Mitsuhiro Yoshioka

NG-methyl-L-arginine, an inhibitor of L-arginine-derived nitric oxide synthesis, stimulates renal sympathetic nerve activity in vivo. A role for nitric oxide in the central regulation of sympathetic tone?

Continuous production of endothelium-derived nitric oxide (NO) in peripheral vessels has been shown to modulate vascular resistance and blood pressure. NO is also formed in the brain upon activation of glutamate receptors, which are thought to mediate central autonomic reflexes. In the present study we assessed whether NO plays a role in central autonomic regulation. For this, we have investigated the effects of NG-methyl-L-arginine (NMA), a selective inhibitor of NO synthesis from L-arginine, on sympathetic renal nerve activity (RNA), blood pressure, and heart rate in the anesthetized rat. NMA elicited a dose-dependent sustained increase in blood pressure (approximately 20 and 30 mm Hg, 5 minutes after 10 and 50 mumol/kg i.v., respectively). Heart rate and RNA decreased transiently (15 beats per minute and 40%, respectively); RNA subsequently increased (100%) while blood pressure remained elevated. Baroreceptor deafferentation markedly altered these responses to NMA; the transient decreases in heart rate and RNA were abolished, whereas the increases in RNA and blood pressure were significantly potentiated. After spinal C-1-C-2 transection, there was no increase in RNA, and blood pressure increased to a smaller extent. L-Arginine blocked the NMA-induced increases in blood pressure and RNA. Thus, in addition to modulating vascular resistance by a peripheral action, NO may also play a role in the central regulation of sympathetic tone.

Effects of conditioned fear stress on 5-HT release in the rat prefrontal cortex

The effects of conditioned fear stress (CFS) on 5-HT release in the medial prefrontal cortex were studied by in vivo microdialysis. CFS (exposure to an environment in which foot-shock had been delivered previously) induced a marked suppression of motility-that is, freezing behavior. The extracellular concentration of 5-HT in the medial prefrontal cortex increased during this freezing behavior, but no significant changes were observed in the concentration of its metabolite, 5-HIAA. The increased 5-HT concentration returned to pretreatment levels when the animals were returned to their home cages. Diazepam (0.5 mg/kg, intraperitoneally) reduced the CFS-induced freezing behavior and prevented the increases in extracellular 5-HT levels. A 5-HT3 receptor antagonist, tropisetron (10 and 100 micrograms/kg), also inhibited both the CFS-induced increase in 5-HT release and the freezing behavior. These findings suggest that there is a relationship between anxiety and 5-HT release in the prefrontal cortex and that the 5-HT3 receptor antagonist tropisetron might have anxiolytic properties.

Dietary Docosahexaenoic Acid Increases Cerebral Acetylcholine Levels and Improves Passive Avoidance Performance in Stroke-Prone Spontaneously Hypertensive Rats

We have recently shown that inferior performance in passive avoidance task is accompanied with decreased hippocampal choline (Ch) in stroke-prone spontaneously hypertensive rats (SHRSP) compared with normotensive control Wistar-Kyoto rats (WKY). We also reported that dietary docosahexaenoic acid (DHA) suppresses the development of hypertension and stroke-related behavioral changes, resulting in the prolongation of the life span of SHRSP. In this study, we examined the effect of dietary DHA on the cerebral acetylcholine (ACh) levels and learning performance in passive avoidance tasks in SHRSP. The arachidonic acid decreased and the DHA increased in plasma lipids dose dependently with dietary DHA treatments, which decreased the systolic blood pressure in SHRSP. Dietary DHA significantly restored the significantly inferior learning performance in passive avoidance response observed in control SHRSP (DHA 0%). Furthermore, the hippocampal ACh levels were correlated positively with the total response latency in passive avoidance tasks. These results suggest that cholinergic dysfunction in the brain of control SHRSP is responsible, at least in part, for the impaired learning ability and the dietary DHA ameliorates this performance failure.

