Pharmacologic profile of MDMA (3,4-methylenedioxymethamphetamine) at various brain recognition sites

We report here an in vitro pharmacologic profile for MDMA (3,4-methylenedioxymethamphetamine) at various brain recognition sites. The rank order of affinities of MDMA at various brain receptors and uptake sites are as follows: 5-HT uptake greater than alpha 2-adrenoceptors = 5-HT2 serotonin = M-1 muscarinic = H-1 histamine greater than norepinephrine uptake = M-2 muscarinic = alpha 1-adrenoceptors = beta-adrenoceptors greater than or equal to dopamine uptake = 5-HT1 serotonin much greater than D-2 dopamine greater than D-1 dopamine. MDMA exhibited negligible affinities (greater than 500 microM) at opioid (mu, delta and kappa), central-type benzodiazepine, and corticotropin-releasing factor receptors, and at choline uptake sites and calcium channels.     

Impact and mechanisms of action of neurotensin on cardiac contractility in the rat left ventricle

Using immunoassay measurements, neurotensin was identified in rat ventricular tissue and in coronary effluent samples. Exogenous neurotensin evoked contractile responses in isolated ventricular preparations, which were equivalent in magnitude to those of norepinephrine and histamine, but greater than those for serotonin and angiotensin II. EC₅₀ values revealed neurotensin to be as potent as serotonin, but more potent than norepinephrine, histamine and angiotensin II. Structure–activity studies indicated that the contractile effects are attributed to the C-terminal portion of neurotensin. Neurotensin-induced responses were decreased by SR 48692, a specific neurotensin receptor antagonist. Neurotensin elicited an increase in coronary effluent norepinephrine concentrations, and a strong relationship between the magnitude of neurotensin-induced contractile effects and increments in myocardial norepinephrine release were noted. Neurotensin-induced contractile responses were abolished by β-adrenoceptor antagonists, but not by histamine, serotonin or angiotensin II receptor antagonists. In conclusion, neurotensin increases ventricular contractility through stimulation of myocardial norepinephrine release.     

Fluoxetine, but not other selective serotonin uptake inhibitors, increases norepinephrine and dopamine extracellular levels in prefrontal cortex

RATIONALE: The selective serotonin uptake inhibitor (SSRI) fluoxetine has been shown to not only increase the extracellular concentrations of serotonin, but also dopamine and norepinephrine extracellular concentrations in rat prefrontal cortex. The effect of other SSRIs on monoamine concentrations in prefrontal cortex has not been thoroughly studied. OBJECTIVE: The aim of this study was to compare the ability of five systemically administered selective serotonin uptake inhibitors to increase acutely the extracellular concentrations of serotonin, norepinephrine and dopamine in rat prefrontal cortex. METHODS: The extracellular concentrations of monoamines were determined in the prefrontal cortex of conscious rats using the microdialysis technique. RESULTS: Fluoxetine, citalopram, fluvoxamine, paroxetine and sertraline similarly increased the extracellular concentrations of serotonin from 2- to 4-fold above baseline. However, only fluoxetine produced robust and sustained increases in extracellular concentrations of norepinephrine and dopamine after acute systemic administration. Fluoxetine at the same dose blocked ex vivo binding to the serotonin transporter, but not the norepinephrine transporter, suggesting that the increase of catecholamines was not due to non-selective blockade of norepinephrine uptake. Prefrontal cortex extracellular concentrations of fluoxetine at the dose that increased extracellular monoamines were 242 nM, a concentration sufficient to block 5-HT(2C) receptors which is a potential mechanism for the fluoxetine-induced increase in catecholamines. CONCLUSION: Amongst the SSRIs examined, only fluoxetine acutely increases extracellular concentrations of norepinephrine and dopamine as well as serotonin in prefrontal cortex, suggesting that fluoxetine is an atypical SSRI.     

Interaction of histamine H1-and H2-receptor antagonists with histamine uptake and metabolism by guinea-pig isolated atrium and mouse neoplastic mast cells cells in vitro.

