Biomedical subjects

W Kehr

Publications and source records attributed to W Kehr.

At least 55 records · Page 3Linked to original sources

PubMed1977

Interaction of haloperidol and gamma-butyrolactone with (+)-amphetamine-induced changes in monoamine synthesis and metabolism in rat brain.

The interaction of (+)-amphetamine with haloperidol and gamma-butyrolactone on synthesis of monoamines in rat brain regions was investigated using an in vivo method, in which the accumulation of dopa and 5-hydroxytryptophan (5-HTP) was measured after inhibition of the aromatic amino acid decarboxylase by means of 3-hydroxybenzylhydrazine. The accumulation of 3-methoxytyramine (3-MT) after inhibition of the monoamine oxidase with pargyline was taken as an indicator of the in vivo release of dopamine (DA) into the extraneuronal space. (+)-Amphetamine at doses of 1--3 mg/kg caused an increase of dopa formation in the DA-rich areas c. striatum and mesolimbic forebrain but had no effect on dopa formation in neocortex and 5-HTP formation in all brain regions investigated. At a dose of 10 mg/kg (+)-amphetamine decreased dopa as well as 5-HTP formation in all brain regions studied. 3-MT accumulation in whole rat brain was stimulated by (+)-amphetamine as well as haloperidol and inhibited by gamma-butyrolactone. Combined treatment with haloperidol and (+)-amphetamine not only potentiated the stimulation of dopa formation but also the increase of 3-MT accumulation. Pretreatment with gamma-butyrolactone antagonized the stimulation of 3-MT formation induced by (+)-amphetamine at a dose of 10 mg/kg. This dose of (+)-amphetamine markedly counteracted the gamma-butyrolactone-induced increase in dopa formation especially in the DA-rich areas. The data support the view that impulse flow in DA neurons facilitates the effect of (+)-amphetamine on DA release and DA synthesis. Inhibition of catecholamine synthesis after high doses of (+)-amphetamine may be due to an increase in cytoplasmatic DA concentration causing end-product inhibition of tyrosine hydroxylase.

4-Butyrolactone↗

PubMed1976

Effect of (+) amphetamine on monoamine synthesis and metabolism after axotomy in rat forebrain.

(+)Amphetamine is known to produce feedback inhibition of catecholamine-containing neurons in the central nervous system due to its indirect receptor stimulating properties. This feedback control may involve postsynaptic receptors and neuronal loops or presynaptic receptors and may be restricted to the catecholaminergic terminal system. In order to study the effect of (+)amphetamine on catecholamine synthesis and metabolism in the terminal system changes in impulse flow were eliminated by cutting the ascending monaminergic axons. Axotomy of the ascending monominergic fibers by means of a complete transverse cerebral hemisection resulted in a 3-fold increase in Dopa formation in the lesioned forebrain during 30 min after inhibition of the aromatic amino acid decarboxylase with 3-hydroxybenzylhydrazine HCl, 100 mg/kg i.p. (+)-Amphetamine sulfate, 10 mg/kg i.p. antagonized the hemisection-induced increase in Dopa formation and reduced the formation of 5-hydroxytryptophan. Pretreatment with haloperidol, 5 mg/kg i.p. failed to counteract the effect of (+)amphetamine. In the intact forebrain the stimulation of Dopa accumulation was more than additive after combined treatment with haloperidol and (+)amphetamine. Hemitransection retarded the disappearance of dopamine and noradrenaline after administration of alpha-methyl-p-tyrosine methylester HCl,300 mg/kg. (+)-Amphetamine, 10 mg/kg accelerated the utilization of dopamine on the lesioned side. Hemitransection reduced the formation of 3-methoxytyramine during 1 h after pargyline, 75 mg/kg i.p. After (+)amphetamine 3-methoxytyramine formation in the intact forebrain was 3 times higher than in the lesioned forebrain. The action of (+)amphetamine on dopamine synthesis and release appears to be dependent on the firing rate in dopamine neurons.

