Changes in brain monoamine content and metabolism induced by paraoxon and soman intoxication. Effect of atropine.

1. Soman induced a decrease in hypothalamic, hippocampal and cortical noradrenaline, an increase in hippocampal and cortical dopamine and an increase in hypothalamic serotonin while paraoxon did not modify these neurotransmitter concentrations. The increases in 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindole acetic acid produced by the two drugs witness an accelerated turnover of dopamine and serotonin. 2. Atropine pretreatment completely antagonized the paraoxon-induced changes but only partially suppressed the soman-induced modifications. 3. These data suggest that soman produces a direct effect on monoamine metabolism which is not related to acetylcholine accumulation.

Dopaminergic metabolism in various rat brain areas after L-dopa loading.

The time course of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxytyramine (3-MT) and 3-methoxytyrosine (3-O-Medopa) concentrations in rat brain after treatment with L-dopa + benserazide has been investigated in the striatum, hypothalamus, hippocampus and cerebellum. These areas were selected for their different dopaminergic activities. After L-dopa loading, DA, DOPAC and HVA were increased in all the structures, but the largest increases were in those tissues with the less dopaminergic activity, while 3-MT increased in the hypothalamus, hippocampus and cerebellum but was lowered in striatum. 3-O-Medopa, which is the direct product of the O-methylation of L-dopa, did not show any specific distribution. The data provide evidence that the striatum, by feed-back mechanisms and specific enzymatic activity, is able to ensure a better regulation of dopaminergic activity than the other structures, thereby overcoming excess L-dopa.

Re-evaluation of the L-dopa loading effect on dopamine metabolism in rat striatum.

Investigation by HPLC with electrochemical detection of dopamine (DA) metabolism in rat striatum after L-dopa + benserazide treatment allowed quantification of the time course evolution of DA, 3,4-dihydroxyphenylacetic acid and homovanillic acid levels. Furthermore, four peaks which did not appear in controls, were detected in treated striatum. One was identified as 3-methoxytyrosine, the level of which was still high 9 h after treatment. 3-Methoxytyrosine, has been detected previously in plasma of parkinsonian patients treated with L-dopa, and the disturbance in DA metabolism could explain some of the side-effects induced by that treatment.

Rat brain monoamine metabolism and hypobaric hypoxia: a new approach.

A chromatographic method with electrochemical detection was used to measure noradrenaline (NA), dopamine (DA), and serotonin (5-HT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxytyramine (3-MT) and 5-hydroxyindoleacetic acid (5-HIAA) in several brain areas (hypothalamus, hippocampus, striatum and rest of the brain) of rats exposed to a 7000 m simulated altitude for 3 hr. This new direct approach, not using a pharmacological tool, provides further information on the hypobaric hypoxia effects on the main DA and 5-HT metabolic steps. In the hypothalamus, a decreased NA level with increased DA and DOPAC contents was considered as the result of dopamine-beta-hydroxylase activity impairment. The decrease of both 5-HIAA and DOPAC in all brain areas provides further evidence of the hypoxia-induced decrement in MAO activity. Furthermore, in the striatum, it was shown that catechol-O-methyl transferase, up to now considered unaffected by hypoxia, may also be altered by oxygen deficiency.

Evidence for an activating effect of tabernanthine on rat brain catecholamine synthesis and elimination.

Tabernanthine increased the synthesis and elimination of catecholamines (CA) in the striatum and the rest of the brain, but not in the hypothalamus. These data provide evidence that tabernanthine may activate CA turnover of some brain structures by acting at 2 steps of the metabolic pathway. The results are discussed in relation to a central stimulating action and a hypoxia antagonistic effect of this drug.

Effects of physostigmine, paraoxon and soman on brain GABA level and metabolism.

The effects of sublethal doses of physostigmine, paraoxon and soman on GABA levels and metabolism were studied in small rat brain areas (hypothalamus, striatum, cerebellum, rest of the brain). Physostigmine induced a significant decrease in striatal GABA level and a reduction of synthesis index in the rest of the brain while organophosphates have little or no effect on GABA level and metabolism. This work provides new data about the physostigmine effect on brain GABA which could be related to the action of the anticholinesterase agents on other non-cholinergic neurotransmitters.