1. Burimamide, metiamide, chlorpheniramine, triprolidine and cocaine, were tested as inhibitors of histamine uptake and metabolism in the guinea-pig atrium and in mouse neoplastic mast cells. 2. Cocaine did not affect the uptake and metabolism of histamine, either in the atrium or in the mast cells. All the antihistamines tested blocked the uptake and metabolism of histamine in both preparations. The order of potency was burimamide greater than chlorpheniramine greater than triprolidine greater than metiamide in the atrium; and burimamide greater than metiamide greater than triprolidine greater than chlorpheniramine, in the mase cells. 3. Comparison of the present results with the antihistamine activity of these blocking agents suggests that no correlation exists between the receptor blocking activity and the ability of these substances to act as inhibitors of histamine uptake and metabolism.     

Orexin A promotes histamine, but not norepinephrine or serotonin, release in frontal cortex of mice

Aim: To investigate the effects of orexin A on release of histamine, norepinephrine, and serotonin in the frontal cortex of mice. Methods: Samples for measuring histamine, norepinephrine, and serotonin contents were collected by in vivo microdialysis of the frontal cortex of anesthetized mice. The histamine, noradrenaline, and serotonin content in dialysates were measured by HPLC techniques. Results: Intracrebroventricular injection of orexin A at doses of 12.5, 50, and 200 pmol per mouse promoted histamine release from the frontal cortex in a dose-dependent manner. At the highest dose given, 200 pmol, orexin A significantly induced histamine release, with the maximal magnitude being 230% over the mean basal release. The enhanced histamine release was sustained for 140 min, and then gradually returned to the basal level. However, no change in norepinephrine or serotonin release was observed under application of the same dose of orexin A. Conclusion: These results suggest that the arousal effect of orexin A is mainly mediated by histamine, not by norepinephrine or serotonin.     

Vascular responses of isolated, perfused canine femoral arteries and veins to vasoactive substances

The stainless steel cannula inserting method was used to observe vascular effects of 9 vasoactive substances on the isolated, perfused canine femoral artery and vein. In the vein, the order of potency for inducing vasoconstriction was norepinephrine greater than histamine = phenylephrine = serotonin greater than prostaglandin F2 alpha greater than ATP greater than xylazine greater than tyramine much greater than KCl. It was demonstrated that the cannula inserting method is useful for observations of venous vascular reactivity.     

Reduced metabolism and turnover rates of rat brain dopamine, norepinephrine and serotonin by chronic desipramine and zimelidine treatments

As part of of an ongoing effort to compare changes in whole body turnover of catecholamines and serotonin in man with those induced by antidepressants in the rat brain, we have evaluated the chronic effects of desipramine (DMI) and zimelidine (ZMI) on brain catecholamines and serotonin in the rat. The amines and metabolites measured include norepinephrine (NE), dopamine (DA) and their metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Three brain areas were analysed; the hypothalamus, caudate nucleus and frontal cortex. Chronic DMI and ZMI reduced hypothalamic MHPG and caudate nucleus DA metabolites, in particular HVA. Both drugs reduced NE and DA turnover rates (estimated after alpha-methyl-p-tyrosine injection) and the rate of MHPG formation in the hypothalamus (estimated after pargyline treatment). They did not change NE turnover rate, but reduced DA turnover rate and rate of HVA formation in the caudate nucleus. Chronic DMI but not ZMI reduced DOPAC rate of formation in the caudate nucleus. Apparently changes in DA turnover and metabolism produced by these antidepressants are better related to changes in HVA than DOPAC concentrations. Similar to their influence on hypothalamic and caudate nucleus catecholamines, both chronic DMI and ZMI produced changes in serotonin concentration in the caudate nucleus and frontal cortex serotonin that suggest a reduction in its turnover rate and metabolism. The reduction in NE turnover in hypothalamus is consistent with the effects of chronic DMI and ZMI on whole body NE turnover observed in man.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vasoconstrictor responses of isolated pig coronary arteries

