Pharmacological significance of biogenic amines in the lungs: Noradrenaline and dopamine

1. The noradrenaline concentration in the lung was less than 0.5 mug/g in eight animal species.2. In the cat, dog, rabbit and goat, tyramine produced a fall in pulmonary resistance, which was reduced by the administration of either reserpine or cocaine. Although an infusion of noradrenaline increased the content of this amine in the lung of the cat, previously depleted by reserpine, the bronchodilator property of tyramine was not restored. The infusion of isoprenaline did not restore the response to tyramine. The role of either catecholamine in mediating the bronchomotor response to tyramine could not be ascertained.3. The concentration of dopamine was as high as 6.4 mug/g in the goat lung and less than 0.5 mug/g in the lungs of the cat, rabbit, dog, rat, mouse, guinea-pig and man. Dopamine, injected intravenously into the cat, dog, rabbit and goat, produced a slight rise in pulmonary resistance. This increase was blocked by tolazoline, indicating that the response was mediated by alpha-adrenoceptors in the bronchial passages. No procedure has been observed to influence the dopamine content of the lung. The release of dopamine cannot, however, be excluded until the blood in the bronchial veins has been analysed.     

Effects of L-dopa on self-stimulation and brain biogenic amines in rats

Effects of various doses of L-DOPA were tested on self-stimulation behaviour in rats with electrodes implanted in the posterior hypothalamus (PH) or area ventralis tegmentum (A10 area) as well as on the concentration of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in the caudate nucleus (CN), diencephalon-midbrain (DM) and pons-medulla (PM). L-DOPA (50, 100 and 150 mg/kg. i.p.) showed a biphasic action on self-stimulation responding with an initial decrease for 40–60 min, followed by an increase for about an hour or more in rats with both PH and A10 electrodes. Both effects were more marked in rats with A10 electrodes. The effects of these doses on spontaneous motor activity were not significant. L-DOPA markedly increased DA levels in the CN and DM, and moderately decreased 5-HT, without significantly altering NE levels in the DM and PM. It appears that L-DOPA-induced changes in self-stimulation responding cannot be correlated with the increase of DA levels in the CN and DM. It is possible that this behaviour involves a system of several neurotransmitters, including biogenic amines and acetylcholine, and a sudden increase of one, such as DA, causes an imbalance in the multitransmitter system and disrupts the behaviour.     

N2-Acetylphenelzine : effects on rat brain GABA,alanine and biogenic amines

Summary The neurochemical properties of N ²-acetyl-phenelzine were compared with those of phenelzine in a rat model. N ²-Acetylphenelzine is a relatively potent inhibitor of monoamine oxidase-A and -B and causes increases in whole-brain levels of noradrenaline and 5-hydroxytryptamine, and decreases in homovanillic acid, 5-hydroxyindole-3-acetic acid, and 3,4-dihydroxyphenylacetic acid after acute i.p. administration of the drug. Phenelzine is a more potent monoamine oxidase inhibitor than is N ²-acetylphenelzine. The most marked difference in the profile was that N ²-acetylphenelzine had no effect on whole brain levels of the amino acid neurotransmitters alanine and -aminobutyric acid, whereas phenelzine caused dramatic increases. Acetylation of phenelzine at the N² position presumably interferes with the inhibition of the transaminase enzymes for -aminobutyric acid and alanine.     

Calcitonin enhances the effects of nimodipine on biogenic amines of rat brain.

1. Nimodipine affects the brain biogenic amines suggesting both inhibition of the striatal dopaminergic system and activation of serotonergic systems in various brain areas. 2. Salmon calcitonin affects serotonergic systems as nimodipine does. 3. It was hypothesized that these effects could be more than additive since they all have been ascribed to inhibition of neuronal calcium influx. 4. Biogenic amines and metabolites were determined in brain areas obtained from rats pretreated with saline or salmon calcitonin (10 MRC U/kg, s.c.) and treated with nimodipine (2.5-20 mg/kg, i.p.). 5. The effects of nimodipine and salmon calcitonin appeared to be merely additive.     