5-Hydroxytryptophan↗

PubMed1976

3-Methoxytyramine as an indicator of impulse-induced dopamine release in rat brain in vivo.

3-Methoxtyramine and dopamine accumulated in vivo in rat brain after monoamine oxidase inhibition with pargyline HCl. A dose of 100 mg/kg i.p. appeared to inhibit monoamine oxidase completely and led to a linear accumulation of 3-methoxytyramine for the first 90 min. Axotomy of the ascending dopaminergic fiber tract by means of a complete transverse cerebral hemisection almost completely blocked 3-methoxytyramine formation provided that catecholamine synthesis was inhibited with H 44/68 (Methylester of alpha-methyl-p-tyrosine). The dopamine receptor agonist apomorphine, 0.5 mg/kg i.p., decreased, while the dopamine receptor antagonist haloperidol, 2 mg/kg i.p., accelerated 3-methoxytyramine formation. gamma-Butyrolactone, 750 mg/kg i.p., not only decreased 3-methoxytyramine formation per se but also effectively antagonized the haloperidol-induced increase in 3-methoxytyramine accumulation. 3-Methoxytyramine formation after inhibition of monoamine oxidase appears to be a reliable indicator of impulse-induced dopamine release and metabolism.

4-Butyrolactone↗

PubMed1976

The role of intraneuronal amine levels in the feedback control of dopamine, noradrenaline and 5-hydroxytryptamine synthesis in rat brain.

The influence of varying brain levels of dopamine, noradrenaline and 5-HT on their respective synthesis rates has been investigated. The first step in monoamine synthesis was studied in vivo by measuring the accumulation of dopa and 5-hydroxytryptophan after inhibition of the aromatic L-amino acid decarboxylase. Variations in monoamine levels were obtained by combined treatment with inhibitors of the decarboxylase (NSD 1015 or Ro 4-4602) and of monoamine oxidase (pargyline). An increase in monoamine levels by pargyline was found to inhibit the synthesis of dopamine, noradrenaline and 5-HT. Conversely, a decrease in monoamine levels induced by the decarboxylase inhibitor Ro 4-4602 appeared to stimulate dopamine and noradrenaline synthesis but had no effect on 5-HT synthesis. The influence of varying levels of dopamine and noradrenaline on the synthesis of these amines could still be demonstrated after blockade of dopamine receptos and of alpha-adrenergic (noradrenaline) receptors by haloperidol, suggesting that the mechanism involved in this feedback control is mediated via end-product inhibition of tyrosine hydroxylase. On the other hand, the stimulating influence of haloperidol on the synthesis of catecholamines does not seem to be directly related to changes in catecholamine levels. It is concluded that the short-term control of catecholamine synthesis presumably involves two independent feedback mechanisms, one intraneuronal mechanism operating via end-product inhibition, and one synaptic mechanism mediated via dopamine and noradrenaline receptors, respectively. Both pre- and postsynaptic receptors may be involved in the latter mechanism.

5-Hydroxytryptophan↗

PubMed1976

Distribution of dopamine in the rat cerebral cortex.

The rat cerebral neocortex was sectioned by 3 transverse cuts and analyzed for dopamine and noradrenaline. Dopamine concentration decreased gradually from the rostral (97 +/- 4 ng/g) to the caudal (59 +/- 2 ng/g) end of the neocortex. Also, the noradrenaline concentration was highest in the rostral part (269 +/- 6 ng/g) and decreased gradually reaching a concentration of 238 +/- 3 ng/g in the caudal part. Since the quotient dopamine/noradrenaline showed similar changes in the neocortex parts investigated the data support the view that dopamine serves as a transmitter in cortical neurons apart from being a precursor for noradrenaline.

Animals↗

PubMed1976

[Interactions of dopamine receptor agonists and antagonists with regard to dopamine synthesis and metabolism].