In helical strips of pig coronary arteries, histamine, serotonin, acetylcholine and a stable analogue of thromboxane A2 (9, 11-epithio-11, 12-methano TXA2: s-TXA2) produced a dose-dependent contraction. The histamine-induced contraction was suppressed by treatment with chlorpheniramine, suggesting an involvement of H1 receptors. Contractile responses to serotonin were attenuated by not only ketanserin, an S2 antagonist, but also by cinanserin and methysergide. Relaxation induced by serotonin in preparations treated with high concentrations of ketanserin were inhibited by cinanserin and methysergide. Norepinephrine contracted coronary arteries treated with propranolol. Contractile responses to norepinephrine were reversed to relaxations by prazosin, which were abolished by treatment with yohimbine. Contractile responses to histamine were potentiated by treatment with low concentrations of serotonin or s-TXA2. Contractile responses to serotonin were also potentiated by low concentrations of histamine or s-TXA2. Removal of the endothelium from pig coronary arterial strips potentiated contractions induced by serotonin, histamine and norepinephrine. These results suggest that, in addition to damaged endothelium, integrating action of endogenous vasoconstrictors, including histamine, serotonin, TXA2 and norepinephrine, may play an important role in producing coronary vasospasm.     

6-hydroxydopamine sympathectomy in the neonatal rat--effects on brain serotonin and histamine

Treatment of newborn rats with 6-hydroxydopamine resulted in a marked increase in the 5-hydroxyindoleacetic acid level in brainstem and hypothalamus whereas the 5-hydroxytryptamine (serotonin) level in these two tissues was slightly but not significantly decreased. The activity of l-tryptophan-5-hydroxylase was increased in brainstem and hypothalamus but not significantly changed in cerebral cortex. The serotonin turnover appeared to be increased in all three brain areas studied. Treatment of neonatal rats with 6-hydroxydopamine had no apparent effect on the tryptophan level of rat brain or on the activities of other enzymes involved in the metabolism of serotonin. The histamine content of rat hypothalamus was significantly increased, although there was no change in the level in the remainder of the brain. It was concluded that sympathectomy by 6-hydroxydopamine in neonatal rats results in changes in brain serotonin and histamine in addition to the reported changes in norepinephrine.     

Effect of 5-hydroxytryptamine blockade with ketanserin on myocardial uptake of epinephrine and norepinephrine in patients with congestive heart failure

Serotonin (5-hydroxytryptamine) has multiple cardiovascular actions. The presence of serotonin in the heart suggests it may be an endogenous source of inotropic support during physiologic or pathologic stress. Serotonin may increase cardiac contractility by augmenting release of norepinephrine at sympathetic nerve endings. Norepinephrine release is markedly elevated in patients with heart failure. To explore the role of serotonin in enhancing norepinephrine release in patients with heart failure, ketanserin, a specific serotonin antagonist, was used as a physiologic tool to examine the effect on transmyocardial norepinephrine flux. Ketanserin (10 mg bolus, 4 mg/hr infusion for +/- 40 min) was administered intravenously to nine patients with congestive heart failure (NYHA III or IV) secondary to congestive cardiomyopathy (N = 7), or ischemic heart disease (N = 2). Plasma catecholamines (norepinephrine, epinephrine, dopamine) were measured in the aorta (Ao) and the coronary sinus (CS) of patients at rest and during supine leg exercise before and after administration of ketanserin. Baseline norepinephrine levels were markedly elevated at rest and during exercise in all patients. Norepinephrine levels were significantly higher in the CS than in the Ao (rest, CS 1185 +/- 235, Ao 878 +/- 381 pg/mL, P less than .05; exercise, CS 2239 +/- 697, Ao 1453 +/- 697 pg/mL, P less than .05). Baseline epinephrine levels were within normal limits. In contrast to norepinephrine levels, epinephrine levels were consistently higher in the Ao than in the CS, indicating unimpaired extraction or uptake across the heart. The relationship between norepinephrine and epinephrine concentration in the Ao and CS suggested a net overflow of norepinephrine in the CS.(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies on 4-(p-bromophenyl)-bicyclo (2,2,2) octan-1-amine as an inhibitor of uptake into serotonin neurones

4-(p-Bromophenyl)-bicyclo (2,2,2)octan-1-amine was a potent antagonist of p-chloroamphe-tamine-induced depletion of brain serotonin and a weaker antagonist of 6-hydroxydopamine-induced depletion of heart norepinephrine in rats and in mice. In both species, this compound was more active in antagonizing serotonin depletion and less active in antagonizing norepinephrine depletion than was the parent compound lacking the p-bromo substituent. In vitro, the bromo analogue was markedly less active than the parent compound in blocking norepinephrine uptake by rat brain synaptosomes and was slightly less active in blocking serotonin uptake. Brain levels of the p-bromo compound were higher than those of the parent compound in rats, apparently accounting for the relatively greater effectiveness of the f-bromo compound in blocking serotonin depeletion in vivo. Thus, 4-(p-bromophenyl)-bicyclo (2,2,2,)octan-1-amine appears to be a potent and relatively selective inhibitor of uptake into serotonin neurones.     

