Taiichiro Imanishi

Ameliorating effects of rolipram on experimentally induced impairments of learning and memory in rodents

The effects of rolipram, a cAMP-specific phosphodiesterase (phosphodiesterase 4) inhibitor, on experimentally-induced amnesia were examined using a 3-panel runway paradigm in rats and a passive avoidance task in mice. Scopolamine, cerebral ischemia induced by four-vessel occlusion and electric convulsive shock impaired working memory in the 3-panel runway task. Rolipram at 0.1 mg/kg reduced the increase in errors induced by scopolamine or cerebral ischemia. Rolipram at 0.32 mg/kg also reduced the increase in errors induced by electric convulsive shock. Dibutyryl cAMP also had similar effects in 3-panel runway experiments. In the passive avoidance task, rolipram reversed the impairments of the avoidance response induced by scopolamine, cycloheximide and electric convulsive shock at 10, 10 and 3 mg/kg, respectively. These results indicate that rolipram ameliorates impairments of learning and memory in rats and mice, and suggest that rolipram might ameliorate the impairments of learning and memory by elevating cAMP levels.

Comparison of the anticholinergic effects of the serotonergic antidepressants, paroxetine, fluvoxamine and clomipramine.

Paroxetine, a selective serotonin reuptake inhibitor, shows relatively high affinity for muscarinic acetylcholine receptors compared to other selective serotonin reuptake inhibitors. To determine whether paroxetine has anticholinergic effects in vivo, we examined the effects of paroxetine on oxotremorine-induced tremor, spontaneous defecation and passive avoidance performance using mice and compared the results with those using fluvoxamine, another selective serotonin reuptake inhibitor, and clomipramine, a tricyclic antidepressant with serotonin selectivity. The potency of antidepressant activity as determined in the tail suspension test was paroxetine>fluvoxamine>clomipramine. Paroxetine and clomipramine inhibited oxotremorine-induced tremor, reduced spontaneous defecation and impaired passive avoidance performance, while fluvoxamine did not have similar effects. A comparison of ED(50) values showed that the ratio of anticholinergic effect to antidepressant activity was fluvoxamine, >3.2; paroxetine, 2.1-2.6; clomipramine, <0.8. These results suggest that paroxetine may induce fewer adverse anticholinergic effects than clomipramine, but more than fluvoxamine.

Anxiolytic-like profile of mirtazapine in rat conditioned fear stress model: Functional significance of 5-hydroxytryptamine 1A receptor and α1-adrenergic receptor

Mirtazapine is an antidepressant with a unique mechanism of action and has been categorized as a Noradrenergic and Specific Serotonergic Antidepressant (NaSSA). Although numerous clinical trials suggested the usefulness of mirtazapine for not only major depressive disorders but also a variety of anxiety disorders, efficacy studies in animal anxiety models have been rarely reported. The present study investigated a potential anxiolytic-like profile of mirtazapine in rat conditioned fear stress model. A 5-hydroxytryptamine (5-HT) 1A receptor partial agonist, buspirone (1-5 mg/kg) exhibited a significant reduction in freezing time, and its maximal effect was reversed by a selective 5-HT(1A) antagonist, WAY-100635 (1 mg/kg). Mirtazapine (1-10 mg/kg) also reduced the freezing time in a dose-related fashion, a substantial proportion (approx. 50%) of which was likewise antagonized by WAY-100635 (1 mg/kg). Mianserin (1-30 mg/kg), a structural analogue for mirtazapine, was ineffective. Furthermore, co-administration of alpha1 adrenoceptor antagonist, prazosin (0.03 mg/kg) completely reversed mirtazapine (10 mg/kg)-induced reduction of freezing time. These findings represent the first demonstration that the anxiolytic-like action of mirtazapine involves activation of 5-HT(1A) receptor and alpha1 adrenoceptor to different extents, and are compatible with one aspect of mirtazapines pharmacological profile as NaSSA.

The selective serotonin reuptake inhibitor fluvoxamine suppresses post-feeding hyperactivity induced by food restriction in rats

Previous studies demonstrated that rats allowed access to running wheel with food restriction schedules run excessively. This hyperactivity consisted of a pre-feeding activity (an increase in running activity before the feeding time, also termed food-anticipatory activity: FAA) and a post-feeding activity (an increase in running activity after the feeding time, succeeding activity: SA). Here we evaluated the effect of fluvoxamine, a selective serotonin reuptake inhibitor, on food restriction-induced hyperactivity in rats. Furthermore, the effect of fluvoxamine on each of the FAA and the SA was also investigated. Rats were individually housed in a running-wheel cage under food restriction for 3 h per day, and running activity was measured for 7 consecutive days. This restricted feeding significantly increased the running activity and decreased body weight. Simultaneous administration of fluvoxamine (50 mg/kg/day, p.o.) for 7 days suppressed the increase in running activity (P<0.05) with no modification of the decrease in body weight or food intake. Analysis of each activity revealed that fluvoxamines efficacy was observed only in the SA (p<0.01). These results suggest that repeated treatment with fluvoxamine attenuates the hyperactivity, which is exclusively dependent on the substantial reduction in the SA.

