Fumihiko Okada

Desensitization of β-Adrenergic Receptor-Coupled Adenylate Cyclase in Cerebral Cortex After In Vivo Treatment of Rats with Desipramine

Abstract: Continuous treatment (1–10 days) of rats with desipramine (10 mg/kg, twice per day) caused desensitization of the β‐adrenergic receptor‐coupled adenylate cyclase system of cerebral cortical membranes. The decrease in the isoproterenol‐stimulated adenylate cyclase activity was more rapid and greater than the decrease in the number of β‐adrenergic receptors in membranes during treatment of the membrane donor rats with desipramine, indicating that the desensitization occurring at an early stage of the treatment was not accounted for solely by the decrease in the receptor number. Neither the guanine nucleotide regulatory protein (N) nor the adenylate cyclase catalyst was impaired by the drug treatment, since there was no decrease in the cyclase activity measured in the presence or absence of GTP, guanyl‐5′‐yl‐β‐γ‐imidodiphosphate [Gpp(NH)p], NaF, or forskolin. Gpp(NH)p‐induced activation of membrane adenylate cyclase developed with a lag time of a few minutes in membranes from control or drug‐treated rats. The lag was shortened by the addition of isoproterenol, indicating that β–receptors were coupled to N in such a manner as to facilitate the exchange of added Gpp(NH)p with endogenous GDP on N. This effect of isoproterenol rapidly decreased during the drug treatment of rats. Thus, functional uncoupling of the N protein from receptors was responsible for early development of desensitization of β‐adrenergic receptor‐mediated adenylate cyclase in the cerebral cortex during desipramine therapy.

Circadian fluctuation of brain acetylcholine in rats ---I. On the variations in the total brain and discrete brain areas

Abstract THE CIRCADIAN fluctuation of brain acetylcholine (Ach) levels was investigated in rats raised in the constant experimental conditions. 1. 1. Rats killed by decapitation exhibited a circadian fluctuation of brain ACh levels with a peak in the light and a trough in the dark phase. The same diurnal pattern was also obtained by the near-freezing method, using liquid nitrogen. 2. 2. The circadian fluctuations of ACh levels in the telencephalon and pons plus medulla oblongata were similar to that of the total brain. But no circadian variation was confirmed in the mesencephalon plus diencephalon.

The maturation of the circadian rhythm of brain serotonin in the rat.

Abstract EXISTENCE of a circadian rhythm in the brain contents of serotonin (5-hydroxytryptamine, 5HT) has been reported in the mouse, hamster, rat and cat (1, 2, 3, 4, 5, 6). Serotonin is considered to be primarily localized in the particular neurons in the central nervous system (7) and probably is a central mediator in the mechanisms for inducing sleep (8). It is also suggested that 5HT within the hypothalamus has an active part in the regulation of the hypothalamo-hypophyseal function and, accordingly, plays a role in producing the circadian periodicity of plasma 17-hydroxycorticosteroids (17-OHCS) (9). However, there have been only two systematic studies, to our knowledge, describing the relationship between the circadian rhythm of the brain 5HT content and that of the plasma corticosterone levels in the rat (3, 10). This paper is concerned with the process of the maturation of the circadian rhythm of brain 5HT in the rat in correlation with the sleep-wakefulness pattern and the circadian rhythm of the plasma corticosterone concentration.

An application of neuroendocrinological studies in autistic children and Heller's syndrome.

The response of plasma 11-hydroxycorticosteroids (11-OHCS) to intravenous pyrogen as well as the circadian rhythm of plasma 11-OHCS levels were investigated in seven autistic children and in two children with Hellers syndrome. In autistic children, the stress response, which is acquired in an earlier stage of development, was adequately sustained. However, the circadian rhythm, which seems to appear at a later stage with the maturity of the CNS, frequently revealed abnormal patterns. Similar findings were obtained in the Hellers syndrome cases, indicating organic changes in the brain. On the basis of these results, it is postulated that in early infantile autism there exist some functional changes in the CNS that show a close correlation to the regulatory mechanism of ACTH secretion.

G proteins (Gi, Go) in the medial temporal lobe in schizophrenia : preliminary report of a neurochemical correlate of structural change

We have measured the amount of Gi (the inhibitory G-protein) or Go (a similar G-protein of unknown function) in 5 areas of the medial temporal lobe of control and schizophrenic brains utilizing pertussis toxin-catalyzed ADP ribosylation. The material used has previously been shown to have asymmetrical structural abnormalities of the ventricular system. The amount of Gi or Go was reduced on the left side in the hippocampus, amygdala and parahippocampal gyrus, the difference reaching significance in the hippocampus. This data is the first report of a neurochemical correlate of the structural change in the brains of patients with schizophrenia. Decreased Gi or Go in hippocampus may relate to other reported neurochemical deficits or other transmembrane signalling abnormalities. Further investigations of these indices of secondary messenger function in relation to structural changes are indicated.

