Accumulation Of 3-methoxytyramine Research Articles

Neonatal ventral hippocampal damage modifies serum corticosterone and dopamine release responses to acute footshock in adult Sprague-Dawley rats.

Rats with excitotoxic neonatal ventral hippocampal lesions (NVHL) manifest in early adulthood a variety of behavioral and neurochemical abnormalities mimicking those seen in patients with schizophrenia. Some of these aberrations implicate malfunction of the midbrain dopamine systems. We studied NVHL effects on dopamine release in the rat frontal cortex, nucleus accumbens, and striatum during acute stress caused by inescapable continuous footshock (0.45 mA). Serum total corticosterone and prolactin levels were used as peripheral indices of stress. As an indirect index of dopamine release, tissue 3-methoxytyramine levels attained in vivo 10 min after monoamine oxidase inhibition was assayed in rats sacrificed by instantaneous microwave fixation of the brain tissue. Nonshocked NVHL rats showed significantly less nucleus accumbens' 3-methoxytyramine accumulation than their sham counterparts. Frontal cortical 3-methoxytyramine levels rose similarly after 20-min footshock in both groups of rats, but while it normalized after 60-min footshock in the sham rats, it did not decrease in the NVHL rats. Nucleus accumbens' 3-methoxytyramine was significantly elevated after either 20-min or 60-min footshock in both groups, whereas striatal 3-methoxytyramine was significantly elevated in the NVHL rats only. Serum corticosterone showed similar elevations in the sham and NVHL rats, but the patterns differed in that there was no attenuation after 60-min footshock in the latter. The lesion did not affect serum prolactin response. These data indicate that neonatal ventral hippocampal damage enhances and prolongs certain neural and neuroendocrine responses to acute physical stressor(s), and thus may affect adaptation and enhance detrimental effects of stress.

3-Methoxytyramine formation following monoamine oxidase inhibition is a poor index of dendritic dopamine release in the substantia nigra.

This study was undertaken, using microdialysis, to compare the extracellular concentration of 3-methoxytyramine and dopamine in dialysate from the striatum and substantia nigra, after pargyline (75 mg/kg), after pargyline plus amphetamine (3 mg/kg), and after pargyline plus reserpine (5 mg/kg) administration. Treatment with pargyline alone increased the extracellular dopamine concentration by 70% in the striatum and by 140% in the substantia nigra and induced in both regions a time-dependent accumulation of 3-methoxytyramine. The addition of d-amphetamine to pargyline increased the extracellular dopamine concentration, compared with pargyline-treated controls, to the same extent in both the substantia nigra (maximally by 360%) and the striatum (maximally by 400%), but the concomitant increase of 3-methoxytyramine accumulation in the dialysate was relatively smaller in the substantia nigra compared with the striatum. Reserpine treatment decreased the extracellular dopamine concentration in both regions below the detection level (<10% of basal value). When pargyline was added to reserpine, the striatal extracellular dopamine concentration increased to 50% of pargyline-treated controls and the striatal 3-methoxytyramine accumulation was less than in pargyline-treated controls. However, in the substantia nigra, the addition of pargyline to reserpine resulted in dopamine concentrations as high as after pargyline only and the 3-methoxytyramine accumulation was not changed compared with pargyline-treated controls. In summary, our results indicate that dopamine in the substantia nigra is released from reserpine-sensitive storage sites and that pargyline-induced 3-methoxytyramine accumulation is a poor indicator of the local dopamine release. The latter observation may be explained by the fact that the dopamine-metabolizing enzyme, catechol-O-methyltransferase, is located inter alia in the dopamine-containing cell bodies/dendrites in the substantia nigra, in contrast to the situation in the terminals in the striatum where catechol-O-methyltransferase is located only in nondopaminergic cells.