Diarrhea and biogenic amines: regional changes in brain histamine concentration and serotonin metabolism following castor oil-induced diarrhea in rats]

Regional changes in concentrations of histamine (HA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the rat brain were investigated after diarrhea induced by castor oil. Significant decreases in body weight were observed from the 3rd day after daily oral administration of castor oil (2.5 ml/kg). HA concentrations in most brain regions decreased in diarrhea induced by a single administration of castor oil. A significant decrease was recognized particularly in the case of the hippocampus. The influence has begun to appear in the thalamus and hypothalamus in consecutive (3 d) administration. HA concentration in the striatal and hypothalamic regions of the rat treated with castor oil for 9 d significantly decreased in comparison with the control group. On the other hand, an inhibition of 5-HT turnover was observed in the thalamus at 3 h after a single administration of castor oil. However, this inhibition was not found in rats treated with castor oil for 3 d. Moreover, 5-HT concentration in the midbrain significantly decreased in rats that acquired the adaptability for the occurrence of diarrhea. These data present a new finding that the occurrence of diarrhea or acquisition of adaptability for diarrheal occurrence affects the central histaminergic or serotonergic neuron system.     

Involvement of brain biogenic amines in the electroencephalographic and behavioural effects of morphine in post-addict rats

Rats were prepared with chronic cortical and temporalis muscle electrodes for recording of the electroencephalogram (EEG) and electromyogram and with chronic indwelling intravenous cannulae for drug administration. To induce dependence on morphine, progressively increasing intravenous doses were delivered automatically over a period of 6–7 days, after which time the injections were discontinued. Administration of morphine (10mg/kg, i.p.) to post-addict rats abstinent for 7 days was followed by the immediate appearance of EEG desynchronization and marked behavioural hyperarousal. After pretreatment of rats with (±) α-methyl-para-tyrosine (α-MPT), para-chlorophenylalanine (p-CPA), or a combination of α-MPT and p-CPA during the period of morphine addiction and withdrawal, these EEG and behavioural effects of morphine, given on the eighth day of abstinence, were unaltered. Brain levels of the catecholamines norepinephrine (NE) and dopamine (DA) measured in un-treated post-addict rats after a morphine test dose (10mg/kg, i.p.) likewise remained unchanged. Brain levels of serotonin (5-HT), determined 30 min after the morphine challenge, were significantly elevated. Determinations of brain NE and DA levels, made 30 min after injection of morphine to postaddict rats pretreated 4 hr earlier with a-MPT, showed a reduction in brain DA utilization. These results suggest that both dopaminergic and serotonergic brain pathways may be involved in the mediation of EEG and behavioural responses to morphine in post-addict rats.     

Changes in tissue oxidative stress,brain biogenic amines and acetylcholinesterase following co-exposure to lead,arsenic and mercury in rats

The present study investigated the toxic effects of individual, combined (binary and ternary) exposure to lead, arsenic and mercury on, (i) oxidative stress (ii) alterations in brain biogenic amines and (iii) tissue metals concentration. Rats were exposed to lead, arsenic and mercury either individually (30 ppm in drinking water), various binary (15 ppm each) or ternary combination (10 ppm each) for a period of 6 months. Lead + arsenic and lead + arsenic + mercury co-exposure led to a significant increase in the blood oxidative stress. Mercury + arsenic and lead + arsenic + mercury co-exposure produced a more pronounced hepatotoxicity while, lead + arsenic and lead + arsenic + mercury produced a significant increase in hepatic oxidative stress. Kidney oxidative stress and changes in brain biogenic amines were more prominent in animals exposed to three metals. Accumulation of three metals did not exhibit the pattern as in the case of oxidative stress. Exposure to two toxic metals also showed less accumulation of toxic metals suggesting possible antagonism. The present study thus provides some interesting observations on the interaction between lead, arsenic and mercury. Co-exposure to lead + arsenic + mercury led to a more pronounced increase in oxidative stress in liver and kidneys compared to other exposed groups.     

HPLC determination of biogenic amines in discrete brain areas in food deprived rats.

Norepinephrine (NE), dopamine (DA), 5-hydroxytryptophan (5-HTP), 5-hydroxytryptamine (5-HT), and 5-hydroxyindole acetic acid (5-HIAA) levels in the lateral hypothalamus (LH), ventromedial hypothalamus (VMH), median raphe (MR) and dorsal raphe (DR) were determined in nondeprived and 48 hr food deprived rats. Simultaneous determination of these compounds was accomplished by means of high performance liquid chromatography (HPLC) with electrochemical detection. When compared with controls, food deprived animals showed significant increases in 5-HT and 5-HIAA levels in the raphe nuclei, significant increases in 5-HIAA in the LH, but no changes in either 5-HT or 5-HIAA levels in the VMH. No changes in catecholamine levels were found in any of the brain areas studied. These results show that indoles in the raphe nuclei, as well as in the LH, are affected by food deprivation. The lack of change in indole levels in the VMH indicates that specific nuclei within the hypothalamus are differentially affected by food deprivation.     