Evidence for an antagonistic action of tabernanthine on hypoxia-induced changes in brain serotonin levels.

The effects of tabernanthine on serotonin (5-HT) levels were determined in several brain areas of rats exposed to various simulated altitudes (1800, 5200, 7000 m). The 5-HT synthesis inhibitor, para-chlorophenylalanine (PCPA), was used to dissociate the effects occurring at synthesis and release levels. Tabernanthine antagonized the decrease in hypothalamic 5-HT levels induced by a 7000 m hypoxia and also suppressed the decrease in PCPA-induced depletion observed at 5200 and 7000 m in the hypothalamus, the striatum and the rest of the brain. It was assumed that tabernanthine stimulates different steps of 5-HT metabolism. These effects, revealed by hypoxia, are related to other peripheral and central properties of this drug.

Brain catecholamine metabolism changes and hypothermia in intoxication by anticholinesterase agents.

Sublethal doses of physostigmine, paraoxon and soman induce a short-lasting fall in rat core temperature potentiated by alpha-methyl-para-tyrosine (alpha-MT) (early effects). When the own hypothermic effect of the anticholinesterase agent has disappeared (late effects), alpha-MT induces a new decrease in temperature. Parallel biochemical studies of catecholamine levels and turnover were performed in several brain areas. The norepinephrine (NE) turnover is generally increased particularly in the hypothalamus, suggesting that NE hypothalamic changes might be linked to a latent perturbation of thermoregulatory mechanisms. Furthermore, it was shown that soman acts differently from the other drugs by inducing quite important changes in both NE and dopamine levels.

Modification of rat brain 5-hydroxytryptamine metabolism by sublethal doses of organophosphate agents.

The early and late effects of sublethal doses of two organophosphate agents (paraoxon and soman) on 5-hydroxytryptamine (5-HT) metabolism were investigated in several rat brain areas. Parallel determinations of acetylcholinesterase (AcChE) inhibition were performed. An increase in 5-HT level was observed during the first phase of soman intoxication and a rise in 5-hydroxyindol acetic acid (5-HIAA) appeared in the early and late effects of both anticholinesterase agents with a predominant action in the striatum. These data suggested that paraoxon and soman induce a long-lasting increase in 5-HT turnover. This action cannot be related neither to the AcChE inhibition nor to the acetylcholine level.

Changes in brain 5-hydroxytryptamine metabolism induced by hypobaric hypoxia.

1. 5-hydroxytryptamine (5-HT) level was measured in hypothalamus, striatum and the rest of the brain of rats exposed to 1800, 5200 and 7000 m simulated altitudes. 2. Moderate hypobaric hypoxia failed to modify 5-HT level, whereas severe hypoxia reduced the amine level by about 30%. 3. Treatment with a synthesis blocking agent (PCPA) revealed a dual effect of hypoxia on the 5-HT elimination. Increased elimination observed at 1800 m was attributed to the hypoxia-induced stress and the decrease (at 5200 and 7000 m) indicated the predominance of enzymatic inhibition. 4. It was assumed that tryptophan hydroxylase was more sensitive than monoamine oxidase to a high hypobaric hypoxia.

Influence of intoxication by anticholinesterase agents on core temperature in rats: relationships between hypothermia and acetylcholinesterase inhibition in different brain areas.

The early and late effect of three anticholinesterase agents (physostigmine, paraoxon and soman) on core temperature and brain acetylcholinesterase (AcChE) inhibition are compared. The study was performed in adult male rats using sublethal doses of all drugs. AcChE activity was determined by hypothalamus, striatum, hippocampus, medulla oblongata-pons and rest of the brain. The co-existence of intoxication symptoms, hypothermia and AcChE inhibitions was clearly shown by the early effects. However, no relationship was found between the degree of hypothermia and that of inhibition whatever brain area. In contrast, late AcChE inhibition was not accompanied by symptoms and lowering of core temperature. Several hypotheses have been suggested to explain this phenomenon: de novo synthesis of enzyme, decreased sensitivity of neurotransmitter or return to normal of brain acetylcholine level through a negative feed back at the presynaptic level. The present data suggest that this latter assumption is the most likely.

hypobaric hypoxia: central catecholamine levels and cortical PO2 and avoidance response in rats treated with apomorphine.