Voluntary ethanol intake in the rat: effects of nicotinic acetylcholine receptor blockade or subchronic nicotine treatment

It has been suggested that the mesolimbic dopamine activating and the reinforcing properties of ethanol involve activation of central nicotinic acetylcholine receptors. To test this hypothesis, the effects of two nicotinic receptor antagonists and of subchronic nicotine treatment on voluntary ethanol consumption (ethanol 6% v/v or water) were studied in ethanol low-, medium- or high-preferring Wistar rats. After systemic mecamylamine (2 mg/kg) but not hexamethonium (10 mg/kg) high- but not low-preferring rats decreased their ethanol intake but, however, not their ethanol preference. When subchronically exposed to nicotine (0.35 mg/kg, s.c. daily) medium-preferring rats markedly increased their ethanol intake and preference. This effect lasted for more than 1 week after interrupting nicotine administration. Ethanol intake levels did not correlate with locomotor activity scores after nicotine challenge (0.35 mg/kg, s.c.) or with exploratory locomotor activity. However, exploratory locomotor activity correlated with locomotor activity scores both after nicotine (0.35 mg/kg, s.c.) and ethanol (0.125 g/kg i.p.) challenge. Dopamine release, as indicated by accumulation of 3-methoxytyramine after monoamine oxidase inhibition, was increased in the limbic forebrain (including the nucleus accumbens, the olfactory tubercles, the amygdala and the septum) after acute nicotine (0.35 mg/kg s.c.) or ethanol (2.5 g/kg i.p.) in animals subchronically exposed to nicotine compared to subchronically vehicle-treated controls. The present results further implicate central nicotinic receptors in the molecular events mediating the reinforcing properties of ethanol, and suggest that subchronic nicotine enhances the responsiveness of mesolimbic dopamine neurons both to nicotine and to ethanol. Clinical implications are discussed.

Dopamine release in the rat cerebellum and hippocampus: a tissue 3-methoxytyramine study

Multiple lines of evidence indicate dopamine is a neurotransmitter or neuromodulator in the cerebellum and hippocampus. In this study, we explored the utility of 3-methoxytyramine as an index of dopamine release in these regions. We found that: (1) cerebellar and hippocampal 3-methoxytyramine levels can be measured by combined gas chromatography-mass fragmentography with negative chemical ionization; (2) basal 3-methoxytyramine accumulation rates following monoamine oxidase inhibition, but not the steady-state tissue levels, are several times lower in these regions than in the frontal cortex; (3) accumulation of 3-methoxytyramine in the hippocampus and cerebellum can be enhanced following electroconvulsive shock, but not acute haloperidol (0.4 mg/kg) treatment. We conclude that 3-methoxytyramine accumulation may be a useful index of dopamine release in the cerebellum and hippocampus, but dopamine release is regulated differently in these regions than in the frontal cortex and striatum.

γ-Butyrolactone-sensitive and -insensitive dopamine release, and their relationship to dopamine metabolism in three rat brain regions

Some data suggest dopamine (DA) release from neuronal terminals is partially independent of impulse flow. We examined the changes in tissue DA and its major metabolite levels 30 and 90 min after treatment with y-butyrolactone (750 mg/kg). Accumulation of 3-methoxytyramine within 10 min of pargyline injection (75 mg/kg) was used as an index of DA release. Thirty minutes after y-butyrolactone injection, DA content was increased maximally in the frontal cortex, nucleus accumbens and striatum (by 91%, 80% and 73%, respectively). 3-Methoxytyramine rates of accumulation were reduced by 77%, 77%, and 92%, respectively. Ninety minutes after the treatment, DA levels remained high in all three areas, while DA release was persistently low in the striatum and nucleus accumbens, but had returned to baseline in the frontal cortex. Changes in 3,4-dihydroxyphenylacetic acid and homovanillic acid levels were not synchronized with changes in DA release in the striatum and nucleus accumbens, and were absent in the frontal cortex. The data suggest that an impulse flow-independent mechanism contributes to approximately one tenth and one fourth of the basal DA release in the terminals of DA neurons originating in the substantia nigra and ventral tegmental area, respectively. The acidic DA metabolite levels become at best poorly associated with DA release during blockade of the DA neuronal firing, probably because of the increased in situ metabolism of newly synthesized DA.

The influence of serotoninergic drugs on dopaminergic neurotransmission in rat substantia nigra, striatum and limbic forebrain in vivo.