Chronic cocaine effects on peripheral biogenic amines: a long-term reduction in peripheral dopamine and phenylethylamine production

The short- (during 12 h after last treatment) and long- (6 weeks after last treatment) term effects of repeated administration of cocaine on the total output of norepinephrine (NE) and its metabolites (sum NE), dopamine (DA) and its metabolites (sum DA) as well as the excretion of 5-hydroxyindoleacetic acid (5-HIAA) and phenylethylamine were evaluated in rats. The concentration of NE, DA and 3,4-dihydroxyphenylacetic acid (DOPAC) in the celiac ganglion after 1, 2 and 3 weeks of repeated cocaine administration were also measured. Sum NE remained unchanged during the cocaine treatment but NE and normetanephrine excretions were significantly decreased and increased respectively. 5-HIAA excretion was significantly reduced only after 3 weeks cocaine treatment. In the celiac ganglion NE and DOPAC contents showed tendencies towards being increased and decreased respectively. DA content was not changed. The excretions of DA, DOPAC, homovanillic acid (HVA) and phenylethylamine were significantly reduced during chronic exposure to cocaine. The above short-term changes in DA and phenylethylamine persisted for periods as long as 6 weeks after 1 week repeated exposure to cocaine. It is concluded that chronic exposure to cocaine can produce preferential long term deficiencies in the production of DA and phenylethylamine in the periphery. Peripheral noradrenergic and serotonergic neuronal systems are apparently minimally affected. The close association between DA or sum DA and phenylethylamine excretion suggest these 2 amines may coexist in the same neuron.     

The effects of an anti-atherosclerotic drug, pyridinolcarbamate, on heart, vascular and brain biogenic amines

The anti-atherosclerotic drug pyridinolcarbamate was investigated in the rat for its effects on heart, blood vessel and brain biogenic amines. The drug increased the concentration of noradrenaline in all tissues and of noradrenaline and 5-hydroxytryptamine in the brain. The possibility of a link between biogenic amines and atherosclerotic disease is discussed.     

Effects of nimodipine on biogenic amines in discrete brain areas.

Discrete brain sections were obtained from rats after once or repeatedly given intraperitoneal nimodipine at doses ranging from 2.5 to 40 mg/kg. The single or the last treatment was carried out at 2-8 h before killing. The biogenic amine and metabolite content of the tissue samples were determined by high-performance liquid chromatography with electrochemical detection. The nimodipine-induced effects, chiefly regarding the brainstem, the thalamus-midbrain and the striatum, consisted of both an increase in 5-hydroxyindoleacetic acid (5-HIAA) levels and a decrease in dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. Since the 5-HIAA/5-hydroxytryptamine (5-HT) ratio was increased, whereas the DOPAC/dopamine (DA) and HVA/DA ratios were decreased, it was argued that nimodipine activated the serotonergic and inhibited the dopaminergic systems. The first effect was enhanced by fasting and, likewise, by drug administration repeated for 5 days, while the second was not affected by fasting, but disappeared after 5 days' treatment. The data obtained appeared to substantiate the usefulness of nimodipine to treat some disorders of the central nervous system.     

MIF-1: effects on norepinephrine, dopamine and serotonin metabolism in certain discrete brain regions

A single injection of melanocyte-stimulating hormone inhibitory factor (MIF-1) in a dose of 3 mg/kg IP produced no significant effect on dopamine turnover. However, a dose of 5 mg/kg increased striatal tyrosine hydroxylase activity by 25% and homovanillic acid level by 27% when compared to control values. No change in either parameter was detected in olfactory tubercles. Dopamine levels also were elevated in striatum, pons-medulla and cerebral cortex in rats receiving 5 mg/kg dose of MIF-1. In olfactory tubercles, dopamine levels were however, reduced to 71% of control values taken as 100%. The concentration of norepinephrine tended to increase in several brain areas examined but, the change was statistically significant only in olfactory tubercles and cerebral cortex. The level of norepinephrine metabolite, 3-methoxy-4-hydroxyphenylethylene glycol, was lowered to 63% in whole brain of animals given MIF-1 at the dose of 5 mg/kg. These data suggest that MIF-1 enhances the turnover of dopamine and norepinephrine in the brain. However, MIF-1 treatment seemed to produce no consistent change in brain serotonin turnover. In striatum and cortex, this neuropeptide increased serotonin but elevated the level of its metabolite, 5-hydroxyindoleacetic acid indicating that the release of this brain amine was decreased in these two brain regions. The levels of 5-hydroxyindoleacetic acid were enhanced in hypothalamus and pons-medulla regardless of the dose of MIF-1 administered.     

