Kouichi Kurata

Comparative study of dopamine metabolism with local cerebral glucose utilization in rat brain following the administration of haloperidol decanoate

The effects of haloperidol decanoate on dopamine (DA) metabolism in discrete regions of rat brain were investigated and compared with changes in local cerebral glucose utilization (LCGU). The concentration of DA and its metabolite, homovanillic acid, and the alpha-methyl-p-tyrosine (alpha-MT)-induced decline of DA were measured in 6 brain regions by a high-performance liquid chromatographic assay. LCGU in 26 brain regions were examined by [14C]2-deoxy-D-glucose autoradiography. At 24-hr after intramuscular injection of haloperidol decanoate (60 mg eq/kg to haloperidol), the concentration of homovanillic acid in the prefrontal cortex, caudate-putamen, accumbens nucleus, lateral amygdala, and medial thalamus showed significant increase compared with control values. On day 21, the increase in these regions was significantly attenuated with no significant difference from the controls. Furthermore, chronic haloperidol rats showed alpha-MT-induced decline of DA to a similar extent in the control rats. LCGU on day 21 showed significant decrease in the parietal cortex, and a tendency toward decrease in the prefrontal cortex, lateral amygdala and medial thalamus compared with the controls. There was no significant change in LCGU in the caudate-putamen or accumbens nucleus. Chronic haloperidol would thus appear to affect energy metabolism mainly in the cortico-thalamo-limbic circuits, and this may not correspond well to presynaptic DA metabolism.

Impact of depressive mixed state in an emergency psychiatry setting: A marker of bipolar disorder and a possible risk factor for emergency hospitalization

BACKGROUND Depressive mixed state (DMX) has been reported to be one of the most useful clinical markers for bipolar II disorder (BP-II) in the outpatient setting. However, the significance of DMX in emergency psychiatry has not been well studied. METHODS A chart review study of 139 patients who were hospitalized in an emergency psychiatric ward with an initial diagnosis of major depressive disorder (MDD). RESULTS In 42 (30.2%) patients, the diagnosis was changed to bipolar disorder after a median observation period of 189 days from hospitalization, and of these, 34 were diagnosed as having BP-II. DMX was observed in 56 (40.3%) patients at the time of hospitalization. Compared with patients who remained in MDD, significantly more patients who later developed bipolar disorder had experienced DMX (59.5% vs. 32.0%, p = 0.0044). In multivariate analysis, DMX was one of the independent predictors of conversion to bipolar disorder (OR 2.45, p = 0.037), and the independent predictors for DMX were chronic depression and atypical features (OR 2.85, p = 0.010; OR 3.67, p = 0.046, respectively). In addition, DMX was significantly more frequently observed at emergency hospitalization than at non-emergency hospitalization (48.6% vs. 29.1%, p = 0.0065). LIMITATIONS A single reviewer evaluated DMX by chart review. CONCLUSION DMX is a useful marker of bipolar disorder (mainly BP-II) in the emergency psychiatric setting and is closely related to emergency hospitalization for mood disorders. To confirm these findings, a prospective study that systematically evaluates DMX is needed.

Hypofrontality does not occur with 6-hydroxydopamine lesions of the medial prefrontal cortex in rat brain

This study examined the effect of lesions of dopamine (DA) nerve terminals the medial prefrontal cortex on local cerebral glucose utilization (LCGU) and dopamine metabolism in the rat brain. Bilateral 6-hydroxydopamine lesions were stereotaxically placed in the medial prefrontal cortex. Twenty-eight days after the lesion, concentrations of DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were determined in eight brain regions with a high-performance liquid chromatographic assay. LCGU was assessed by [14C]2-deoxy-D-glucose autoradiography. The lesion produced a striking reduction in DA (to 6% of the control value), and a moderate reduction in DOPAC and HVA in the medial prefrontal cortex. The ratio of DOPAC to DA in the medial prefrontal cortex was significantly elevated in the 6-OHDA lesioned animals. In contrast to DA depletion, LCGU in the medial prefrontal cortex of the lesioned rats was unaltered when compared with the control. These findings suggest that decreased energy metabolism in the frontal cortex, i.e., hypofrontality, does not occur with decreased DA innervation of that site.

Changes in Local Cerebral Glucose Utilization and Dopamine Metabolism in the Rat Brain Following Acute Administration of Haloperidol

Abstract: The effects of acute administration of haloperidol on local cerebral glucose utilization (LCGU) in 26 discrete regions of the rat brain were examined by the quantitative autoradiographic [14C] 2‐deoxy‐D‐glucose technique and compared with the changes in dopamine (DA) metabolism in 13 brain regions examined by a high performance liquid chromatographic assay. A moderate dose (0.25 mg/kg) of acute haloperidol significantly reduced LCGU in a few brain regions; a high dose (1.0 mg/kg) reduced LCGU in 11 regions including the prefrontal cortex, thalamus and other subcortical structures, but not in the caudate putamen or accumbens nucleus. However, the levels of DA metabolite in the caudate‐putamen, accumbens nucleus, prefrontal cortex, and medial thalamus were strikingly elevated with both doses of haloperidol. Thus, the changes in LCGU did not parallel presynaptic DA metabolism in terms of direction or distribution, and they might represent mainly the activities of postsynaptic sites.