The effects of serotoninergic drugs on dopaminergic neurotransmission in the substantia nigra, the striatum and the limbic forebrain of rat have been investigated. The accumulation of 3-methoxytyramine (3-MT) following inhibition of monoamine oxidase with pargyline was used as an indirect measure of dopamine (DA) activity in vivo. The effects of the following serotoninergic drugs were tested: the 5-HT1A receptor agonist 8-OH-DPAT, the 5-HT1B receptor agonist trifluoromethyl-phenylpiperazine (TFMPP), CGS 12066 B and RU 24969, the 5-HT1A/1B antagonist (+/-)pindolol, the 5-HT2/1C receptor antagonist ritanserin, the 5-HT2/1C receptor agonist DL-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), the 5-HT3 receptor antagonist BRL 43694, the unselective 5-HT receptor antagonist methiothepin, and carbidopa + L-5-hydroxytryptophan (L-5-HTP) to achieve a general, unselective stimulation of multiple 5-HT receptors. In the substantia nigra, carbidopa + 5-HTP treatment increased the 3-MT accumulation by 26% and decreased the DA concentration to 67% of controls, tentatively suggesting a 5-HTP-induced displacement of nigral DA. A minor, non dose-related reduction in nigral 3-MT was seen after the 5-HT1A receptor agonist 8-OH-DPAT. None of the other serotonin receptor acting drugs induced any pronounced effect on the nigral 3-MT accumulation. Taken together, the findings provide little support for the idea that one single 5-HT receptor subtype serves a modulatory function on DA activity in the substantia nigra. In the striatum and the limbic forebrain, trifluoromethyl-phenylpiperazine dose-dependently increased the 3-MT accumulation to maximally 200%-220% of controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of ( d-amphetamine on dopaminergic neurotransmission; a comparison between the substantia nigra and the striatum

The effects of ( d-amphetamine (d-AMP) on dopaminergic neurotransmission in the cell body/dendritic region of the nigrostriatal pathway, the substantia nigra, have been investigated and compared to the effects obtained in the terminal region of the pathway, the striatum. The rate of synthesis of dopamine (DA) was quantified as accumulation of 3,4-dihydroxyphenylalanine (DOPA), after inhibition of aromatic l-amino acid decarboxylase with 3-hydroxybenzyl-hydrazine (NSD 1015). As measures of the metabolism of DA the concentrations of the metabolites of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) were determined. As indices of release of DA, the accumulation of 3-methoxytyramine (3-MT), after inhibition of monoamine oxidase with pargyline and the disappearance of DA, after inhibition of its synthesis with α-methyl- p-tyrosine were assessed. ( d-Amphetamine insignificantly increased the concentration of DA in the striatum but profoundly decreased it in the substantia nigra (to 60% of controls). Both in the striatum and in the substantia nigra treatment with d-AMP induced clearcut decreases of the concentrations of DOPAC. Also the concentration of HVA was profoundly decreased in the striatum but only marginal effects on HVA were observed in the substantia nigra. In both structures of the brain, d-AMP increased the concentration of 3-MT. Depending on the dose, d-AMP increased or had no effect on the accumulation of DOPA in the striatum but consistently decreased it in the substantia nigra. In the striatum, d-AMP increased the pargylineinduced accumulation of 3-MT, without affecting the concentration of DA. However, in the substantia nigra the concentration of DA was profoundly decreased (to 50% of controls) in combination with unaltered accumulation of 3-MT, unless the rats were pretreated with haloperidol. If so, the effects of d-AMP on the concentration of DA and accumulation of 3-MT were the same in the substantia nigra and in the striatum. The results indicate that d-AMP depleted stores of DA in the substantia nigra, due to its releasing action, in combination with its decreasing effect on the rate of synthesis of DA. The decrease in rate of synthesis of DA is suggested to be due to the d-AMP-induced decrease in the firing rate of dopaminergic neurones.