Effect of conditioned fear stress on dopamine release in the rat prefrontal cortex

The effects of conditioned fear stress (CFS) on dopamine release in the medial prefrontal cortex were studied by in vivo microdialysis in the rat. CFS (exposure to an environment in which foot-shock had been delivered previously) induced a marked suppression of motility, i.e., freezing behavior. Extracellular concentrations of dopamine in the medial prefrontal cortex were increased by CFS. The increase of dopamine returned to the pretreatment levels when rats were returned to the home cages. Diazepam (0.5 mg/kg, i.p.) suppressed both the CFS-induced freezing behavior and extracellular dopamine levels in the medial prefrontal cortex. These findings suggest that anxiety and dopamine release in the prefrontal cortex might be related.

Pharmacological aspects of anticancer drug-induced emesis with emphasis on serotonin release and vagal nerve activity.

Cytotoxic drug-induced nausea and vomiting are the side effects most feared by cancer patients. Emesis is an instinctive defense reaction caused by the somatoautonomic nerve reflex, which is integrated in the medulla oblongata. Emesis caused by cytotoxic drugs such as cisplatin is associated with an increase in the concentration of 5-hydroxytryptamine (5-HT) in the intestine and the brainstem. It is proposed that cytotoxic drugs evoke 5-HT release from the enterochromaffin (EC) cells in the intestinal mucosa and that the released 5-HT stimulates the 5-HT receptors on the adjacent vagal afferent nerves. The depolarization of the vagal afferent nerves stimulates the vomiting center in the brainstem and eventually induces a vomiting reflex. 5-HT released from EC cells seems to mediate the cisplatin-induced emesis sensitive to 5-HT(3) receptor antagonists. The release of 5-HT from the EC cells, however, is regulated by polymodal mechanisms on autoreceptors or heteroreceptors. The precise role of 5-HT on the occurrence of vomiting has not been fully elucidated. The present review aims to describe the role of 5-HT in anticancer drug-induced emesis from the viewpoint of 5-HT release and afferent vagus nerve activity. Various methods for predicting emesis are also evaluated.

Central distribution and function of 5-HT6 receptor subtype in the rat brain

The purpose of the present study was to elucidate the distribution of 5-HT6 receptor mRNA and possible physiological functions of the 5-HT6 receptor subtype using antisense oligonucleotides (AOs) in rats. Continuous intracerebroventricular injection of AOs caused a 30% reduction in the number of [3H]-lysergic acid diethylamide binding sites. Conditioned fear stress-induced increase in 5-HT release from the prefrontal cortex was significantly inhibited by treatment with AOs. The present study suggests that 5-HT6 receptors may be functionally expressed in the brain, where one of the functions appears to be in the mediation of certain anxiety disorders.

Effects of acute repetitive transcranial magnetic stimulation on dopamine release in the rat dorsolateral striatum

Animal studies have shown that descending pathways from the frontal cortex modulate dopamine (DA) release in the striatum. This modulation is thought to be relevant to the pathophysiology of Parkinsons disease. In human, repetitive transcranial magnetic stimulation (rTMS) can result in functional changes in the cortex. The present study intended to clarify the effects of acute rTMS treatment using various stimulation intensities on the extracellular DA concentrations in the rat dorsolateral striatum. The frontal brain of each rat received acute rTMS treatment, which consisted of 500 stimuli from 20 trains in a day. Each train was applied at 25 Hz for 1 s with 1-min intervals between trains. The neurochemical effects of acute rTMS treatment were investigated by determining the extracellular concentrations of DA in the rat dorsolateral striatum using in vivo microdialysis. Acute rTMS treatment of the frontal brain using the stimulation intensity of almost 110% motor threshold (MT) markedly and continuously increased the extracellular DA concentrations in the rat dorsolateral striatum. The present study demonstrates that acute rTMS treatment of the frontal brain affects the DAergic neuronal system in the rat dorsolateral striatum, and may have therapeutic implications for Parkinsons disease.

Consecutive evaluation of nitric oxide production after transient cerebral ischemia in the rat hippocampus using in vivo brain microdialysis

The time-course effects of transient cerebral ischemia on nitric oxide (NO) formation in the rat hippocampus were evaluated by the consecutive determination of oxidative NO metabolites (NO2- and NO3-), using brain microdialysis under the freely moving condition. Bilateral carotid artery occlusion (CAO; 2-vessel occlusion, 2VO; 10 and 20 min) and combined vertebral artery occlusion (4VO; 10 min) produced a transient increase in hippocampal NO2- and NO3- levels, according to the duration and degree of ischemic insults. In addition, 4VO produced a gradual increase in hippocampal NO2- and NO3- levels over a 24 h period after reperfusion, which was abolished by an inducible NO synthase inhibitor, aminoguanidine (10 mg/kg, intraperitoneally). These findings suggest that the dynamic changes in oxidative NO metabolite levels reflect NO production following transient cerebral ischemia, which is possibly mediated in part by an inducible NO synthase, in the rat hippocampus.

