Tatsuo Miyauchi

Effects of antidepressants in the rat forced swimming test

Effects of antidepressants and other drugs on the behaviour of rats in the forced swimming test were examined. Acute and chronic administration of antidepressants reduced the duration of immobility during the first 5 or 10 min of a 30 min test by prolonging escape-directed behaviour which appeared only during this period. However, the drugs did not affect the duration of immobility during the last 20 or 25 min, when the rats were in a state of almost complete immobility. In contrast, methamphetamine, caffeine and scopolamine reduced the duration of immobility not only during the first 5 min but also the next 15 or 25 min without prolonging the escape-directed behaviour but by increasing general motor activity. The effect of antidepressants was potentiated by chronic treatment as compared to acute administration. In the chronic experiments, a significant reduction in the duration of immobility was first observed on the 6th day of the treatment. Although a single injection of diphenhydramine caused an effect similar to antidepressants, this effect disappeared after chronic treatment. These results indicate that immobility itself is not affected by antidepressants. However, it is suggested that the reduction in the duration of immobility only during the first 5 min of the test, which was caused by the prolongation of the escape-directed behaviour, and the potentiation of the effect after chronic treatment are an action specific to antidepressants.

Involvement of α- and β1-adrenergic mechanisms in the immobility-reducing action of desipramine in the forced swimming test

The influences of various monoaminergic agents on the immobility-reducing action of desipramine (DMI) in the forced swimming test were examined. 5-Methoxy-N,N-dimethyltryptamine and methysergide, a serotonin agonist and antagonist, respectively, did not affect the duration of immobility. Pimozide, a dopamine antagonist, prolonged the duration of immobility at a dose of 0.5 mg/kg. However, at the doses tested, these drugs had no effect on the action of desipramine. Phenoxybenzamine, an alpha-adrenergic antagonist, prolonged the duration of immobility only with the largest dose (20 mg/kg), but the action of desipramine was completely blocked by this drugs at all doses. Intracerebroventricular injection of a beta-adrenergic agonist, isoproterenol (ISO), and two selective beta 1-adrenergic antagonists, atenolol (ATE) and practolol, dose-dependently diminished and potentiated, respectively, the action of desipramine although these drugs had no effect on the duration of immobility when given alone. A beta 2-adrenergic antagonist derived from oximino-9-fluorene, (IPS 339) did not influence the duration of immobility or affect the action of desipramine. The effect of isoproterenol was almost completely blocked by the pretreatment with atenolol and practolol but not by IPS 339. Subcutaneously-injected isoproterenol did not affect the action of desipramine. Isoproterenol and atenolol had no effect on the concentration of desipramine in brain regions. Phenylephrine, a postsynaptic alpha-adrenergic agonist, reduced the duration of immobility as did desipramine, but this action was not affected by isoproterenol and atenolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Potentiating effect of lithium chloride on aggressive behaviour induced in mice by nialamide plus L-DOPA and by clonidine

Effects of acute administration of LiCl on aggressive behavior and alterations in brain norepinephrine (NE), dopamine (DA) and serotonin (5-HT) contents induced by nialamide plus L-DOPA and by clonidine were examined in mice. Effects of LiCl on turnover and metabolism of brain NE were also investigated. LiCl potentiated the aggressiveness induced by both nialamide plus L-DOPA and by clonidine. Increase in levels of brain NE, DA and 5-HT by nialamide plus L-DOPA was not affected by LiCl. The potentiating effect of LiCl on clonidine aggression was not observed in mice pretreated with disulfiram. Although LiCl did not alter the steady state levels of brain NE, DA and 5-HT, it increased the turnover of NE and decreased the content of endogenous normetanephrine. These results favour the assumption that lithium reduces the ability of nerve terminal vesicles to store NE leading to an increased turnover and decreased concentration of NE at receptor sites.

Effects of acutely and chronically administered antidepressants on the brain regional 3-methoxy-4-hydroxyphenylethyleneglycol sulfate in the forced swimming rat

Abstract The reducing effect of desipramine (DMI) on the duration of immobility induced in rats by forced swimming was markedly potentiated after chronic injection of the lower dose, whereas the action of chronic amitriptyline (AMI) was similar to that of acute treatment. MHPG-SO4 in most of the brain regions, particularly that in the septal area, was increased by the forced swimming. Unlike the effect in the normal rats, acutely administered AMI and DMI did not reduce MHPG-SO4 in the brain regions other than the septal area in the forced swimming rats. Similar to the effect in the normal rats, chronic treatment with DMI increased MHPG-SO4 in the cortex, hippocampus and the thalamus in the forced swimming rats. In these rats, MHPG-SO4 in the septal area was still lowered by both drugs. These results indicate that 1) inhibitory effect of acutely administered AMI and DMI on the presynaptic noradrenergic neurons disappears in most of the brain regions after the forced swimming, 2) chronic treatment with DMI increases the noradrenergic activity in the cortex, hippocampus and thalamus and 3) both acute and chronic treatments with the drugs inhibit the forced swimming-induced increase in noradrenergic activity in the septal area. The relevance of these effects to the behavioral action of the drugs is discussed.