Effects of acute and chronic clozapine and haloperidol administration on 3-metnoxytyramine accumulation in rat prefrontal cortex, nucleus accumbens and striatum

The accumulation of 3-methoxytyramine (3-MT), a reflection of dopamine release, was measured in the prefrontal cortex, nucleus accumbens, and striatum following administration of acute and chronic clozapine and haloperidol. Several doses of each drug were used. The effects of chronic drug treatment were measured 1 h (chronic 1 h groups), 24 h (chronic 24 h groups) and 48 h (chronic 48 h groups) after the final dose of each drug. In the prefrontal cortex, clozapine and haloperidol elevated 3-MT more in the acute groups than in the chronic 1 h groups, suggesting that partial tolerance developed. In the striatum and nucleus accumbens, acute and chronic (chronic 1 h) haloperidol produced equal increases in 3-MT above the appropriate baselines, suggesting that no tolerance developed. In the striatum, clozapine reduced 3-MT in the chronic l h group after high doses (25 mg/kg), and in the chronic 24 h group. These results suggest that neuroleptics may not produce the reduction in dopamine release that has been predicted with the development of depolarization inactivation. The reduction of striatal dopamine release during chronic clozapine treatment may be related to clozapine not being associated with the development of tardive dyskinesia.

CGP 28014, a new inhibitor of cerebral catechol-O-methylation with a non-catechol structure

CGP 28014 (N-(2-pyridone-6-yl)-N',N'-di-n-propylformamidine) or its methanesulfonate salt CGP 28014 A was suspected to be a catechol-O-methyl-transferase (COMT) inhibitor because it was found to reduce the levels of homovanillic acid (HVA) and to increase those of 3,4-dihydroxyphenylacetic acid (DOPAC) in the rat striatum, after oral or intraperitoneal administration. These effects were maintained after repeated administration. The compound was only weakly active as a COMT inhibitor in vitro. However, its effect on striatal HVA and DOPAC was not prevented by pretreatment with the inhibitor of microsomal drug metabolizing enzymes in the liver, proadifen, indicating that, if CGP 28014 acts as a prodrug, its conversion to the active compound is not by oxidative metabolism in the liver. Also, there was no evidence that conversion to 2-amino-6-hydroxypyridine could explain its effects. The in vivo effect of CGP 28014 was substantiated in two additional in vivo test systems. Thus, it inhibited the accumulation of 3-methoxytyramine in the rat striatum after MAO inhibition by clorgyline, and the formation of O-methyl-DOPA from exogenously administered DOPA. It proved to be equipotent or nearly so with tropolone, and also showed a similar duration of action. Similar to tropolone, it increased S-adenosylmethionine levels in the striatum. Pyrogallol, on the other hand, decreased them, because being a substrate of COMT, it consumes methyl groups. This suggests that CGP 28014 does not inhibit COMT because it is a substrate of the enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis and Release of Dopamine in Rat Brain: Comparison Between Substantia Nigra Pars Compacta, Pars Reticulata, and Striatum

Dopamine (DA) is synthesized and released not only from the terminals of the nigrostriatal dopaminergic neuronal pathway, but also from the dendrites in the substantia nigra. We have investigated the regulation of the DA turnover, the DA synthesis rate, and the DA release in the substantia nigra pars compacts (SNpc) and pars reticulata (SNpr) in vivo. As a measure of DA turnover, we have assessed the concentrations of 3,4-dihydroxyphenylacetic acid and homovanillic acid. As a measure of the DA synthesis rate, we have determined the 3,4-dihydroxyphenylalanine accumulation after inhibition of aromatic L-amino acid decarboxylase by 3-hydroxybenzylhydrazine. As a measure of DA release, we have investigated the disappearance rate of DA after inhibition of its synthesis by alpha-methyl-p-tyrosine and the 3-methoxytyramine accumulation following monoamine oxidase inhibition by pargyline. Both the DA turnover and the DA synthesis rate increased following treatment with the DA receptor antagonist haloperidol and decreased following treatment with the DA receptor agonist apomorphine in the SNpc and in the SNpr, but the effects of the drugs were less pronounced than in the striatum. gamma-Butyrolactone treatment, which suppresses the firing of the dopaminergic neurons, increased the DA synthesis rate in the striatum (165%), but had no such effect in the SNpc or SNpr. Haloperidol, apomorphine, and gamma-butyrolactone increased, decreased, and abolished, respectively, the DA release in the striatum, but the drugs had no or only slight effects on the alpha-methyl-p-tyrosine-induced DA disappearance and on the pargyline-induced 3-methoxytyramine accumulation in the SNpc or SNpr. Taken together, these results indicate that the DA synthesis rate, but not the DA release, are influenced by DA receptor activity and neuronal firing in the SNpc and SNpr. This is in contrast to the situation in the striatum, where both the DA synthesis rate and the DA release are under such control.

