Takashi Moroji

Effects of phencyclidine metabolites on serotonin uptake in rat brain

The effects of phencyclidine (PCP) and its metabolites on serotonin (5-hydroxytryptamine, 5-HT) receptors were studied. PCP and its metabolites inhibited the uptake of [3H]5-HT and the binding of [3H]paroxetine in rat brain, while they failed to inhibit either [3H]5-HT binding to 5-HT1 receptors or [3H]ketanserin binding to 5-HT2 receptors. The trans-isomer of 4-phenyl-4-(I-piperidinyl)cyclo-hexanol (trans-4-PPC), the major metabolite of PCP, rather than PCP itself, inhibited [3H]5-HT uptake most potently. These results suggest that the serotonergic effects of PCP, in part, may be based on the effects of PCP metabolites on 5-HT uptake.

Quantitative autoradiographic localization of [3H]3-OH-PCP (1-(1(3-Hydroxyphenyl)cyclohexyl)piperidine) binding sites in rat brain

Binding of a novel radioligand, [3H]3-OH-PCP (1(1(3-hydroxyphenyl) cyclohexyl)piperidine), to N-methyl-D-aspartate (NMDA) receptor-coupled and -uncoupled PCP sites was investigated in the rat brain. The highest densities of [3H]3-OH-PCP binding were observed in the hippocampal formation, notably in the stratum radiatum and oriens of CA1 region, and dentate gyrus. There were relatively high levels of binding in the olfactory system, superficial layer of cortices, the amygdala and the thalamus. In contrast, lower levels of binding were found in the globus pallidus, cerebellum, and brain stem, except for the superior colliculus. These findings demonstrate that [3H]3-OH-PCP binds to discrete regions within the rat brain. Its distribution is consistent with autoradiographic localization of [3H]TCP and [3H]MK-801 binding sites in the rat brain, suggesting that [3H]3-OH-PCP binds to NMDA/PCP ion-channel complexes in preference to sigma sites.

Possible expression of a σ1 site in rat pheochromocytoma (PC12) cells

Abstract To examine the functional interaction between the σ binding sites and nicotinic acetylcholine receptors, we investigated the effects of various σ receptor ligands on nicotine-evoked Ca 2+ uptake in differentiated PC12 cells. The IC 50 values of σ receptor ligands tested in this uptake study did not correlate with their K i values in the [ 3 H]1,3-di(2-tolyl)guanidine ([ 3 H]DTG) binding to guinea pig brain reported by Rothman et al. (1991). To clarify further the binding characteristics of the σ binding sites on PC12 cells, we examined the effects of σ receptor ligands on [ 3 H] N,N -dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine HCl ([ 3 H]NE-100) binding to PC12 membranes. The K i values of the various drugs tested for [ 3 H]NE-100 binding site closely correlated with their K i values for the DTG site-1 reported by Rothman et al. (1991). This study showed that PC12 cells express σ 1 -like sites and the inhibitory effect of σ receptor ligands on the nicotine-evoked Ca 2+ uptake was not directly coupled with either the σ 1 or σ 2 sites.

Inhibitory effects of psychotomimetic σ ligands on nicotine-induced K+ flux from differentiated PC12 cells

In NGF-treated PC12 cells, nicotine-induced K+ release was measured with a K(+)-sensitive microelectrode. The K+ outflow via nicotinic ACh receptor cation channels was inhibited by various psychotomimetic sigma ligands in the sequence of PCP, dextromethorphan >> DTG, MK 801, (+)SKF10047 >> (+)3-PPP. The K+ release was not affected by the neuroleptic sigma ligand haloperidol nor by the calcium antagonist nifedipine. The results suggest that psychotomimetic sigma ligands inhibit nicotine-stimulated K+ flux by interacting with nicotinic, rather than via sigma 2 receptors.

Effects of methamphetamine on daily rhythms of hypothalamic norepinephrine, serotonin and plasma corticosterone levels in the rat

Abstract The relationship between daily rhythms of hypothalamic norepinephrine (NE) and serotonin (5HT) contents and the circadian rhythm of plasma corticosterone (Comp. B) levels was studied in the rat. It was found that levels of hypothalamic NE, 5HT and plasma Comp. B exhibited distinct daily flucturations in the control condition. In animals treated with methamphetamine, the daily rhythms of hypothalamic 5HT contents and plasma Comp. B levels remained unchanged, whereas the daily rhythm of hypothalamic NE contents was completely abolished. As a result, it was suggested that the daily rhythm of hypothalamic NE is not functionally related to the circadian change of pituitary-adrenocortical activity.

Effects of the major metabolite of phencyclidine, the trans isomer of 4-phenyl-4-(1-piperidinyl)cyclohexanol, on [3H]N-(1-[2-thienyl] cyclohexyl)-3,4-piperidine ([3H]TCP) binding and [3H]dopamine uptake in the rat brain.

The major metabolite of phencyclidine (PCP), the trans isomer of 4-phenyl-4-(1-piperidinyl)cyclohexanol [(trans)-4-PPC], inhibited [3H]N-(1-(2-thienyl)cyclohexyl)-3,4-piperidine ([3H]TCP) binding to well-washed rat cortical membranes with much less activity than PCP itself. In contrast, it inhibited [3H]dopamine ([3H]DA) uptake in rat striatal synaptosomes to a similar extent as PCP. Considering our previous observations that intraperitoneally administered (trans)-4-PPC elicits dose-related increases in locomotor activity and rearing in mice, (trans)-4-PPC as well as PCP may be involved in psychotomimetic effects of PCP due to its inhibitory effect on DA uptake.

Behavioral effects of phencyclidine and its major metabolite, (trans)4-phenyl-4-(1-piperidinyl)cyclohexanol, in mice.

To elucidate the biological activity of natural metabolites of phencyclidine (PCP), we examined the behavioral effects of a major metabolite, the trans isomer of 4-phenyl-4-(1-piperidinyl)cyclohexanol [(trans)PPC], in mice, (Trans)PPC caused dose-related increase in locomotor activity and rearing in mice when injected intraperitoneally at the doses ranging from 10 to 30 mg/kg. (Trans)PPC at any dose tested failed to produce swaying and falling. On the other hand, PCP at the doses ranging from 1 to 10 mg/kg caused swaying and falling as well as hyperlocomotion in a dose-related manner. These indicate that unlike PCP, hyperlocomotion and rearing may be the predominant behavioral responses to (trans)PPC in the 10-30 mg/kg dose range. Furthermore, it is feasible to surmise that not only PCP but also its major metabolite (trans)PPC is involved in psychotic reactions produced by PCP.

Neuroendocrinological Studies in Mental Disorders and Psychotropic Drugs

The circadian variation of the adrenocortical hormone levels in plasma was studied in 105 patients with various mental disorders. Examinations were repeated on the same subjects to follow up changes in the course of the diseases. Effects of prolonged administration of Methamphetamine and Chlorpromazine on the circadian rhythm of plasma corticosteroids were also investigated in albino rats.

EFFECT OF ELECTRIC CONVULSIVE THERAPY AND INSULIN SHOCK THERAPY ON THE PITUITARY GONADOTROPIN PRODUCTION OF PSYCHOTIC PATIENTS

Physiological effect of electric convulsive therapy and insulin shock therapy was investigated in terms of pituitary gonadotropin production.