Effect of tetrahydroisoquinoline (TIQ), one of endogenous substances inducing parkinsonism, on isolated rat vas deferens

1. The effect of tetrahydroisoquinoline (TIQ) was examined on isolated rat vas deferens. 2. TIQ shifted the concentration-response curve for norepinephrine towards lower concentrations: the pD2-value of norepinephrine in the presence of TIQ was significantly greater than in its absence. 3. Tyramine-induced contraction in the presence of TIQ decreased by a significant 35% more than in the absence of TIQ. 4. These results indicate that the pharmacological effect of TIQ is due to the inhibition of the neuronal uptake of catecholamines.     

Cerebral vascular effects of peptide histidine methionine in canine and bovine species

Peptide histidine methionine (PHM) is a neuropeptide with structural homology to vasoactive intestinal peptide (VIP), itself a putative vasodilatory neurotransmitter. Intra-arterial administration of PHM caused a transient, dose-dependent increase in canine vertebral artery blood flow in vivo. PHM was less potent in this effect than VIP. The interaction of PHM with the vasoconstrictor amines, norepinephrine, histamine, and serotonin, was examined using isolated strips of the bovine middle cerebral artery. PHM shifted the concentration-response curves for vasocontraction by norepinephrine and histamine to the right but did not affect the vasocontraction induced by serotonin. These results suggest that PHM may have a role in the regulation of the cerebral circulation.     

Effect of nisoxetine on uptake of catecholamines in synaptosomes isolated from discrete regions of rat brain

Nisoxetine inhibits the high affinity uptake of norepinephrine by synaptosomes hypothalamus, brain stem and cerebral cortex of rat brain with inhibitor constants, K_i values, of 1, 2 and 6 nM respectively. The drug also inhibits the high affinity uptake of dopamine by hypothalamic synaptosomes with a K_i value of 9 nM. In corpus striatum, however, the K_i values for nisoxetine to inhibit the uptake ofdopamine and norepinephrine are 360 and 220 nM respectively. Thus, nisoxetine has about 200-fold greater affinity for the uptake sites of norepinephrine than for those of dopamine. Nisoxetine administered at 10 mg/kg i.p. to rats reduces the high affinity uptake of catecholamines by synaptosomes of brain regions. A low affinity process for uptake of catecholamines also occurs in synaptosomes of hypothalamus, brain stem and cerebral cortex but is not blocked by 10^?8M nisoxetine. The significance of the low affinity uptake processes is discussed.     

Change in the biogenic amine content in rats in acute and chronic alcohol poisoning

In Wister line rats subject to determination were the epinphrine, norepinephrine, DOPA, dophamine, serotonin conents and monaminoxidase activity in the blood, liver and brain in acute alcohol poisoning. Acute alcohol poisoning did not produce any substantial changes in the content of biogenic amines in the blood, liver and brain of the rats. With chronic poisoning the content of catecholamines, serotonin increased while the monaminoxidase activity in the study organs declined, this bearing witness to the effect of alcohol on the metabolism of biogenic amines.     

Effect of microinjection of histamine into the brain on plasma levels of epinephrine and glucose in freely moving rats

The effect of histamine administered to the brain on the plasma levels of epinephrine, norepinephrine and glucose was investigated in freely moving rats. Histamine (10 micrograms) administered intracerebroventricularly (into the lateral ventricle) induced a hyperglycemic response with preceding increases in plasma catecholamines, especially epinephrine. When histamine (5 micrograms) was injected into three different levels of the ventricular system, the magnitude and duration of the resulting increases in plasma epinephrine and glucose were in the following rank order: the third ventricle greater than aqueduct much greater than fourth ventricle. These results suggest that the sites of action of histamine are located rostrally from the midbrain. Microinjections of histamine (1 microgram) into the hypothalamic nuclei including the medial preoptic area, paraventricular nucleus, ventromedial hypothalamic nucleus, posterior hypothalamic nucleus and mammillary body had no elevating effect on the plasma levels of epinephrine and glucose. Other brain regions, such as the lateral septum, medial amygdaloid nucleus and periaqueductal grey of the midbrain, were also excluded as possible sites of histamine action. From the present results, it seems that histamine stimulates plural sites close to the ventricular system to induce hyperglycemic responses.     