Inhibition of nigrostriatal release of dopamine in the rat by adenosine receptor agonists: A 1 receptor mediation

The stable analogues of adenosine, N-ethylcarboxamidoadenosine (NECA), R-phenylisopropyladenosine (R-PIA) and cyclohexyladenosine (CHA), dose-dependently decreased levels of 3-methoxytyramine (3-MT) in the striatum and antagonized pargyline-dependent accumulation of 3-methoxytyramine. These agents were equipotent with ED 25 values of approximately 1 mg/kg, (p.o.) in inhibiting pargyline-dependent accumulation of 3-methoxytyramine. Since CHA and R-PIA are relatively selective for A 1 receptors and NECA is almost equipotent at A 1 and A 2 sites, the data of undifferentiated potency for these 3 agents on release of dopamine (levels of 3-MT) would argue in favor of mediation of A 1 receptors in this phenomenon. This conclusion was further supported by experiments with the A 1-selective antagonist, 8-cyclopentyl-l,3-dipropylxanthine (CPDX), which antagonized the actions of CHA. Similar antagonism of CHA-dependent decreases in levels of cyclic GMP in the cerebellum, an action known to be mediated by A 1 receptors, was also observed. These data support previous studies which indicated an adenosine receptor-mediated modulation of nigrostriatal release of dopamine. In addition, the present data indicate that this is an action on A 1 receptors.

3-Methoxytyramine accumulation: effects of typical neuroleptics and various atypical compounds.

The accumulation of 3-methoxytyramine (3-MT), the O-methylated metabolite of dopamine (DA), in rat striatum was used to assess the effects of drugs on dopaminergic activity. This was accomplished by pretreating rats with pargyline to completely inhibit 3-MT catabolism. Under the conditions used, 3-MT accumulation was linear over time for at least 90 minutes. Apomorphine and gamma-butyrolactone, drugs which depress the activity of DA-containing neurons, decreased striatal 3-MT accumulation; whereas typical neuroleptics (haloperidol, fluphenazine, chlorpromazine), which increase the activity of DA-containing neurons, increased striatal 3-MT accumulation. In addition, a number of other drugs which block DA receptors and exert various atypical actions on dopaminergic functioning were examined. These "atypical" compounds (clozapine, buspirone, molindone) also increased striatal 3-MT accumulation, but were generally less potent than the typical neuroleptics examined. Moreover, the potencies of the typical neuroleptics and "atypical" compounds that were tested appear to be somewhat related to their affinities for D-2 DA receptors, as measured by their abilities to displace 3H-spiperone from rat striatal membrane preparations. Interestingly, this relationship was less evident when NaCl was omitted from the 3H-spiperone binding assay buffer. The potential antipsychotic drugs, BW 234U and SCH 23390, were also investigated for their effects on 3-MT accumulation and 3H-spiperone binding, and they were relatively inactive in both of these measures of dopaminergic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of rolipram, a novel antidepressant, on monoamine metabolism in rat brain.

The phosphodiesterase inhibitor and putative antidepressant rolipram (0.3-30 mg/kg i.p.) stimulated the accumulation of dopa following inhibition of the aromatic amino acid decarboxylase with 3-hydroxybenzylhydrazine HCl dose-dependently in all brain regions investigated, suggesting that both dopamine and noradrenaline synthesis was enhanced. The stimulatory effect of rolipram on dopa accumulation in dopamine rich regions persisted even after pretreatment with gamma-butyrolactone which by itself increased dopa accumulation three fold. Following inhibition of catecholamine synthesis with alpha-amethyl-p-tyrosine rolipram accelerated the disappearance of noradrenaline and slowed the disappearance of dopamine. At low doses rolipram tended to reduce the pargyline-induced accumulation of 3-methoxytyramine. Rolipram attenuated the accumulation of 5-hydroxytryptophan in the neocortex and the diencephalon of 3-hydroxybenzylhydrazine HCl pretreated rats. The data suggest that rolipram enhances noradrenergic transmission by direct stimulation of tyrosine hydroxylase and by an increase of neuronal activity. Despite a stimulatory effect on tyrosine hydroxylase rolipram does not appear to alter dopamine release and metabolism to a large extent. In view of the occurrence of head-twitches the rolipram-induced reduction of 5-hydroxytryptamine metabolism may be due to feedback inhibition.