Intraperitioneal injection of d-amphetamine sulfate, 0.3-3 mg/kg, led to a marked rise in dopa formation in the dopamine rich areas c. striatum and mesolibbic cortex of the rat brain inhibiton of the aromatic amino acid decarboxylase with 3-hydroxybenzylhydrazine HCL (NSD 1015). However, amphetamine given in a dose of 10 mg/kg decreased the tyrosine hydroxylation rate in the mesolimbic cortex as well as the norepinephrine containing neocortex. In combination with haloperidol the stimulating effect of the neuroleptic on dopa formation was markedly potentiated by amphetamine in rat forebrain. Also, amphetamine potentiated the haloperidol induced increase in dopamine release in vivo measured as 3-methoxytyramine formation. The functional antagonists haloperidol and d-amphetamine appear to have synergistic effects on dopaminergic neurons.

Animals↗

PubMed1975

Functional and biochemical aspects of catecholamine metabolism in brain under hypoxia.

Animals exposed to 6% oxygen showed a partial inhibition of the rate of tyrosine hydroxylation and a blockade of the conditioned avoidance response. The behavioral disruption was suggested to result, at least in part, from a dopaminergic disturbance, since the behavior was restored by the administration of DOPA or apomorphine but not by 5-hydroxytryptophan. Biochemical data showed a selective retardation in brain dopamine (DA) disappearance after synthesis inhibition. Methoxytyramine formation was markedly retarded. Analysis of this effect indicated that the decreased DA turnover was related to the release of transmitter rather than to an effect on catechol-O-methyltransferase (COMT) or monoamine oxidase (MAO). In addition, there was evidence for a partial inhibition of MAO activity by hypoxia as well as a decreased activity of dopamine-betahydroxylase. It was concluded that the disruption of behavior was related to decreased dopaminergic receptor activation and that decreased synthesis played at most a contributory role.

5-Hydroxytryptophan↗

PubMed1975

Influence of L-3-methoxytyrosine on monoamine synthesis in rat brain.

Rats were injected i.p. with L-3-methoxytyrosine, 100 or 300 mg/kg. One h later brain, liver, heart and blood plasma were analyzed for catecholamines and their precursors. In brain Dopa as well as dopamine and noradrenaline levels were unchanged, while demethylation of L-3-methoxytyrosine might have occurred in peripheral organs since Dopa levels in liver and dopamine in heart were elevated. 3-Methoxytyramine could not be detected in brain and liver after treatment with L-3-methoxytyrosine. Monoamine synthesis in vivo was measured in whole brain by determining the accumulation of Dopa and 5-hydroxytryptophan 30 min after the i.p. injection of NSD 1015(3-hydroxybenzylhydrazine HC1, 100 mg/kg), an inhibitor of the aromatic amino acid decarboxylase. L-3-Methoxytyrosine attenuated the formation of Dopa and 5-hydroxytryptophan by about 25% in brain tissue. The effect was paralleled by a decrease in the brain concentration of tryptophan.

5-Hydroxytryptophan↗

PubMed1975

Attempts to measure endogenous levels of dopa and 5-hydroxytryptophan in rat brain.

We have used previously published analytical methods of high sensitivity, developed in our laboratory, in an attempt to detect endogenous dopa and 5-hydroxytryptophan (5-HTP) in normal rat brain. In the brains of rats killed by decapitation we were unable to detect any dopa and found only a few ng/g of 5-HTP. Higher levels were found in the brains of rats killed by exposing their heads to microwaves. The levels of dopa found under these conditions varied considerably between different rat strains, and also between different experiments on the same strain, ranging between 2.5 and 13.8 ng/g. True resting levels may be lower than those observed because the procedure necessitated a short-lasting immobilization stress which increased the dopa (but not 5-HTP) levels. The 5-HTP levels were also variable and ranged between 5 and 25 ng/g. The highest levels of dopa and 5-HTP were found in the Japanese Wistar strain with spontaneous hypertension. Some analytical pitfalls are pointed out.

5-Hydroxytryptophan↗

PubMed1975