A feasibility study of differential delivery of levodopa ester and benserazide using site-specific intestinal loops in rats.

To study the effect of varied intestinal delivery of levodopa ester, levodopa and its butyl ester were administered as bolus or continuous infusions into site-specific, in situ ligated intestinal loops of rats. Benserazide, a carboxylase inhibitor, was not administered, coadministered with ester, or infused into the duodenal loop prior to ester dosing. While the proximal colon minimally absorbed levodopa itself, it substantially absorbed the ester. Coadministration of benserazide and ester at the colon did not increase absorption; however, prior infusion of benserazide into the duodenum enhanced the colonic absorption of ester. Compared to bolus infusion, continuous delivery of the ester resulted in a more sustained levodopa concentration in plasma, and less metabolism into dopamine. The results were repeated for methyl ester, and the relative differences between the results of methyl and butyl esters versus levodopa were similar. The overall results at the duodenum, jejunum, and ileum were also comparable, likewise were those for the proximal, middle, and distal colons. The results of the study are encouraging: a combination of the continuous delivery of levodopa ester with an immediate-release of benserazide optimizes levodopa bioavailability, potentially leading to a much more effective use of levodopa in the treatment of Parkinson's patients.

Role of serotonin type 1A receptors in fluvoxamine-induced inhibition of marble-burying behavior in mice.

This study examined the roles of presynaptic and postsynaptic serotonin type 1A receptors in fluvoxamine-induced inhibition of marble-burying behavior in mice. The effect of fluvoxamine was attenuated by the serotonin type 1A receptor antagonist WAY100635 at 1 mg/kg, while it was enhanced by the antagonist at 0.1 mg/kg. Fluvoxamine (30 mg/kg) and WAY100635 (0.1 and 1 mg/kg) did not affect spontaneous locomotor activity. These results suggest that the effect of fluvoxamine is mediated by postsynaptic serotonin type 1A receptors and it is enhanced by an inhibition of presynaptic serotonin type 1A receptors.

Modification of cocaine-induced behavioral and neurochemical effects by serotonin1A receptor agonist/antagonist in mice.

Administration of cocaine causes a locomotor stimulant effect and increases extracellular levels of serotonin (5-HT) and dopamine (DA) in the brains of rodents. Previous studies show that 5-HT1A receptor agonist and antagonist modify the cocaine-induced behavioral and neurochemical effects in the rats. However, the role of the 5-HT system on the effects of cocaine has not been studied in the prefrontal cortex. The present study examined in ddY-strain male mice the effects of the 5-HT1A receptor agonist osemozotan and the receptor antagonist WAY100635 on cocaine-induced locomotor stimulant effect and increases in extracellular levels of 5-HT and DA in the prefrontal cortex. The cocaine-induced locomotor stimulant effect was attenuated by osemozotan and enhanced by WAY100635. The cocaine-induced increase in extracellular levels of 5-HT was attenuated by osemozotan, and enhanced by WAY100635. The cocaine-induced increase in extracellular levels of DA was enhanced by osemozotan, but not affected by WAY100635. These results suggest that the prefrontal 5-HT system plays a pivotal role in the locomotor stimulant effect of cocaine in mice.

Effects of osemozotan, ritanserin and azasetron on cocaine-induced behavioral sensitization in mice.

Repeated intermittent administration of psychostimulants causes behavioral sensitization in rodents. Previous studies using serotonin (5-HT) receptor ligands show that the 5-HT system is involved in cocaine-induced behavioral sensitization in rats, but the role of the 5-HT system has not been studied in mice. The present study examined the effects of the 5-HT(1A) receptor agonist osemozotan, the 5-HT(2) receptor antagonist ritanserin and the 5-HT(3) receptor antagonist azasetron on cocaine-induced behavioral sensitization in male ddY mice. Repeated administration of cocaine for 7 days enhanced cocaine-induced locomotor activity, and this sensitization was observed even after withdrawal for 7-14 days. Cocaine-induced behavioral sensitization after a 7-day withdrawal was significantly reduced with the coadministration of osemozotan, ritanserin or azasetron with cocaine repeatedly for 7 days. A single injection of osemozotan or ritanserin before cocaine challenge also reduced repeated cocaine-induced behavioral sensitization. However, none of these ligands inhibited cocaine-induced behavioral sensitization, when each drug was administered for 7 days after repeated cocaine administration. These results suggest that the central 5-HT system plays a role in the development and expression, but not maintenance, of behavioral sensitization in cocaine-treated mice.

Reciprocating dialysis tube method: periodic tapping improved in vitro release/dissolution testing of suppositories.