Transdihydrolisuride, a partial dopamine receptor antagonist: Effects on monoamine metabolism

The 9,10-transdihydro analogue of the dopaminergic ergot derivative lisuride, transdihydrolisuride (TDHL) stimulated the accumulation of dopa following inhibition of the aromatic amino acid decarboxylase with 3-hydroxybenzylhydrazine HCl in striatum (0.1–10 mg/kg i.p.), in the dopamine rich part of the limbic system (at 3 mg/kg i.p.) and in the neocortex (0.3–10 mg/kg i.p.). At a low dose (0.03 mg/kg) however, TDHL inhibited dopa accumulation in the limbic system. In γ-butyrolactone-pretreated rats TDHL not only inhibited the accumulation of dopa in striatum and in the dopamine-rich part of the limbic system but also antagonized the inhibitory effect of lisuride on dopa accumulation. The accumulation of 5-hydroxytryptophan was reduced in striatum, in parts of the limbic system and neocortex only at high doses of TDHL (3 and 10 mg/kg i.p.). TDHL (0.03 or 3 mg/kg i.p.) did not change the α-methyl-p-tyrosine methylester HCl-induced disappearance of dopamine buy accelerated the disappearance of noradrenaline at a dose of 3 mg/kg in all brain regions studied. The striatal level of dihydroxyphenylacetic acid was increased by TDHL dose dependently, the maximum effect being only half of that induced by haloperidol. TDHL (0.3 and 3 mg/kg i.p.) stimulated the accumulation of 3-methoxytyramine and normetanephrine following monoamine oxidase (MAO) inhibition with pargyline. The data suggest that TDHL is a mixed agonist-antagonist at central dopamine receptors. Under normal conditions the antagonistic component appears to predominate in the nigrostriatal and mesolimbic system. The stimulation of noradrenaline turnover was most likely due to an adrenoceptor antagonistic action of TDHL.

3-Methoxytyramine and normetanephrine as indicators of dopamine and noradrenaline release in mouse brain in vivo.

Intraperitoneal administration of pargyline HCl induced a dose-dependent accumulation of 3-methoxytyramine and normetanephrine in mouse brain in vivo. As judged by the decrease of 5-hydroxyindole acetic acid levels a dose of 200 mg/kg of pargyline appeared to inhibit monoamine oxidase completely. This dose led to an approximately linear accumulation of 3-methoxytyramine and normetanephrine during the first 3 hours. gamma-Butyrolactone, 750 mg/kg i.p. reduced the accumulation of 3-methoxytyramine despite a marked increase of dopamine. (+)-Amphetamine stimulated 3-methoxytyramine as well as normetanephrine accumulation at doses of 3 and 10 mg/kg i.p. In line with the concept of receptor-mediated negative feedback control of catecholaminergic transmission the dopamine receptor agonists apomorphine, 0.3 mg/kg i.p., lisuride, 0.05--0.3 mg/kg i.p., and bromocriptine, 10 mg/kg i.p., decrease 3-methoxytyramine formation while the dopamine receptor blocking agent haloperidol, 1 mg/kg i.p., led to a 3-fold increase. The alpha-adrenoceptor agonist clonidine, 0.1 mg/kg i.p., reduced the formation of normetanephrine and the alpha-adrenoceptor antagonists yohimbine, 10 mg per kg i.p., phenoxybenzamine, 20 mg/kg i.p., and mianserine, 50 mg/kg i.p., stimulated normetanephrine accumulation 1.5- to 4-fold. 3-Methoxytyramine and normetanephrine accumulating after inhibition of monoamine oxidase appear to be reliable indicators of dopamine and noradrenaline release and metabolism.