Behavioural and pharmacological relevance of stroke-prone spontaneously hypertensive rats as an animal model of a developmental disorder

The present study evaluates juvenile stroke-prone spontaneously hypertensive rats (SHRSP) as an animal model of a developmental disorder, which is diagnosed according to hyperactivity-impulsivity and/or inattention. To characterize behavioural alterations, we studied motor activity, as well as emotional and cognitive behaviours in juvenile SHRSP, with and without methylphenidate, a psychostimulant. Ambulatory and rearing activities in the open-field environment were significantly higher in SHRSP than in Wistar–Kyoto rats (WKY). In the elevated plus maze task, the entries into open arms, as an index of impulsivity, were significantly increased in SHRSP. In the Y-maze task, spontaneous alternation behaviour, as an index of attention, was significantly lowered in the male SHRSP, but not in the female SHRSP, indicating that spontaneous alternation deficit is gender specific. Methylphenidate (0.01–1 mg/kg, i.p.) significantly attenuated locomotor hyperactivity at low doses and dose-dependently improved the spontaneous alternation deficit in SHRSP. Our findings reveal that juvenile SHRSP manifest problematic behaviours resembling a developmental disorder, attention-deficit/hyperactivity disorder (ADHD), namely hyperactivity-impulsivity and/or inattention. Methylphenidate alleviated the behavioural symptoms of hyperactivity and inattention. We propose that juvenile SHRSP are an appropriate animal model of a developmental disorder resembling ADHD, from behavioural and pharmacological perspectives.

Pharmacological characterisation of 5-HT receptors positively coupled to adenylyl cyclase in the rat hippocampus.

The pharmacological properties of 5-hydroxytryptamine (5-HT) receptors positively coupled to adenylyl cyclase in the rat hippocampus were investigated using selective agonists and antagonists. 5-HT (0.008–125 μM) stimulated cyclic AMP formation in homogenates of rat hippocampus in a concentration-dependent manner. The maximal increase in cyclic AMP formation occurred at 1 μM (141 ± 6%) and the half-maximal effect (EC50) at 50 ± 22 nM. Cyclic AMP accumulation induced by 1 μM 5-HT was partly inhibited by the selective 5-HT1A receptor antagonist WAY 100,635 (1 μM), the selective 5-HT4 receptor antagonist SB 203,186 (1 μM), and the 5-HT2A/C/ 5-HT7 receptor antagonist mesulergine (25 μM). WAY 100,635, SB 203,186 and mesulergine inhibited the effect of 5-HT (1 μM) by 47%, 33% and 49%, respectively. The combination of WAY 100,635 (1 μM) with SB 203,186 (1 μM) or mesulergine (25 μM) resulted in stronger inhibition than with each antagonist alone, and the combination of all three antagonists produced almost total blockade (95%) of 5-HT-induced cyclic AMP accumulation. 5-Carboxamidotryptamine (5-CT; 0.008–125 μM), a 5-HT1/5-HT7 receptor agonist, and SDZ 216–454 (0.008– 125 μM), a selective 5-HT4 receptor agonist, concentration-dependently stimulated cyclic AMP formation, but the maximal effect of each agonist was smaller than that of 5-HT alone. SDZ 216–454 (5 μM) and 5-CT (5 μM) in combination stimulated cyclic AMP formation in an additive manner. 8-OH-PIPAT and 8-OH-DPAT, two selective 5-HT1A agonists, produced a small but significant increase in cyclic AMP formation at concentrations above 0.04 μM and 10 μM, respectively. These findings suggest that at least three 5-HT receptor subtypes, i.e. 5-HT1A, 5-HT7 and 5-HT4 receptors, are involved in mediating 5-HT-induced cyclic AMP formation in rat hippocampus.