Comparison among the effects of nifedipine,nimodipine and nisoldipine on the brain biogenic amines of normal or haloperidol treated rats

1. Previous studies have shown that dihydropyridine calcium antagonists affected the metabolism of the brain biogenic amines more extensively than the non-dihydropyridine ones. The effects of three dihydropyridines (nifedipine, nimodipine or nisoldipine, 0.05–0.10 mmol/kg i.p.) on brain monoamines and metabolites have been evaluated on both normal and haloperidol treated rats.2. The small changes induced by the drugs on normal rats were markedly increased in the haloperidol treated rats, clearly showing an inhibition of dopaminergic systems.3. These effects were selective for the striatum and cerebral cortex, with nisoldipine being more effective than nimodipine or nifedipine.4. The effects of the three drugs on serotonergic systems were similar or more marked on haloperidol treated rats than on normal rats. These effects, showing activation of serotonergic systems, displayed some regional specificity and different potency of the three compounds. Nisoldipine also appeared to be the most effective drug on serotonergic systems.5. In conclusion nisoldipine, as well as other calcium antagonists, may have a place in the treatment of some mood disorders.     

Drug interactions with brain biogenic amines and the effects of amphetamine isomers on locomotor activity.

Administration of single IP doses of 1.0 or 4.0 mg/kg of d-amphetamine evoked an increase in mouse spontaneous motor activity (SMA); in contrast, 1.0 mg/kg of l-amphetamine had no significant effect, while 4.0 mg/kg caused a decreased SMA. Pretreatment with aMT or pargyline had little effect on the actions of the l-isomer, but reduced the magnitude and duration of the stimulatory effect of d-amphetamine. Pretreatment with p-chlorophenylalanine had little effect on the actions of d-amphetamine but completely abolished the depressant actions of the l-isomer. Reserpine pretreatment markedly reduced basal SMA levels; such pretreatment caused both d- and l-amphetamine to act as stimulants of SMA.     

Studies on the effects of some biogenic amines on plasma fibrinogen level of rats and rabbits.

Intramuscular administration of iproniazid caused significant elevation of plasma fibrinogen in rats and rabbits. The elevation may be due to accumulation of monoamines, as the drug inhibited plasma monoamine oxidase quite strongly. This possibility was further supported by the fact that the direct administration of 5HT also elevated the plasma fibrinogen level by about 50 per cent. The effect of 5HT was more pronounced (about 75 per cent) when rabbits were pretreated with reserpine. The above observation has also been confirmed by reserpine-treated rats where different biogenic amines like 5HT, tryptamine, tyramine and epinephrine at low doses elevated plasma fibrinogen level. These biogenic monoamines possibly mediated their action through synthesis of protein since the increase of plasma fibrinogen level after 5HT administration was prevented by pretreatment of animals with actinomycin D or cyclohexamide.     

Effects of narcotic analgesics on serotonin metabolism in brain of rats and mice.

The effects of narcotic analgesics on the brain 5-hydroxytryptamine (5-Ht) and 5-hydroxyindoleacetic acid (5-HIAA) levels of rats and mice were investigated in relation to our preceding data on the effect of humoral modulatorents. The results suggest that morphine accelerates the release of brain 5-HT both in rats and mice, and that neither methadone nor pethidine alters the brain 5-HT and 5-HIAA levels in rats. The morphine-induced increase in brain 5-HT turnover is likely to be involved in the morphine-induced decrease in locomotor activity and hypothermia in rats. The activity-decreasing effects of methadone or pethidine, on the other hand, are mediated by mechanisms different from those which mediate the effects of morphine. In contrast, an increase in brain 5-HT turnover in mice apparently does not play an important role on activity-increasing effects of morphine but rather participates in other pharmacological effects of morphine.