Catecholamine and 5-hydroxytryptamine synthesis and release in the brain of mutant spastic han-wistar rats

The in vivo synthesis of catecholamines and 5-hydroxytryptamine was measured in various brain regions of mutant Han-Wistar rats with progressive spastic paresis and of unaffected littermates by measuring the accumulation of dopa and 5-hydroxytryptophan following inhibition of aromatic amino acid decarboxylase with 3-hydroxybenzylhydrazine HCl. The accumulation of 3-methoxytyramine in the forebrain of normal and mutant spastic Han-Wistar rats, following inhibition of monoamine oxidase with pargyline HCl, was taken as an indicator of dopamine release in vivo. Dopa accumulation in the dopamine-rich part of the limbic system was 22% lower in mutant rats than in their unaffected twins. In both groups of rats the concentration of dopamine in the striatum, the limbic system, hemispheres and diencephalon was nearly the same. However, the accumulation of 3-methoxytyramine in the forebrain of mutants was only 60% of that found in their unaffected littermates. The noradrenaline concentration in the striatum, hemispheres and cerebellum of mutant rats was about 40% lower than in the respective regions of normal rats, whereas the accumulation of dopa in the brain regions where noradrenaline is the predominant catecholamine was unchanged or even increased as in cerebellum of mutant rats. 5-Hydroxytryptamine levels of mutant rats were either slightly higher or in the range of normal controls, while 5-hydroxytryptophan accumulation was markedly higher in diencephalon, striatum, cerebellum and brain stem of mutant rats. 5-Hydroxyindole acetic acid levels were also higher in all brain regions of mutant rats. The data indicate that the neurochemical correlates of monoaminergic neurotransmission are altered in some brain regions of mutant spastic Han-Wistar rats.

Involvement of the nerve flow in the release of extragranular dopamine

It is generally accepted that reserpine blocks the granular storage mechanism in catecholaminergic neurones and that (+)-amphetamine (AMP) releases dopamine (DA) from extragranular storage sites. In the present experiments it was investigated whether release from extragranular stores was dependent on ongoing nerve impulses. In three of the four experiments the accumulation of 3-methoxytyramine (3MT) after inhibition of monoamine oxidase was used as indicator for impulse-induced DA release. HA-966 (1-hydroxy-3-amino-pyrrolidone-2) or γ-hydroxybutyrate (GHB) was used to interrupt nerve impulses in the nigrostriatal pathway. After reserpine pre-treatment HA-966 and GHB blocked the pargyline-induced 3MT increase, while they increased DA levels concomitantly. If AMP was injected instead of reserpine, and no inhibitor of monoamine oxidase was given, no definite conclusion could be drawn about the interaction because AMP was suspected of partially inhibiting monoamine oxidase. Therefore monoamine oxidase was fully blocked by pargyline in two further experiments. Under these conditions HA-966 antagonized the AMP-induced 3MT accumulation, irrespective of whether a high (10 mg/kg) or a low (2 mg/kg) dose of AMP was given. GHB, however, was only effective if the low AMP dose was used. It is concluded that interruption of nerve impulses in the dopaminergic pathway inhibits the release from extragranular storage sites.

Effect of pentoxifylline and aminophylline on biogenic amine metabolism of the rat brain

In the brain of rats injected with pentoxifylline [3,7-dimethyl-1(5-oxo-hexyl)-xanthine] or aminophylline the following was observed: (i) dose-dependent increases of tryptophan and 5-droxyindoleacetic acid levels and of 5-hydroxytryptophan and dihydroxyphenylalanine accumulation after treatment with the decarboxylase inhibitor benserazide HCl; (ii) acceleration of norepinephrine turnover following α-methyl-p-tyrosine; (iii) increase of 3-methoxytyramine accumulation following pargyline. On a molar basis pentoxifylline was more potent than aminophylline in affecting brain biogenic amine metabolism.

Interaction of haloperidol and ?-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.

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.