The learning of a conditioned avoidance response, the catecholamine levels in some cerebral structures, and the evolution of the cortical PO2, were studied under hypobaric hypoxia (300 torr) and under normoxia, in rats treated or not with apomorphine, at the dose of 1 or 10 mg/kg i.p. Apomorphine at 1 mg/kg improves the learning capacity and stabilises the cerebral catecholamine levels under hypoxia; no modification of the evolution of the cortical PO2 during hypoxia was observed between control rats and rats treated with this dose of apomorphine. Apomorphine at 10 mg/kg totally inhibits learning under normoxia or hypoxia. It is therefore possible to suppose that the antihypoxic protective mechanism of low-dose apomorphine is due to a stabilization of the levels of both dopamine and noradrenaline during hypoxia, but not to an increase in the cerebral oxygen availability. These data suggest the clinical possibility of using other dopaminergic stimulating agents for their eventual antihypoxic properties.

Effect of tabernanthine on the turnover time of brain catecholamines in normal and hypobaric hypoxic rats.

The central effects of tabernanthine on noradrenaline and dopamine turnover times were studied in the hypothalamus, the striatum and the remainder of the brain of normal and hypobaric hypoxic rats, the latter state corresponding to 5,200m (410mm Hg) and 7,000m (320mm Hg). Catecholamine cerebral level were not modified by the drug in either instance. At normal atmospheric pressure the catecholamine turnover times were slightly decreased by tabernanthine. Hypobaric hypoxia alone increased noradrenaline and dopamine turnover times by inhibiting oxygen-dependent enzymes. Tabernanthine antagonized the effect of hypobaric hypoxia especially in dopaminergic areas. Antagonism was complete at 5,200m but only partial at 7,000m. This phenomenon may be related to the stimulatory properties of the drug.

The effect of various stimulated altitudes on the turnover of norepinephrine and dopamine in the central nervous system of rats.

The elimination rate constant, half-life and turnover time of dopamine (DA) and norepinephrine (NE) were determined, after inhibiting their biosynthesis by alpha-methyl-para-tyrosine (alpha MT), in the hypothalamus, striatum and the remainder of the brain of rats exposed to different degrees of hypobaric hypoxia, corresponding to altitudes of 1,800, 3,800, 5,200 and 7,000 meters. The effects varied as a function of the degree of hypoxia and the brain region studied. The turnover time of NE in the hypothalamus remained unchanged, regardless of the altitude, while in the rest of the brain the rate constant of neurotransmitter elimination decreased inversely as a linear function of the degree of hypoxia. On the contrary, the changes of the DA turnover time in the striatum and the rest of the brain, were biphasic, being accelerated by moderate altitudes (1,800 m) and retarded by the two highest simulated altitudes studied as a function of hypoxia. The differential effects of hypoxia on NE and DA turnovers are attributed to different sensitivities of the respective enzyme systems.

[Effect of normobaric and hypobaric hypoxia on norepinephrine turnover in the rat heart (author's transl)]. / Influence de l'hypoxie normobare et hypobare sur le taux de renouvellement de la noradrénaline cardiaque

1. After administration of 3H norepinephrine (NE), the turnover rates of NE were determined by the decrease in radioactivity. 2. Rats were housed by groups in chambers and either maintained as controls or exposed to a hypoxic environment (PIO2 = 90 torr). The turnover rates of NE were not altered by normobaric hypoxia (fig. 1, table I). 3. Hypobaric hypoxia (barometric pressure was reduced to 500 mm Hg and PIO2 was 105 torr) increased the turnover rates of NE (fig. 2, table II). 4. The role of the sympathetic nervous system during exposure to hypoxia in Rats is discussed with regard to functional adaptation.

High altitude influence on the level and turn-over time of cardiac norepinephrine in rats.

In rats exposed to an altitude of 2,900 meters the level of endogenous cardiac norepinephrine decreases after the 5th day of exposure. The turner-over time of the amine proceeds in 3 steps which are probably related to periods of stress and adaptation: initial increase, important decrease from the 5th day and return to a normal value from the 12th day.