients.

Development of novel PET probe [11C](R,R)HAPT and its stereoisomer [11C](S,S)HAPT for vesicular acetylcholine transporter imaging: A PET study in conscious monkey

Carbon‐11‐labeled (R,R)trans‐8‐methyl‐2‐hydroxy‐3‐[4‐[2‐aminophenyl]piperizinyl]‐tetralin ([11C](R,R)HAPT) and its stereoisomer [11C](S,S)HAPT were developed for imaging vesicular acetylcholine transporters (VAChTs), exclusively located in presynaptic cholinergic neurons. Both positron emission tomography (PET) probes were evaluated in the brain of conscious monkey (Macaca mulatta) using high‐resolution PET. Time‐activity curves (TACs) of [11C](R,R)HAPT peaked within 5 min after the injection in all regions except the caudate and putamen, both of which showed peaks around 20 min postinjection. The regional distribution patterns of [11C](R,R)HAPT determined as total distribution volume (Vt) were highest in the putamen, high in the caudate, intermediate in the amygdala, hippocampus, and thalamus, lower in the cingulate gyrus and frontal, temporal, and occipital cortices, and lowest in the cerebellum. In contrast, the distribution and TACs of [11C](S,S)HAPT were homogeneous in all regions. The uptake of [11C](R,R)HAPT was reduced by 1 mg/kg (−)‐vesamicol, a specific VAChT antagonist, in all regions except the cerebellum, but not by 0.1 mg/kg SA4503, a specific sigma‐1 receptor agonist. These results well reflect the in vitro affinity assessments using rat cerebral membranes. They also demonstrate that [11C](R,R)HAPT is a potential PET probe for noninvasive and quantitative imaging of VAChT in the living brain. Synapse 68:283–292, 2014.