Potentiating effect of lithium chloride on methamphetamine-induced stereotypy in mice

Single administration of LiCl potentiated the methamphetamine-induced stereotypy in mice, without affecting the concentration of methamphetamine in brain. During MAO inhibition, the level of 3-methoxytyramine (3-MT), an O-methylated metabolite of dopamine, was reduced by LiCl, but the elevated 3-MT level observed after the administration of methamphetamine was not influenced by LiCl.

The significance of beta-adrenoceptor down regulation in the desipramine action in the forced swimming test

SummaryThe present studies were undertaken to clarify whether centralβ-adrenoceptor down regulation is responsible for the greater effect of chronic treatment with desipramine (DMI) compared with acute treatment in the forced swimming test in rats. Repetitive administration of DMI activated the rat behaviour pattern and consequently reduced the duration of immobility. The degree of activation depended on the length of treatment, i.e. no effect when given in a single dose, moderate effect when given subchronically (3 doses) and marked activation after chronic (31 doses) treatment. Chronic treatment with DMI also produced a decrease in3H-dihydroalprenolol (3H-DHA) binding site in the cerebral cortex. Acute stimulation of brainβ-adrenoceptors by intracerebroventricular (i.c.v.) isoprenaline significantly, though partially, attenuated the behavioural effect of chronic DMI by β1-adrenoceptor-related mechanisms. Similarly, chronic i.c.v. co-administration of atenolol or practolol, β1-adrenoceptor antagonists, together with DMI attenuated bothβ-adrenoceptor down regulation and the behavioural activation by chronic DMI. On the other hand, chronic i.c.v administration of isoprenaline, supposedly leading to down regulation ofβ-adrenoceptors, facilitated the activating behavioural effect of DMI, as a single dose became effective. Changes, however, in3H-DHA binding parameters in the cerebral cortex were not observed after chronic isoprenaline. These results suggest that down regulation ofβ-adrenoceptors in brain is reponsible, at least in part, for the marked activatory effect of chronic DMI in the forced swimming test, possibly by reducing an inhibitory function of β1-adrenoceptor mediated mechanisms.

β-adrenoceptor mediated inhibition of behavioral action of desipramine and of central noradrenergic activity in forced swimming rats

The immobility-reducing action of desipramine (DMI) in forced swimming rats was attenuated by intracerebroventricular (i.c.v.) injection of isoproterenol (ISO) and potentiated by i.c.v. atenolol (ATE), a beta 1-adrenoceptor antagonist. The effect of ISO was blocked by ATE. When administered i.c.v. in normal rats, ISO reduced the contents of 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), a major metabolite of noradrenaline, in the septal area, thalamus and hypothalamus while ATE had no effect in most of the brain regions. However, in forced swimming rats treated with DMI, ISO reduced MHPG-SO4 in 6 out of 8 brain regions tested and conversely, ATE increased the levels in the amygdala, septal area and hypothalamus. Similar to the behavioral effect, the effect of ISO was antagonized by ATE. These results support the hypothesis that central beta 1-adrenergic mechanisms inhibit the immobility-reducing action of DMI by reducing the activity of noradrenergic neurons in the brain.

Effect of acute and chronic treatment with tricyclic antidepressants on 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4) contents in various regions of rat brain

1. Effects of acute and chronic treatment with desipramine (DMI) and amitriptyline (AMI) on 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4) levels in eight brain regions were examined in rats. 2. A single injection of DMI decreased MHPG-SO4 levels in all brain regions except the midbrain, whereas the effect disappeared after the chronic treatment except in the septal area. MHPG-SO4 levels in the hippocampus and thalamus were increased after the chronic treatment with the drug. 3. A single and chronic administration of AMI decreased MHPG-SO4 levels in the thalamus and hippocampus, respectively. 4. These results indicate that the effects of acute and chronic treatment with the tricyclic antidepressants on the central noradrenergic systems differ in different regions of rat brain.

Participation of Prostaglandin and Adrenergic Nervous System in Renin Release Induced by Changes in Renal Arterial Pressure in Rats

The response of plasma renin activity (PRA) to stepwise reductions in renal arterial pressure (RAP) induced by suprarenal aortic constriction (SAC) or hydralazine (0.1-30 mg/kg i.v.), and the effect of indomethacin (5 mg/kg i.v.) or propranolol (1.5 mg/kg) s.c.) on the PRA response were examined in anesthetized rats whose right kidneys had been removed 6-7 days earlier. The stepwise reduction of RAP by SAC or hydralazine produced a steep increase in PRA when RAP was below approximately 100 mm Hg. Above this level, PRA was unaffected by changes in RAP. The SAC-induced increase in PRA was nearly abolished by indomethacin. On the other hand, propranolol failed to affect the SAC-induced increase in PRA. The hydralazine-induced renin release was remarkably suppressed by either indomethacin Or propranolol. These results suggest that SAC-induced renin release is mainly dependent on the prostaglandin system, whereas hydralazine-induced renin release is dependent on the prostaglandin and the adrenergic nervous system. We estimated the threshold pressure for increasing renin release is approximately 100 mm Hg.