MK-801 at doses < 100 pglkg given orally induced an ipsilaterally directed rotational response in rats with a unilateral nigrostriatal lesion produced by 6-hydroxydopamine. (+)-Amphetamine, amfonelic acid, and methylphenidate also evoked ipsilateral turning with their dose-response lines lying considerably to the right of that for MK-801. Rotations caused by a standard test dose of 50 pglkg of MK-801 were reduced by pretreatment with haloperido1 (EDso = 0.068 mglkg IP), clozapine ( E L = 3.35 rnglkg IP), or prazosin (ED% = 0.15 mglkg SC). MK-801 -induced turning was also inhibited by pretreatment with a-methyl-ptyrosine (a-MPT) and blocked by reserpine.Locomotor activity in mice was increased by MK-801, amfonelic acid, (+)-amphetamine, and methylphenidate. Following administration P.o., MK-801 was the most potent in this regard and methylphenidate the least. Stimulation of locomotor activity by equivalent doses of the four compounds was differentially affected by pretreatment with a-MPT or reserpine, Reserpinization abolished the increase in activity usually produced by MK-801, amfonelic acid and methylphenidate, whereas (+)-amphetamine was only partially (36%) inhibited. Locomotor stimulation by (+)-amphetamine was, on the other hand, markedly reduced in a-MPT-pretreated mice, while the actions of the other three compounds were not significantly altered. The ability of all four compounds to increase motor activity was significantly antagonized by haloperidol, but prazosin at the dose (3 mglkg SC) examined was an effective antagonist of only MK-801 and (+)-amphetamine. MK-801 has effects in rodents resembling indirect-acting central sympathomimetic substances such as amfonelic acid, ( +)-amphetamine, and methylphenidate. The central sympathomimetic actions of MK-801 are mediated via catecholamine-dependent processes.Results from the drug-interaction studies in mice (locomotor activity) indicate that the precise mechanism of action of MK-801 differs from that of the other three compounds.

 Sustained intracellular Ca 2+ overload in pancreatic acinar and ductal cells is a hallmark of biliary and alcohol-induced acute pancreatitis, which leads to impaired ductal ion and fluid secretion. Orai1 is a plasma membrane Ca 2+ channel that mediates extracellular Ca 2+ influx upon endoplasmic reticulum Ca 2+ depletion. Our results showed that Orai1 is expressed on the luminal plasma membrane of the ductal cells and selective Orai1 inhibition impaired Stim1-dependent extracellular Ca 2+ influx evoked by bile acids or ethanol combined with non-oxidative ethanol metabolites. The prevention of sustained extracellular Ca 2+ influx protected ductal cell secretory functions in in vitro models and maintained exocrine pancreatic secretion in in vivo AP models. Orai1 inhibition prevents the bile acid-, and alcohol-induced damage of the pancreatic ductal secretion and holds the potential of improving the outcome of acute pancreatitis.

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Serotonin 2C receptors (5-HT 2C Rs) are implicated in the pathomechanism and treatment of anxiety and depression. Recently, as a new biomarker of depression, alterations in the gamma power of the electroencephalogram (EEG) have been suggested. Chronic treatment with the selective serotonin reuptake inhibitor (SSRI) antidepressant escitalopram has been shown to cause sleep-wake stage-dependent alterations in gamma power. However, despite the antidepressant potency of 5-HT 2C R-antagonists, there is no data available regarding the effects of selective 5-HT 2C R-antagonists on gamma activity. Therefore, we investigate the acute effect of the 5-HT 2C R-antagonist SB-242084 on gamma power in different vigilance stages when given in monotherapy, or in combination with chronic escitalopram treatment. We administered SB-242084 (1 mg/kg, intraperitoneally) or vehicle to EEG-equipped rats after a 21-day-long pretreatment with escitalopram (10 mg/kg/day, via osmotic minipumps) or vehicle. Frontoparietal EEG, electromyogram, and motor activity were recorded during the first 3 h of passive phase, after the administration of SB-242084. Quantitative EEG analysis revealed that acute SB-242084 increased gamma power (30-60 Hz) in light and deep slow-wave sleep, and passive wakefulness. However, in active wakefulness, rapid eye movement sleep, and intermediate stage, no change was observed in gamma power. The profile of the effect of SB-242084 on gamma power was similar to that produced by chronic escitalopram. Moreover, SB-242084 did not alter chronic escitalopram-induced effects on gamma. In conclusion, the similarity in the effect of the 5-HT 2C R-antagonist and chronic SSRI on gamma power provides further evidence for the therapeutic potential of 5-HT 2C Rantagonists in the treatment of depression and/or anxiety.

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