Evidence for monoaminergic involvement in triadimefon-induced hyperactivity

Triadimefon is a triazole fungicide that produces hyperactivity in both mice and rats similar to that seen following administration of compounds with catecholaminergic activity (e.g., d-amphetamine). To determine whether the triadimefon-induced hyperactivity is due to an action on CNS catecholaminergic systems, we evaluated the effects of combined treatment of triadimefon with either the tyrosine hydroxlase inhibitor d,l--methyl-p-tyrosine methyl ester HCl (MPT) or the amine depletor reserpine. Adult male Long-Evans hooded rats, approximately 70 days of age were used. Dosage-effect functions were determined for MPT (0–200 mg/kg IP), reserpine (0–2.5 mg/kg IP), d-amphetamine (0–3 mg/kg IP), and methylphenidate (0–40 mg/kg IP). Motor activity was measured as photocell interruptions in figure-eight mazes. The interaction between triadimefon and MPT was determined with the following groups: 1) vehicle control; 2) 200 mg/kg triadimefon PO; 3) 100 mg/kg MPT; and 4) both MPT and triadimefon. A similar design was used to determine the interaction between triadimefon and reserpine (0.62 mg/kg), MPT and d-amphetamine (1.5 mg/kg), and reserpine and methylphenidate (5.0 mg/kg). In the first experiment MPT did not block the increased motor activity produced by triadimefon (i.e., both triadimefon alone and MPT in combination with triadimefon produced significant increases in motor activity). MPT did, however, block d-amphetamine-induced hyperactivity. Since MPT did not antagonize the effect of triadimefon, these data suggest that increased motor activity produced by triadimefon is not mediated through release of newly synthesized catecholamines. In contrast, pretreatment with reserpine blocked the hyperactivity induced by both triadimefon and methylphenidate, which suggests that triadimefon-induced hyperactivity may be due to an interaction with CNS catecholamines stored in reserpine-sensitive pools.The research described in this article has been reviewed by the Health Effects Research Laboratory, US Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use. Presented in part at the Annual Meeting of the Society for Neuroscience, New Orleans, LA, November, 1987     

Reversal of the reserpine-induced ptosis by l-threo-3,4-dihydroxy-phenylserine (l-threo-DOPS), a (−)-norepinephrine precursor,and its potentiation by imipramine or nialamide

Summary The effect of l-threo-DOPS on the reserpine-induced ptosis in mice and its modification by imipramine, a norepinephrine (NE) uptake inhibitor, or nialamide, a monoamineoxidase inhibitor, were studied.Intraperitoneal (i.p.) injection of l-threo-DOPS (800 mg/kg) significantly reduced the severity of the ptosis. This reversal of the ptosis by l-threo-DOPS was markedly potentiated by i.p. injection of either imipramine (2.5 mg/kg) or nialamide (30 mg/kg). Response to l-threo-DOPS was also significantly potentiated by intracerebroventricular (i.c.v.) injection of imipramine (10 g). On the other hand, this treatment with imipramine (10 g, i.c.v.) also significantly potentiated the reversal of the ptosis by NE (20 g, i.c.v.), but the reversal by the subcutaneous (s.c.) injection of NE (1 and 3 mg/kg) was not affected.Reserpine (5 mg/kg, i.p.) markedly decreased the brain content of NE in mice, whereas l-threo-DOPS (400 mg/kg, i.p.) slightly restored it. Moreover, by the pretreatment with nialamide (30 mg/kg, i.p.), l-threo-DOPS produced a significant increase in the brain content of NE in reserpinetreated mice.These results suggested that l-threo-DOPS was capable of reversing the reserpine-induced ptosis due to the formation, at least in part of (–)-NE at the synaptic sites of central noradrenergic neurons.     

Inositol reduces depressive-like behaviors in two different animal models of depression

  Rationale: Myo-inositol is an isomer of glucose that is a precursor in the phosphatidylinositol (PIP) cycle, a source of two second messengers: diacylglycerol (DAG) and inositol triphosphate (IP₃). Clinical studies have reported that inositol is effective in relieving symptoms of depression. Objective: The present study examined the effects of inositol on two animal models of depression: the Porsolt forced swim test, a behaviorally based model; and the reserpine-induced immobility model, a pharmacologically based model. Methods and results: Chronic inositol injections (daily for 14 days) of 1.2 g/kg (but not at lower doses) reduced immobility time and increased struggle time in the Porsolt test compared with control animals. The same dose and treatment schedule also reduced complete immobility time but did not affect ambulatory activity in the reserpine test compared with controls. Chronic oral treatment with inositol (10% in food for 14 days) had effects similar to IP inositol in the Porsolt test. Conclusions: The effect of inositol in animal models of depression supports its possible importance as a new treatment for the disorder, and permits research on its mechanisms of action. Received: 31 August 1998 / Final version: 18 November 1998     

Effect of lisuride and LSD on monoamine synthesis after axotomy or reserpine treatment in rat brain

Summary The effect of d-lysergic acid diethylamide (LSD) and lisuride on the synthesis of monoamines was evaluated in rat brain regions using an in vivo method in which the accumulation of dopa and 5-hydroxytryptophan (5-HTP) is measured after inhibition of the aromatic amino acid decarboxylase by means of 3-hydroxybenzylhydrazine.LSD (50–1000 g/kg i.p.) caused a dose-dependent increase in dopa formation and a slight elevation of tyrosine and tryptophan concentrations in the intact rat forebrain; moreover, it reduced the accumulation of 5-HTP.The increase in dopa formation in the terminal system of the rat forebrain following an axotomy of the ascending monoaminergic fiber system was antagonized by LSD at a dose of 0.5 mg/kg i.p. Haloperidol (2 mg/kg i.p.) counteracted the effect of LSD.The increase in dopa formation in c. striatum and the dopamine-rich part of the limbic system following treatment with reserpine was antagonized by lisuride as well as by LSD. However, lisuride was at least 10 times as potent as LSD. In reserpinized animals LSD counteracted the inhibitory effect on dopa accumulation of the direct dopamine receptor stimulant apomorphine while lisuride did not. The data suggest that LSD is a weak agonist at dopamine receptors in vivo with partial receptor blocking properties at higher doses, while the action of lisuride on dopamine receptors is a potent, purely agonistic one.with technical assistance of Ruth NeumeisterPart of this paper has been presented at the Spring Meeting 1977 of the German Pharmacological Society at Mainz (Kehr, 1977b)     