A pharmacokinetic study of clomipramine in regions of the brain

Abstract: The pharmacokinetic profiles of clomipramine (CMP) and the serial changes of its concentration in specific brain regions were investigated in rats after an acute treatment with intravenous CMP (10 mg/kg). The CMP concentrations in plasma declined triexponentially and fitted a three‐compartment open model. The brain to plasma concentration ratio showed a constant value, 22.2 ± 4.9, 30 minutes after the injection. Regional brain differences in the CMP distribution and accumulation were also found. Four hours after the injections, the hippocampus was found to have the highest drug concentration, and the concentrations in this region were in the following order; thalamus, striatum, amygdala, cortex > pons + medulla oblongata > hypothalamus, bulbus olfactorius + septum, mesencephalon > cerebellum. Particularly, unique kinetics were observed in the cortex, amygdala and hippocampus.

Immobilization stress-induced increment of lactate metabolism in the basolateral amygdaloid nucleus is attenuated by diazepam in the rat.

Using in vivo microdialysis technique, extracellular lactate levels were measured in the basolateral amygdaloid nucleus of the rat under immobilization stress. Immobilization stress (40 min) led to a tetrodotoxin-reversible increase in dialysate lactate levels. Diazepam (1.0 mg/kg, i.p.) reduced the ability of immobilization stress to increase lactate levels. Furthermore, the attenuation of the immobilization stress-induced increase of lactate levels by diazepam was antagonized by pretreatment with flumazenil (15 mg/kg, i.p.), a selective antagonist at benzodiazepine receptors. These findings suggest that immobilization stress increases lactate levels in rat basolateral amygdaloid nuclei, which is attenuated by stimulation of benzodiazepine receptors.

Effects of D1 and D2 antagonists on the transient increase of dopamine release by dopamine agonists by means of brain dialysis

The effects of selective D1 and D2 antagonists, R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7- ol(SCH-23390) and sulpiride, on the transient increase of dopamine (DA) release induced by DA agonists, apomorphine (APO) and 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (SKF-38393) were examined in the caudate-putamen of freely moving rat by means of microdialysis during local coinfusion of a DA antagonist and agonist. Infusion of 10(-5) M and/or 10(-6) M concentrations of SCH-23390 suppressed a brief increase in DA release induced by both 10(-4) M of APO and 10(-5) M of SKF-38393. On the other hand, 10(-5) M and/or 10(-6) M of sulpiride exerted little or no effect. A possible explanation for this phenomenon was discussed.

Biphasic effect of locally applied apomorphine and 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine on the release of striatal dopamine investigated by means of brain dialysis

The effects of 3 kinds of dopamine (DA) agonists, apomorphine (APO), 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (SKF-38393) and quinpirole (QPL), on DA release were examined in the caudate-putamen of the freely moving rat by means of microdialysis during local administration of various concentrations of these DA agonists. Infusion of 10(-4) M and 10(-5) M concentrations of APO and 10(-5) M and 10(-6) M of SKF-38393 induced a brief increase in DA release followed by a marked decrease. This phenomenon was sensitive to tetrodotoxin (10(-6) M) infusion. On the other hand, all the tested doses of QPL, 10(-4) M, 10(-5) M, 10(-6) M and 10(-7) M, reduced DA release without showing transient increase.

Differential Effect of Haloperidol on Dopamine Release and Metabolism in Caudate Putamen and Anteromedial Frontal Cortex Using Intracerebral Dialysis

The differential effects of haloperidol on dopamine release and its metabolism were investigated in the anteromedial frontal cortex and the caudate putamen using the intracerebral dialysis method in anesthetized rats after single intraperitoneal injections of 0.01, 0.125 and 2 mg/kg haloperidol. The basal levels of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid, collected every 20 min from the caudate putamen, were 22, 7.7 x 10(3) and 5.5 x 10(3) pg/30 microliters, respectively, and were much higher than those from the anteromedial frontal cortex, which were 1.8, 2.6 x 10(2) and 4.6 x 10(2) pg/30 microliters, respectively. There was a clear difference in the time-response curve of dopamine release between the two brain regions after the injection of 0.125 mg/kg haloperidol, but no difference after the administration of the other doses. The measurements of 3,4-dihydroxyphenylacetic acid and homovanillic acid showed a difference between the two brain structures after injection of the other doses. These findings suggest that there is a difference between the anteromedial frontal cortex and the caudate putamen with respect to the regulating mechanism of dopamine release and its metabolism.

Heterogeneous Distribution of Mianserin in Rat Brain during Chronic Continuous Infusion

The mianserin (MIS) distribution in 12 brain regions was investigated after 2- and 14-day continuous MIS infusion, starting with 19 mg/kg/day on the first day. There was no significant difference between the 2nd and 14th day with respect to MIS concentration, brain/serum concentration ratio in whole brain or MIS serum level. The MIS distribution was heterogeneous on the 2nd and 14th day and did not change with time. The concentrations were highest in cortex and hippocampus and lowest in cerebellum, hypothalamus, and bulbus olfactorious and septum. This distribution pattern differs from those found with tricyclic antidepressant drugs.