A combination of mirtazapine and milnacipran augments the extracellular levels of monoamines in the rat brain.

Mirtazapine, an antidepressant, antagonizes α(2)-adrenergic autoreceptors and heteroreceptors, which leads to enhanced noradrenergic and serotonergic transmission without inhibiting monoamine transporters. Using a microdialysis technique, we investigated whether co-administration of mirtazapine and a serotonin noradrenaline reuptake inhibitor (SNRI), milnacipran, augments the effects of each drug on the extracellular levels of monoamines by pharmacological synergy. Mirtazapine increased the extracellular levels of noradrenaline and serotonin in the dorsal hippocampus. In contrast, it increased the levels of noradrenaline and dopamine without changing serotonin levels in the prefrontal cortex. Milnacipran increased the levels of all monoamines evaluated in both areas, and the combined treatment with mirtazapine augmented these changes. The combined treatment with idazoxan, an α(2) adrenoceptor antagonist, and milnacipran also increased all monoamine levels in the prefrontal cortex. Ketanserin, a serotonin 5-HT(2A) receptor antagonist, showed no effect in combination with milnacipran, while SB242084, a 5-HT(2C) receptor antagonist, augmented the effects of milnacipran on the levels of serotonin and dopamine in the prefrontal cortex. These results suggest that combined treatment with mirtazapine and milnacipran augments the extracellular levels of noradrenaline, serotonin and dopamine through the blockade of α(2) adrenoceptors without regional specificity, whereas mirtazapine enhances serotonergic transmission in a region-specific manner. 5-HT(2C) receptor antagonism may also partly contribute to the amplification effects of mirtazapine on serotonin and dopamine levels. These neurochemical changes could play a role in reported advantageous clinical effects in patients treated with an SNRI and mirtazapine.

Possible involvement of peripheral serotonin 5-HT3 receptors in fluvoxamine-induced emesis in Suncus murinus.

Selective serotonin reuptake inhibitors fluvoxamine and fluoxetine, as well as serotonin (5‐HT), induced vomiting in Suncus murinus (a house musk shrew). Fluvoxamine‐ and fluoxetine‐induced vomiting gradually decreased with their repeated administration. Vomiting induced by serotonin also decreased with repeated treatment with serotonin. In these shrews, fluvoxamine‐induced vomiting was partially inhibited. Fluvoxamine might induce vomiting, at least partially, by indirectly activating peripheral 5‐HT3 receptors, since serotonin has been reported to induce vomiting by activating peripheral 5‐HT3 receptors and granisetron, a 5‐HT3 antagonist, partially suppressed fluvoxamine‐induced vomiting in our previous finding. In addition, fluvoxamine‐induced vomiting was impaired more effectively using a step‐wise dose‐up schedule of fluvoxamine than a fixed high‐dose schedule. Therefore, a careful dosing strategy starting with a low dose might be effective for avoiding emesis associated with the clinical use of fluvoxamine.

Asenapine reduces anxiety-related behaviours in rat conditioned fear stress model.

Objective Asenapine is an atypical antipsychotic that is currently available for the treatment of schizophrenia and bipolar I disorder. Although the atypical antipsychotics clozapine and olanzapine are effective for depression and anxiety in schizophrenia, as demonstrated by animal model studies, this has not been clarified for asenapine. Therefore, we compared the effects of asenapine in the conditioned fear stress model with those of clozapine and olanzapine. Method Rats were individually fear conditioned using electrical foot shock in a Skinner box. Approximately 24 h later, individual animals were returned to the same Skinner box (without electrical shock) and their freezing behaviour was observed for 5 min. Animals were treated with asenapine, clozapine, olanzapine, the 5-HT1A receptor partial agonist buspirone, or the 5-HT2C receptor antagonist SB242084 at 30 min before freezing behaviour assessment. The 5-HT1A receptor antagonist WAY100635 or the 5-HT2C receptor agonist Ro60-0175 was also used concomitantly with asenapine. The effects of asenapine, clozapine, and olanzapine on serotonin release in the rat hippocampus were also measured using in vivo microdialysis. Results Asenapine reduced freezing behaviour, while neither clozapine nor olanzapine reduced freezing behaviour. Buspirone and SB242084 also reduced freezing behaviour. The effect of asenapine in reducing freezing behaviour was not altered by the concomitant administration of WAY100635 or Ro60-0175. Both asenapine and clozapine, but not olanzapine, increased serotonin release in the rat hippocampus. Conclusion Asenapine may have superior therapeutic effect on anxiety symptoms than other agents, although the underlying mechanism of its anxiolytic activity remains unknown.