Tadashi Nishikawa

Eating and drinking cause increased dopamine release in the nucleus accumbens and ventral tegmental area in the rat : measurement by in vivo microdialysis

Dopamine (DA) release was simultaneously monitored in the nucleus accumbens (NAC) and ventral tegmental area (VTA) of conscious rats using in vivo microdialysis. During dialysis perfusion, rats were allowed access to food or water for 20 min following a 36 h food and water deprivation period. DA release increased significantly in the NAC and VTA in response to eating and drinking. The increases in both regions continued until 20-60 min after the end of the feeding or drinking session. These results show that the mesolimbic DA pathway is activated in response to ingestive behavior, and that DA release occurs in the cell body (A10) region as well as in the mesolimbic DA nerve terminals.

Marked enhancement of noradrenaline turnover in extensive brain regions after activity-stress in rats.

Male Wistar rats were exposed to a 5-day activity-stress procedure wherein animals were housed in running-wheel activity cages and fed for only 1 hr each day (wheel-housed/food-restricted rats). This activity-stress procedure produced marked elevation in levels of the major metabolite of noradrenaline (NA), 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), in eight brain regions, while a reduction of NA level occurred in several of these brain regions. These rats also exhibited excessive running activity and developed severe gastric glandular ulcers. Rats fed ad lib and housed in activity cages (wheel-housed/ad lib-fed) and rats housed in standard-individual cages and which received either 1-hr daily feeding (control cage-housed/food-restricted) or ad lib feeding (control cage-housed/ad lib-fed) showed neither significant changes in brain NA metabolism nor gastric ulcers. These results suggest that the interaction of a restricted feeding regimen and an increase running wheel activity caused marked enhancement of NA turnover in several brain regions, which is one of the neurochemical mechanisms underlying the physiological and behavioral changes produced by the activity-stress paradigm.

Biphasic and long-lasting effect of ceruletide on tardive dyskinesia.

A 55-year-old schizophrenic inpatient with buccolingual dyskinesia was treated with a single dose of ceruletide 0.8 μg/kg IM. Time-course effects of the drug were then followed for up to 6 weeks after injection. To assess changes in severity of bucco-lingual dyskinesia objectively, electromyogram (EMG) and microvibration (MV) were recorded. Simultaneously, bucco-lingual dyskinesias were also evaluated by using a five-point rating scale. Before injection of ceruletide, severity of dyskinesia was “moderate” and 3–4 Hz of dyskinetic oral movements were dominant. “Extremely severe” and repetitious gross oral movements (around 1 Hz) were observed within a few minutes after injection and continued for up to 1 h. Thereafter, oral movements tended to decrease, and they disappeared completely 3 weeks after injection. This biphasic and long-lasting effect of ceruletide on tardive dyskinesia might contribute to further understanding of the physio-pathophysiological role of cholecystokinin-like peptides in the brain, and provide a basis for practical treatment of tardive dyskinesia.

Clonidine Therapy for Tardive Dyskinesia and Related Syndromes

Twenty-nine patients with tardive dyskinesia (n = 20) or related syndromes [spontaneous dyskinesia (n = 3), levodopa-induced dyskinesia (n = 3), tardive dystonia (n = 3)] were treated with clonidine. Clinical effects of this drug were observed for up to 4 years. Seventy-five percent of patients showed at least moderate improvement, and in 50% of patients, full resolution occurred. In most cases, patients received concomitant medications, including neuroleptics and benzodiazepines. Two patients received clonidine alone, and dyskinesia was only minimally improved; however, when bromocriptine was added, prompt improvement occurred on this combined regimen. On the basis of these findings, we suggest that not only receptor supersensitivity of dopaminergic neurons but also involvement of noradrenergic neurons is important in the pathophysiology of tardive dyskinesia and related syndromes.

Daily increase in noradrenaline turnover in brain regions of activity-stressed rats

Changes in contents of noradrenaline (NA) and its major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4) in brain regions (the hypothalamus, amygdala, thalamus, hippocampus, midbrain, cerebral cortex, pons plus medulla oblongata and basal ganglia) of male Wistar rats were evaluated after 1, 3 or 5 days of exposure to the activity-stress paradigm, wherein rats were housed in a cage with a running-wheel and restricted to 1-hr of feeding per day. When compared to the non-stressed control rats, contents of MHPG-SO4 in all the brain regions except of the basal ganglia in the stressed rats increased as rapidly as 1 day and continued to increase throughout the 5-day activity-stress period. Contents of NA did not change significantly in most of these brain regions. The daily increase in regional NA turnover by continuous exposure to the activity-stress paradigm was related to the large increases in running activity and gastric ulcers, and to body weight loss at the 3-day and 5-day testing periods. These data suggest that pathological states produced by a 5-day activity-stress paradigm may reflect concomitant disturbances of noradrenergic function in various brain regions. The activity-stress paradigm is regarded as an intense and progressive stress, because it induces an increase in NA response in extended brain regions.