G-proteins (Gi, Go) in the basal ganglia of control and schizophrenic brain

We detected the existence of Gi (the inhibitory G-protein) or Go (a similar G-protein of unknown function) in the striatum of control and schizophrenic brains utilizing pertussis toxin-catalyzed ADP ribosylation. The level of Gi/Go was significantly decreased by 42% in the putamen of the left hemisphere in schizophrenics; caudate head and globus pallidus levels were unchanged. Decreased Gi or Go may underlie enhanced dopamine function in the schizophrenic brain.

Reduced concentrations of the α-subunit of GTP-binding protein Go in schizophrenic brain

Concentrations of the α-subunits of GTP-binding protein, Go (Goα) and of Gi 2 (Gi 2α) in 6 areas (the hippocampus, parahippocampus, putamen, caudate head, orbital frontal cortex, and lateral temporal cortex) of control and schizophrenic postmortem brains were investigated using the highly sensitive enzyme immunoassay method. There was a significant decrease in Goα in the hippocampus and caudate head of the right hemisphere in schizophrenic patients compared to controls; the ANOVA (a general linear model; SAS Type II) demonstrated a significant diagnosis × side interaction only in the hippocampus. In other areas of the brain, analysis by grouping under diagnosis, side, age, gender, and postmortem delay showed no significant deviations in Goα between controls and schizophrenics. The concentrations of Gi 2α did not differ significantly in any area. These findings contrasted with the results yielded by ADP-ribosylation, which showed decreased pertussis toxin ADP-ribosylated amounts in the hippocampus and putamen of the contralateral (left) hemisphere. Some abnormal receptor — Go or Gi 1 signalling in hippocampus, putamen or caudate head may be involved in the pathogenesis of schizophrenia.

Pertussis Toxin Attenuates 5‐Hydroxytryptamine1A Receptor‐Mediated Inhibition of Forskolin‐Stimulated Adenylate Cyclase Activity in Rat Hippocampal Membranes

Abstract: The inhibition of forskolin‐stimulated adenylate cyclase activity by 5‐hydroxytryptamine (5‐HT) receptor agonists was measured in rat hippocampal membranes isolated from animals treated with vehicle or islet‐activating protein (IAP; pertussis toxin). In vehicle‐treated animals, 5‐HT, 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin, buspirone, and gepirone were potent in inhibiting forskolin‐stimulated adenylate cyclase activity with EC50 values of 60, 76, 376, and 530 nM, respectively. IAP treatment reduced by 30–55% the 5‐HT1A agonist inhibition of adenylate cyclase activity via 5‐HT1A receptors. The data indicate that the inhibitory guanine nucleotide‐binding protein or Go (a similar GTP‐binding protein of unknown function purified from brain) mediates the 5‐HT1A agonist inhibition of hippocampal adenylate cyclase.

Bradycardia- and tachycardia-dependent termination of ventricular bigeminy: Mechanism of ventricular extrasystoles with fixed coupling

Fourteen men with intermittent ventricular bigeminy were selected for this study because coupling intervals of the extrasystoles were considerably long and usually fixed, and bradycardia-dependent (10 cases) and/or tachycardia-dependent (12 cases) termination of bigeminy occurred. In all cases, when the heart rate ranged between two certain values, ventricular bigeminy with fixed-coupled extrasystoles was sustained. In all cases showing bradycardia-dependent termination, bigeminy was suddenly terminated with no changes in coupling of the preceding extrasystoles when the heart rate was decreased below a certain lower value. In all cases showing tachycardia-dependent termination except one, when the heart rate increased beyond a certain higher value, coupling intervals gradually lengthened until bigeminy was terminated. These findings strongly suggest the possibility that, in a considerably large number of clinical cases, ventricular extrasystoles with fixed coupling are caused by longitudinal dissociation of conduction in the reentrant pathway of extrasystoles.

Mechanism of irregular parasystole: Differentiation of second-degree entrance block from electrotonic modulation

Experts had believed for a long time that the parasystolic rhythm is regular and independent of sinus rhythm. In 1974, Kinoshital reported a case of ventricular parasystole in which when a sinus impulse fell late in the parasystolic cycle, it hastened the next ectopic discharge. Since then, many cases of such “irregular” parasystole have been reported,2-14 and it has been shown that in most clinical cases of parasystole, such hastening of the ectopic discharge can be observed.15, l6 There are two theories to explain hastening of the ectopic discharge: one, which was postulated by Kinoshita et a1.,l-12, 15* I6 is type I second-degree entrance block; the other, which was postulated by Jalife and Moe,17 is electrotonic modulation. According to both theories, the parasystolic cycle can be divided into the early period and the late period, and only when nonparasystolic impulses fall in the late period do they hasten the next ectopic discharge. Thus the coupling intervals of ectopic QRS complexes to the preceding sinus QRS complexes have a discontinuous distribution; that is, there is a gap in distribution bet,ween the coupling intervals to early intervening sinus QRS complexes and those to late intervening sinus QRS complexes. The upper limit of the gap is seen when a sinus QRS complex occurs at the terminal portion of the early period; the lower limit of the gap is seen when it occurs at the initial portion of the late period. At the site of entrance block, the length of the early period is invariable according to both theories. Although these characteristics resemble each other, their mechanisms are quite different.