Clonidine-induced locomotor hyperactivity in rats

Summary The -adrenergic agonist, clonidine, causes sedation in normal rats. The present study demonstrates that clonidine evokes strong locomotor stimulation in rats pretreated with 6-hydroxydopamine plus reserpine. Similar, but less intensive hyperactivity is observed in rats given clonidine after combined pretreatment with 6-hydroxydopamine plus p-chlorophenylalanine plus -methyl-p-tyrosine, or with reserpine plus low doses of yohimbine. The -adrenolytic drugs, phenoxybenzamine, phentolamine and aceperone, as well as high doses of yohimbine, antagonise the clonidine-induced locomotor stimulation; in contrast, the dopamine receptor blocking agents, pimozide and spiroperidol, exert no antagonistic effect. The results indicate that in the brain of normal animals, clonidine predominantly activates presynaptic -adrenoceptors on noradrenergic neurones and thereby induces sedation. After destruction of the noradrenergic fibres by 6-hydroxydopamine plus reserpine, activation of postsynaptic -adrenoceptors prevails so that hyperactivity results.This study was supported by Polish Academy of Sciences (10.4). Preliminary accounts were presented at the Pharmacology Meeting, Hannover, September 14–17, 1976 and at the 1 st Joint Symposium of Hungarian and Polish Pharmacological Societies, Zakopane, October, 13–15, 1976     

Lack of correlation between changes in cyclic nucleotides and subsequent induction of tyrosine hydroxylase in rat adrenal medulla

Summary Pretreatment of rats with dexamethasone (2.5 mol/kg, a dose which blocks the release of ACTH from the pituitary gland) abolished the reserpine-mediated increase in cAMP and the increase in the cAMP/cGMP ratio in the adrenal medulla. In contrast, the reserpine-mediated induction of tyrosine hydroxylase (TH) remained unchanged. Hypophysectomy had a similar effect to dexamethasone treatment. Since changes in cAMP and changes in the cAMP/cGMP ratio are not indispensible prerequisites for the subsequent induction of TH, a causal relationship between the two phenomena seems to be excluded.     

Alteration of basal ganglia evoked responses by reserpine and L-Dopa

The effects of reserpine and L-Dopa on basal ganglia evoked potentials were investigated in cats. The caudate response resulting from substantia nigra stimulation and the substantia nigra response elicited by globus pallidus stimulation were increased at several hours after the systemic administration of reserpine. L-Dopa in the presence of dopa decarboxylase inhibition (MK-486) depressed these responses and reversed the effect of reserpine at 0.5 h after administration. Reserpine did not reverse the L-Dopa effect. Reserpine and L-Dopa caused no significant change in responses between other basal ganglia structures. These data give evidence that the basal ganglia are major sites for reserpine and L-Dopa action.     

褐苞薯蓣对小鼠脾虚证的影响

目的：观察褐苞薯蓣对小鼠脾虚证的影响。方法：用利血平致小鼠脾虚模型，以其体重、体温、胸腺及脾重、血清刚果红与木糖含量为指标，观察实验结果。结果：褐苞薯蓣能使体重、体温、胸腺重、脾重、血清木糖含量增加，对血清刚果红含量减少不显著。怀山药的结果与褐苞薯蓣相似，但对后3个指标影响不明显。结论：褐苞薯蓣有补脾作用和特异性免疫作用，怀山药与其相似，但略逊。     

Opposite effects of glutamate antagonists and antiparkinsonian drugs on the activities of DOPA decarboxylase and 5-HTP decarboxylase in the rat brain

This study measured the activities of L-DOPA and 5-HTP decarboxylase (DDC and 5-HTPDC) in the substantia nigra and corpus striatum of reserpine-treated rats. Acute injection of the NMDA receptor antagonists CGP 40116 (5 mg/kg) and HA 966 (5 mg/kg), and to a lesser extent eliprodil (10 mg/kg), greatly elevated DDC in both structures, whilst having no effect on (nigra) or inhibiting (striatum) 5-HTPDC. L-DOPA (25 mg/kg) on its own inhibited both enzymes in either brain region. The weak NMDA receptor-channel blockers (and antiparkinsonian drugs) budipine (10 mg/kg), memantine (40 mg/kg) and amantadine (40 mg/kg) strongly increased DDC, whilst not affecting or decreasing 5-HTPDC activity in nigra and striatum. The L-DOPA-induced suppression of DDC was mostly reversed by all three antiparkinsonian drugs, whilst L-DOPA-induced inhibition of 5-HTPDC was only reversed by CGP 40116 (striatum only). It is concluded that glutamate exerts a differential physiological influence on the biosynthesis of dopamine and 5-HT in the brain, by tonically suppressing DDC and tonically stimulating 5-HTPDC. The L-DOPA-induced reduction in DDC may help to explain the eventual loss of efficacy of L-DOPA therapy in parkinsonian patients. It is suggested, however, that it may be possible to extend the lifetime of L-DOPA therapy with drugs which potentiate the activity of DDC, such as budipine and the 1-aminoadamantanes.