The reciprocating dialysis tube (RDT) method can be used for in vitro release/dissolution testing of suppositories and has been reported to show good in vitro and in vivo correlation. However, for suppositories with viscous excipients, the result remains variable and generally under-predicts in vivo absorption. The purpose of this study was to assess whether periodic tapping of the closure of the RDT could improve in vitro release testing of suppositories. Two commercially available acetaminophen suppositories (A and B) that showed characteristic release behavior under normal rectal temperatures (37 and 38 degrees C) were chosen as test suppositories. In the absence of tapping, suppository A showed different release profiles at 37 and 38 degrees C, but the difference disappeared with periodic tapping. This finding was consistent with minimum temperature effect in the rectal absorption of suppository A in rabbits. Suppository B showed distinct release profiles at 37 and 38 degrees C irrespective of tapping, and the rectal absorption of suppository B in rabbits was affected by temperature. The test variability (CV% and ranges of release values) was substantially reduced in the presence of tapping. In conclusion, the addition of periodic tapping to RDT method developed in this study could improve in vitro release testing of suppositories.

Protective effect of the radical scavenger edaravone against methamphetamine-induced dopaminergic neurotoxicity in mouse striatum.

The administration of high doses of methamphetamine causes the degeneration of striatal dopaminergic fibers in the brains of rodents, and oxidative stress appears to be one of the main factors of neurotoxicity. This study examined whether edaravone, a radical scavenger, protects against methamphetamine-induced neurotoxicity in mice. Methamphetamine treatment (4 mg/kg, s.c. x 4 with 2 h intervals) showed striatal dopaminergic degeneration as observed by decreases in dopamine levels and tyrosine hydroxylase immunoreactivity in the striatum. The neurotoxicity was reduced by edaravone (3 mg/kg, i.p.), when it was administered four times 30 min before methamphetamine at 2 h intervals and additionally four times after methamphetamine at 12 h intervals. An immunohistochemical study showed that methamphetamine increased 3-nitrotyrosine immunoreactivity, an in vivo marker of peroxynitrite production, and activated microglia and astrocytes in the striatum. Edaravone blocked the increase in 3-nitrotyrosine immunoreactivity and the activation of astrocytes, but it did not affect the activation of microglia. Edaravone did not affect methamphetamine-induced hyperthermia and striatal dopamine release. These results suggest that edaravone protects against methamphetamine-induced neurotoxicity in the striatum by blocking peroxynitrite production. This study also suggests that methamphetamine activates microglia in a radical-independent mechanism.

Effect of zotepine on dopamine, serotonin and noradrenaline release in rat prefrontal cortex.

The present study examined the effect of zotepine, an atypical antipsychotic, on the in vivo release of monoamines in the prefrontal cortex of rats using microdialysis. Local perfusion of zotepine at 10 microM increased extracellular levels of serotonin (5-HT), as well as dopamine and noradrenaline, in the prefrontal cortex. However, systemic administration of zotepine did not affect 5-HT release, although it increased the dopamine and noradrenaline release. These results suggest that the prefrontal 5-HT system does not contribute to the antidepressant effect of zotepine. The difference in the effect of zotepine between local and systemic treatment is discussed.

Antidepressant-like effect of coadministration of sulpiride and fluvoxamine in mice.

We have recently reported that coadministration of sulpiride, an antipsychotic drug, and fluvoxamine, a selective serotonin (5-HT) reuptake inhibitor, selectively increases in vivo dopamine release in the prefrontal cortex. This study examined the effects of coadministration of these drugs on duration of immobility in the tail suspension test using mice. Neither sulpiride (3 or 10 mg/kg) nor fluvoxamine (10 or 20 mg/kg) alone affected immobility time, whereas coadministration significantly reduced immobility time. WAY 100635, a 5-HT(1A) receptor antagonist, did not affect the effects of sulpiride and fluvoxamine coadministration, but reduced immobility time in combination with fluvoxamine (20 mg/kg). A high dose of fluvoxamine alone (60 mg/kg) also reduced immobility time. These results suggest that the antidepressant-like effects of fluvoxamine in combination with sulpiride or WAY 100635 in the tail suspension test are mediated by the activation of dopamine or 5-HT systems, respectively.

The selective Na+-Ca2+ exchange inhibitor attenuates brain edema after radiofrequency lesion in rats.

2-[4-[(2,5-Difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a specific inhibitor of the Na+-Ca2+ exchanger, exerts cytoprotective action and reduces brain infarct volume after cerebral ischemia. We examined the effect of SEA0400 on vasogenic brain edema in rats. Histological observations showed that radiofrequency current caused brain infarct and extravasation of endogenous albumin in the brain. SEA0400 (3 and 10 mg/kg, i.v.) significantly suppressed the increase in brain water content with attenuation of Evans blue dye and sodium fluorescein extravasation after radiofrequency lesion. The findings suggest that the Na+-Ca2+ exchanger plays a role in vasogenic edema formation after radiofrequency lesion.