Atomoxetine-induced increases in monoamine release in the prefrontal cortex are similar in spontaneously hypertensive rats and Wistar-Kyoto rats.

Spontaneously hypertensive rats (SHRs) are used as a model for attention-deficit/hyperactivity disorder (ADHD), since SHRs are hyperactive and show defective sustained attention in behavioral tasks. The psychostimulants amphetamine and methylphenidate and the selective norepinephrine reuptake inhibitor atomoxetine are used as ADHD medications. The effects of high K(+) stimulation or psychostimulants on brain norepinephrine or dopamine release in SHRs have been previously studied both in vitro and in vivo, but the effects of atomoxetine on these neurotransmitters have not. The present study examined the effects of administration of atomoxetine on extracellular norepinephrine, dopamine, and serotonin levels in the prefrontal cortex of juvenile SHRs and Wistar-Kyoto (WKY) rats. Baseline levels of prefrontal norepinephrine, dopamine, and serotonin were similar in SHRs and WKY rats. Systemic administration of atomoxetine (3 mg/kg) induced similar increases in prefrontal norepinephrine and dopamine, but not serotonin, levels in both strains. Furthermore, there was no difference in high K(+)-induced increases in extracellular norepinephrine, dopamine, and serotonin levels in the prefrontal cortex between SHRs and WKY rats. These findings indicate that monoamine systems in the prefrontal cortex are similar between SHRs and WKY rats.

Effects of acute and chronic administration of venlafaxine and desipramine on extracellular monoamine levels in the mouse prefrontal cortex and striatum.

Prefrontal catecholamine neurotransmission plays a key role in the therapeutic actions of drugs for attention-deficit/hyperactivity disorder (ADHD). We have recently shown that serotonin/noradrenaline reuptake inhibitors and the noradrenaline reuptake inhibitor desipramine attenuated horizontal hyperactivity in spontaneously hypertensive rats, an animal model of ADHD, and that these drugs are potential pharmacotherapeutics for ADHD. In this study, we used in vivo microdialysis to study the effects of acute and chronic (once daily for 3 weeks) administration of the serotonin/noradrenaline reuptake inhibitor venlafaxine and the noradrenaline reuptake inhibitor desipramine on noradrenaline, dopamine, and serotonin levels, and the expression of the neuronal activity marker c-Fos in the mouse prefrontal cortex and striatum. Both acute and chronic venlafaxine administration increased prefrontal noradrenaline, dopamine, and serotonin levels and striatal noradrenaline and serotonin levels. Both acute and chronic desipramine administration increased prefrontal noradrenaline and dopamine levels and striatal noradrenaline levels, with chronic administration yielding stronger increase. Chronic desipramine did not affect striatal dopamine and serotonin levels. Both acute and chronic venlafaxine administration increased the expression of c-Fos in the prefrontal cortex, whereas chronic, but not acute, desipramine administration increased the expression of c-Fos in the prefrontal cortex. Both acute and chronic venlafaxine administration increased the striatal c-Fos expression to some degree, whereas desipramine administration did not. These results suggest that acute and chronic venlafaxine and chronic desipramine administration maximally activate the prefrontal adrenergic and dopaminergic systems without affecting striatal dopaminergic systems in mice.

The analgesic effect of tramadol in animal models of neuropathic pain and fibromyalgia.

(±)-Tramadol hydrochloride (tramadol) is a widely used analgesic for the treatment of cancer pain and chronic pain. Although many animal studies have shown antinociceptive effects of tramadol in both acute and chronic pain, little is known about the effect of tramadol in putative animal models of fibromyalgia. In this study, we compared the antiallodynic effects of oral administration of tramadol in two kinds of rat chronic pain models, neuropathic pain induced by partial sciatic nerve ligation (PSL) and reserpine-induced myalgia (RIM). In PSL rats, the threshold for responses induced by tactile stimulation with von Frey filaments was significantly decreased seven days after the operation, suggesting that the operation induced tactile allodynia. Orally administered tramadol showed a potent and dose-dependent antiallodynic effect on PSL-induced allodynia. In RIM rats, the threshold was significantly decreased five days after reserpine treatment. Orally administered tramadol also attenuated reserpine-induced tactile allodynia. To explore the mechanism of the antiallodynic effect of tramadol in RIM rats, we investigated the effect of the opioid antagonist naloxone on the tramadol-induced analgesic effect in these rats. The effect of tramadol was partially antagonized by naloxone, suggesting that the opioid receptor is involved at least in part in the antiallodynic effect of tramadol in RIM rats. These data indicate that orally administered tramadol produced improvement in both PSL rats and RIM rats at similar doses and provide evidence that the opioid system is partly involved in the analgesic effect of tramadol in RIM rats.