Effect of ceruletide on tardive dyskinesia: a pilot study of quantitative computer analyses on electromyogram and microvibration

Seven patients with bucco-lingual dyskinesia were treated with a single dose of ceruletide 0.8 μg/kg IM, a potent analogue of cholecystokinin octapeptide. Time-course effects of the drug were then followed up to 6 weeks after injection in the longest case. To assess changes in severity of dyskinesia objectively, electromyogram and microvibration were recorded. These data were subjected to the Fast Fourier Transform and an averaged power spectrum was computed. The effect of ceruletide on dyskinesia within 2 h after injection differed (three cases: inhibitory, two cases: facilitatory, two cases: no effect). It was notable that a long-lasting inhibitory effect of this peptide was observed in two severe irreversible cases. The present findings might contribute to further understanding of the physiopathophysiological role of cholecystokinin-like peptides in the brain and to practical treatment of tardive dyskinesia.

Prophylactic effects of neuroleptics in symptom-free schizophrenics: Roles of dopaminergic and noradrenergic blockers

A clinical trial was undertaken to determine the role of dopaminergic and noradrenergic blockers in the maintenance treatment of remitted schizophrenics. One hundred and six remitted schizophrenic outpatients were treated with one of nine treatments, viz., thioridazine 25 mg or 75 mg, pimozide 2 mg or 6 mg, and their respective combinations, for 1 year in a double-blind controlled study employing a randomized design. The data from a previous study were utilized as a retrospective placebo group. Pimozide prolonged the number of symptom-free days in a dose-dependent manner and did so more markedly than thioridazine. Combined administration of pimozide and thioridazine prolonged the number of symptom-free days to a greater extent than their single administration. However, an inverted U-shaped dose-response curve was obtained with the combined administration of these agents. These data suggest that both the dopaminergic and noradrenergic blocking action of neuroleptics are important in preventing relapse in remitted schizophrenics.

Prophylactic effect of neuroleptics in symptom-free schizophrenics

Prophylactic effects of psychotropic drugs on 55 schizophrenics in remission were evaluated for 3 years in a double-blind controlled study employing a cross-over design. Patients were randomly assigned to the following drugs orally administered twice a day: placebo; diazepam 15 mg; imipramine 50 mg; chlorpromazine 75 mg; and haloperidol 3 mg. The number of days of remission for each patient was recorded. Since only two patients received all five drug treatments, the data were analyzed using the number of days allocated to the “first assigned drugs” only and the cross-over aspect of the experimental design was disregarded. All patients treated with either the placebo, diazepam or imipramine relapsed within a year. On the other hand, four patients treated with chlorpromazine, or with haloperidol, were in remission for more than 1 year. Fifty percent of the patients relapsed within 16 days with placebo; 88 days with diazepam; 30 days with imipramine; 165 days with chlorpromazine; and 74 days with haloperidol. Within a year, only chlorpromazine significantly prolonged the remission state as compared to placebo and imipramine. At the end of the 3-year trial, both chlorpromazine and haloperidol significantly prolonged the remission state as compared to the other three drugs. These data suggest that neuroleptic treatment for a longer period is vitally important to prevent relapse even in schizophrenics in remission and that such a trial seems an efficient method for investigating the prophylactic effects of neuroleptics.

Naloxone Attenuates Drinking Behavior in a Schizophrenic Patient Displaying Self-induced Water Intoxication

This study was performed to examine the effect of naloxone on drinking behavior in a schizophrenic inpatient with psychosis, intermittent hyponatremia, and polydipsia (PIP syndrome). His body weight was checked five times daily, and the maximum and minimum weight gains during a day were chosen as an index of polydipsia. Both daily (0.6 mg) and repeated (0.6 mg for 6 days) injections of naloxone suppressed his weight gain significantly for 2 weeks. Withdrawal of the drug for 4 weeks resulted in weight gain recovering to control level. Thereafter, a second trial was performed to examine the long-term effect of this treatment. A daily naloxone (0.6 mg) injection series was performed once every 2 weeks for six series (12 weeks). This drug regimen also suppressed his weight gain in a continuous fashion. The study showed that naloxone seems to be a potential treatment for PIP syndrome and that endogenous opioid systems play a part in the compulsive drinking behavior of the PIP syndrome.

Prophylactic effect of neuroleptics in symptom-free schizophrenics: A comparative dose-response study of haloperidol and propericiazine

Remitted schizophrenic outpatients were treated in order to prevent relapse with three doses of haloperidol or propericiazine for 1 year in a double-blind controlled study employing a randomized design. The drugs ability to prevent relapse was evaluated by counting the number of symptom-free days for each patient before any sign of relapse or over-dose appeared. Patients were randomly assinged to the following drugs orally administered once per day at night: placebo; haloperidol 1 mg, 3 mg, and 6 mg; propericiazine 10 mg, 30 mg, and 60 mg. Serum prolactin levels in each patient were estimated by radioimmunoassay. All patients treated with placebo relapsed within 1 year and the relapse rate with placebo was significantly higher than with any dose of the two neuroleptics. Haloperidol increased the number of symptom-free days in a dose-dependent manner. Propericiazine at 10 mg and 30 mg also increased the number of symptom-free days dose-dependently but at 60 mg, the number decreased. It appears that propericiazine shows an inverted U-shaped dose-response curve. Prolactin levels were elevated dose-dependently by both drugs but failed to show a significant correlation with the number of symptom-free days. The present results indicate that haloperidol is superior to propericiazine from the viewpoint of the wider “therapeutic window” in maintenance treatment and antidopaminergic properties of neuroleptics, wherein it is important to prevent relapse even in remitted schizophrenics.