Working memory is a dynamic neural system for temporarily maintaining and processing information. The prefrontal cortex (PFC) plays an important role in working memory. However, several evidences indicate that the thalamic mediodorsal nucleus (MD) also participates in working memory. Neurophysiological studies revealed that MD neurons exhibit sustained delay activity, which is considered to be a neural correlate of the temporary maintenance of information. Most MD neurons with delay activity represented information regarding motor responses, whereas some represented information regarding visual cues, suggesting that the MD participates more in prospective aspects of working memory, in contrast to the PFC, in which a minority participates in prospective aspects of working memory. A population vector analysis revealed that the transformation of sensory-to-motor information occurred during the earlier phase of the delay period in the MD compared with the PFC. These results indicate that reverberating neural circuits constructed by reciprocal connections between the MD and the PFC could be an important component for constructing prospective information in the PFC.

It is well accepted that drug transporters play a pivotal role in hepatobiliary excretion of anionic drugs, in which drug-drug interactions and genetic polymorphisms are known to cause variations. However, PET probes for in vivo functional characterization of these transporters have not been established yet. We used PET to investigate hepatic uptake and subsequent canalicular efflux of 11 C-labeled (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin methyl ester [(15R)-11 C-TIC-Me)] in healthy subjects. Methods: Serial PET scans of the abdominal region in healthy male subjects were obtained with or without the organic anion-transporting polypeptide (OATP) inhibitor rifampicin after intravenous injection of (15R)-11 C-TIC-Me as a radiotracer. Venous blood samples and PET images were obtained at frequent intervals up to 30 min after administration of the PET tracer. Dynamic imaging data were evaluated by integration plots of data collected for 2-10 min and for 10-30 min after tracer administration for the determination of tissue uptake clearance and biliary efflux clearance, respectively. Results: After rapid hydrolysis in blood, the acid form-11 C-labeled (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin [(15R)-11 C-TIC]-accumulated in the liver (37% of the dose by 17 min), and the radioactivity was then excreted into the bile (6.2% by 30 min). Rifampicin (600 mg by mouth), a potent OATP inhibitor, significantly reduced the radioactivity excreted into the bile (by 44%) by inhibiting both uptake (by 45%) and subsequent canalicular efflux (by 62%). (15R)-11 C-TIC is an in vitro substrate of OATP1B1 and OATP1B3, and clinically relevant concentrations of rifampicin inhibited uptake by OATP1B1 and OATP1B3. These results demonstrated that in humans, (15R)-11 C-TIC-associated radioactivity is excreted into the bile by organic anion transport systems. Conclusion: We demonstrated that PET image analysis with (15R)-11 C-TIC-Me is useful for investigating variations in OATP function in the human hepatobiliary transport system.

The thalamic mediodorsal nucleus (MD) has strong reciprocal connections with the dorsolateral prefrontal cortex (DLPFC), suggesting that the MD, like the DLPFC, participates in higher cognitive functions. To examine MD's participation in cognitive functions, we analyzed the characteristics of task-related activities sampled homogeneously from the MD while two monkeys performed a spatial working memory task using oculomotor responses. Of 141 task-related MD neurons, 26, 53, and 84% exhibited cue-, delay-, and response-period activity, respectively. Most of cue- and response-period activities showed phasic excitation, and most of delay-period activity showed tonic sustained activation. Among neurons with response-period activity, 74% exhibited presaccadic activity. Most cue-period, delay-period, and presaccadic activities were directional, whereas most postsaccadic activity was omni-directional. A significant contralateral bias in the best directions was present in cue-period and presaccadic activity. However, such bias was not present in delay-period activity, although most neurons had a best direction toward the contralateral visual field. We compared these characteristics with those observed in DLPFC neurons. Response-period activity was more frequently observed in the MD (84%) than in the DLPFC (56%). The directional selectivity and bias of task-related activities and the ratios of pre- and postsaccadic activities were different between MD and DLPFC. These results indicate that the MD participates in higher cognitive functions such as spatial working memory. However, the manner in which these two structures participate in these processes differs, in that the MD participates more in motor control aspects compared with the DLPFC.

By use of several prostacyclin analogs and an in vitro autoradiographic technique, we have found a novel subtype of the prostacyclin receptor, one having different binding properties compared with those of the known prostacyclin receptor in the rat brain. Isocarbacyclin, which is a potent agonist for the known prostacyclin receptor, had high affinity for the novel subtype (dissociation constant (K d ) of 7.8 nM). However, iloprost, which is usually used as a stable prostacyclin analog, showed low affinity binding ( 3 H]iloprost also had high affinity in these regions, and the binding specificity was similar to that for the known prostacyclin receptor. Hemilesion studies of striatal neurons lesioned by kainate or of dopaminergic afferents lesioned by 6-hydroxydopamine revealed that the binding sites of the novel subtype exist on neuronal cells in the striatum, but not on the presynaptic terminal of afferents or on glial cells. Electrophysiological studies carried out in the CA1 region of the hippocampus revealed that prostacyclin analogs have a facilitatory effect on the excitatory transmission through the novel prostacyclin receptor. The widespread expression of the prostacyclin receptor in the central nervous system suggests that prostacyclin has important roles in neuronal activity. Prostaglandins (PGs)1 and thromboxane are formed from arachidonic acid by cyclooxygenase and the respective synthase for each PG, such as PGD synthase and PGI 2 synthase. These prostanoids exert a variety of functions through their specific membrane receptors coupled to G proteins not only in the peripheral organs, but also in the central nervous system. For example, PGD 2 acts as a sleep inducer (1, 2), produces hypothermia (3), inhibits luteinizing hormone-releasing hormone release (4), and is involved in biphasic modulation of pain sensation (5) and modification of olfaction (6). PGE 2 has hyperthermic (7), sedative (8), anticonvulsive (9, 10), and antidiuretic effects (11) and induces wakefulness (12, 13), stimulates luteinizing hormone-releasing hormone release (14), modifies pain (5, 9), and regulates food intake (11). Also, PGF 2␣ has an antidiuretic effect (15) and an inhibitory effect on oxytocin release (16). These three PGs are reported to be involved in the modulation of neurotransmitter release as well (17). Prostacyclin, discovered in 1976, is known to be a potent vasodilator and also to have an inhibitory effect on platelet aggregation (18). In the brain, however, it is not clear whether prostacyclin has specific functions or not. It seems that the chemical instability of prostacyclin and lack of knowledge about the prostacyclin receptor in the brain have hampered the investigation.Recently, we reported the presence and distribution of the prostacyclin receptor in the central nervous system by use of [ 3 H]iloprost, a stable prostacyclin analog, and an in vitro autoradiographic technique (19). High density binding was observed in the nucleus of the solitary tract (NTS) and in the spinal trigeminal nucleus in the lowe...