Effects of dietary histidine and methionine loading in rats with a portacaval shunt

To elucidate disturbances of brain amine metabolism in hepatic coma, the effects of dietary histidine and methionine loading on the brain levels of amino acids and transmitter amines and on behavior were examined in rats with a portacaval shunt (PCS rats). Surgical construction of a portacaval shunt exaggerated the increase in brain histamine caused by dietary histidine loading 4 weeks after operation. Although the marked increase in the brain level of methionine itself did not affect on the brain levels of catecholamines, serotonin, and histamine, brain level of 5-HIAA was decreased in PCS rats on methionine-enriched diet. Diminished spontaneous activity was observed in PCS rats on either diet, which could not be related to the disturbance of brain amine metabolism caused by excess histidine and methionine. These results indicated that histamine was involved in the derangement of brain amine metabolism in PCS rats, and that direct effect of dietary methionine loading on the brain levels of transmitter amines was not observed in PCS rats. The etiological relation of these substances to hepatic coma should be further investigated.     

Effects of carbamazepine and anti-depressant drugs on endogenous catecholamine levels in the cerebroventricular compartment of the rat

Concentrations of endogenous norepinephrine, dopamine and epinephrine in cerebroventricular perfusates were used to evaluate the effects of drugs on the availability of extracellular catecholamines in the intact rat brain. Administration of the antidepressant drugs imipramine, desmethylimipramine or tranylcypromine resulted in marked increases of both norepinephrine and dopamine concentrations while epinephrine levels were not affected. Treatment with a similar dose of carbamazepine — an anticonvulsant drug with antidepressant activity — resulted in a significant increase in dopamine concentrations without apparent effect on either norepinephrine or epinephrine. It is suggested that at the applied dose, carbamazepine may act to modify the uptake, release or metabolism of dopamine in brain areas adjacent to the cerebroventricular space without affecting the other catecholamines.     

Central and peripheral norepinephrine metabolism in rat strains selectively bred for differences in response to stress

Rats of the Maudsley nonreactive (MNRA) strain were found to contain higher levels of norepinephrine in heart, spleen, and hypothalamus than animals of the Maudsley reactive (MR) strain. Total adrenal catecholamines were also greater in nonreactive animals. There was a trend toward higher endogenous norepinephrine concentration in MR rats in brainstem and telencephalon, but this was not statistically significant. Turnover measurements calculated from the fall of norepinephrine at 1 and 4 hours after a single dose of levo-α-methylparatyrosine showed no significant strain differences in telencephalon or brainstem, but MNRA animals had a faster rate of norepinephrine decline in heart than had MR rats. Possibly indicative of a higher rate of norepinephrine metabolism, the percentage of ³H-non-catechol metabolites relative to total counts was higher in brainstem of MNRA rats 90 min after intraventricular injection of ³H-norepinephrine. However, the disagreement between this estimate of norepinephrine metabolism and that provided by the α-methyl-paratyrosine technique prevents a conclusive statement about norepinephrine metabolism in the two strains. The results are discussed in the light of the established differences in behavior between the strains as well as other work exploring relationships between catecholamine metabolism and emotionality.     

Cimetidine and ketotifen inhibit stimulated aggregation and histamine liberation from rabbit blood platelets

The effect of cimetidine and ketotifen was studied on thrombin-stimulated rabbit platelet aggregation as well as on histamine and serotonin liberation. Both drugs inhibited the stimulation of platelets in a dose-dependent way. The effect of ketotifen on stimulated aggregation was about twice that of cimetidine. Stimulated histamine and serotonin liberation was more inhibited by ketotifen than by cimetidine. Both drugs inhibited the liberation of serotonin to a greater extent than that of histamine.