Methylphenidate and venlafaxine attenuate locomotion in spontaneously hypertensive rats, an animal model of attention-deficit/hyperactivity disorder, through α2-adrenoceptor activation.

Recent clinical studies have shown that serotonin-norepinephrine reuptake inhibitors such as venlafaxine and duloxetine are effective against symptoms of attention-deficit/hyperactivity disorder such as inattention, oppositionality, and hyperactivity. We have recently found that these serotonin-norepinephrine reuptake inhibitors, like methylphenidate, reduced the hyperactivity in spontaneously hypertensive rats (SHR), an animal model of attention-deficit/hyperactivity disorder. The present study investigated whether the α2-adrenoceptor and the dopamine-D1 receptor are involved in the behavioral effects of methylphenidate and venlafaxine in SHR. Adolescent male SHR showed greater horizontal locomotion in a familiar open field than male Wistar Kyoto and Wistar rats, and methylphenidate (0.3 mg/kg) and venlafaxine (30 mg/kg) reduced horizontal locomotion in SHR, but not Wistar Kyoto or Wistar rats. The effects of methylphenidate and venlafaxine were blocked by idazoxan (an α2-adrenoceptor antagonist), but not by SCH23390 (a dopamine-D1 receptor antagonist). These findings suggest that the α2-adrenoceptor plays a key role in the effects of methylphenidate and venlafaxine on enhanced locomotion in SHR.

Effects of serotonin-norepinephrine reuptake inhibitors on locomotion and prefrontal monoamine release in spontaneously hypertensive rats.

Catecholamine neurotransmission in the prefrontal cortex plays a key role in the therapeutic actions of drugs for attention-deficit/hyperactivity disorder (ADHD). Recent clinical studies show that several serotonin-norepinephrine reuptake inhibitors have potential for treating ADHD. In this study, we examined the effects of acute treatment with serotonin-norepinephrine reuptake inhibitors on locomotion and the extracellular levels of monoamines in the prefrontal cortex in spontaneously hypertensive rats (SHR), an animal model of ADHD. Adolescent male SHR exhibited greater horizontal locomotion in an open-field test than male WKY control rats. Psychostimulant methylphenidate (0.3 and 1 mg/kg), the selective norepinephrine reuptake inhibitor atomoxetine (1 and 3 mg/kg), and serotonin-norepinephrine reuptake inhibitors duloxetine (10 mg/kg), venlafaxine (10 and 30 mg/kg) and milnacipran (30 mg/kg) reduced the horizontal activity in SHR, but did not affect in WKY rats. The selective norepinephrine reuptake inhibitor reboxetine (10 mg/kg) and the tricyclic antidepressant desipramine (10 and 30 mg/kg) also reduced the horizontal activity in SHR, whereas the selective serotonin reuptake inhibitor citalopram (30 mg/kg) did not. Microdialysis studies showed that atomoxetine, methylphenidate, duloxetine, venlafaxine, milnacipran, and reboxetine increased the extracellular levels of norepinephrine and dopamine in the prefrontal cortex in SHR. Citalopram did not affect norepinephrine and dopamine levels in the prefrontal cortex, although it increased the serotonin levels. Neither duloxetine nor venlafaxine increased the dopamine levels in the striatum. These findings suggest that serotonin-norepinephrine reuptake inhibitors, similar to methylphenidate and atomoxetine, have potential for ameliorating motor abnormality in the SHR model.

Design and synthesis of 3-substituted benzamide derivatives as Bcr-Abl kinase inhibitors.

A series of 3-substituted benzamide derivatives structurally related to STI-571 (imatinib mesylate), a Bcr-Abl tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML), was prepared and evaluated for antiproliferative activity against the Bcr-Abl-positive leukemia cell line K562. About ten 3-halogenated and 3-trifluoromethylated benzamide derivatives were identified as highly potent Bcr-Abl kinase inhibitors. One of these, NS-187 (9b), is a promising new candidate Bcr-Abl inhibitor for the therapy of STI-571-resistant chronic myeloid leukemia.