Berta Knoll

Phenylethylamine and tyramine are mixed-acting sympathomimetic amines in the brain.

On the helical strip of a capacitance vessel, the pulmonary artery of the rabbit, phenylethylamine (PEA) and tyramine act solely via displacement of noradrenaline from their storage sites and this effect is inhibited by desmethylimipramine (DMI). In contrast, on a resistance vessel, the perfused central ear artery of the rabbit, PEA enhances stimulation induced contractions in 0.2-0.8 microgram/ml concentration [catecholaminergic activity enhancer (CAE) effect], and increases smooth muscle tone (noradrenaline displacing effect) in 4-6 micrograms/ml concentration. This latter effect only is blocked by DMI. Tyramine acts similarly and is more potent than PEA. On the isolated brain stem PEA, tyramine and (-)methamphetamine are, in the presence of cocaine and DMI, highly potent enhancers of stimulation induced release of 3H-noradrenaline, 3H-dopamine and 3H-serotonin. Compounds with specific CAE effect in the brain, (-)deprenyl and 1-phenyl-2-propylaminopentane [(-)PPAP], antagonize tetrabenazine-induced depression of performance of rats in the shuttle box. PEA and tyramine, which are rapidly metabolized in vivo, are ineffective in this test up to 40 mg/kg, whereas (-)methamphetamine, the stable PEA derivative, is highly effective. Compounds with CAE effect enhance at low concentrations the slow inward Ca2+ current in the sino-auricular fibers of the frog heart and inhibit it in high concentration. PEA and tyramine enhance Ca2+ influx from 0.05 to 4 micrograms/ml and inhibit it in 8 micrograms/ml. In conclusion, PEA and tyramine stimulate primarily coupling of action potential to transmitter release in the catecholaminergic neurons in the brain and displace catecholamines in higher concentration only.

(−)Deprenyl and (−)1-phenyl-2-propylaminopentane, [(−) PPAP] act primarily as potent stimulants of action potential — transmitter release coupling in the catecholaminergic neurons

The activity of the catecholaminergic neurons in the rat brain is enhanced significantly 30 min after the subcutaneous injection of very small doses of (-)deprenyl (threshold doses: 0.01 mg/kg for noradrenergic neurons and 0.025 mg/kg for dopaminergic neurons). As a catecholaminergic activity enhancer (CAE) substance (-)deprenyl is about ten times more potent than its parent compound, (-)methamphetamine. While the (+)methamphetamine is 3-5 times more potent than (-)methamphetammine in releasing catecholamines, the (-)methamphetamine is the more potent CAE substance. The mechanism of the CAE effect of (-)deprenyl and (-)PPAP, a deprenyl-derived substance devoid of MAO inhibitory potency, was studied in rats by measuring: a) the release of catecholamines from striatum, substantia nigra, tuberculum olfactorium and locus coeruleus; b) the stimulation induced release of 3H-noradrenaline from the isolated brain stem; and c) the antagonistic effect against tetrabenazine-induced depression of learning in the shuttle box. The CAE effect was found to be unrelated: a) to the inhibition of MAO activity; b) to the inhibition of presynaptic catecholamine receptors; c) to the inhibition of the uptake of catecholamines; and d) to the release of catecholamines. It was concluded that (-)deprenyl and (-)PPAP act primarily as potent stimulants of action potential-transmitter release coupling in the catecholaminergic neurons of the brain. We show that both (-)deprenyl and (-)PPAP enhance the inward Ca2+ current in sino-auricular fibers of the frog heart. (-)PPAP was much more potent than either (+)PPAP or (-)deprenyl in this test.

Structure - Activity studies leading to ( - )1-(Benzofuran-2-yl)-2-propylaminopentane, (( - )BPAP), a highly potent, selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain

The catecholaminergic and serotoninergic neurons in the brain change their performance according to the physiological need via a catecholaminergic/serotoninergic activity enhancer (CAE/SAE) mechanism. Phenylethylamine (PEA), tyramine and tryptamine are the presently known endogenous CAE/SAE substances which enhance the impulse propagation mediated release of catecholamines and serotonin in the brain. A PEA derivative, (-)deprenyl (selegiline), known as a selective inhibitor of MAO-B, is for the time being the only CAE/SAE substance in clinical use. Aiming to develop a selective CAE/SAE substance much more potent than (-)deprenyl, a series of new 1-aryl-2-alkylaminoalkanes, structurally unrelated to PEA and the amphetamines, was designed and prepared. Among them, (-)1-(benzofuran-2-yl)-2-propylaminopentane ((-)BPAP) was selected as a promising candidate substance for further studies. (-)BPAP significantly enhanced in rats the impulse propagation mediated release of catecholamines and serotonin in the brain 30min after acute injection of 0.36nmol/kg sc. In the shuttle box, (-)BPAP was in rats about 130 times more potent than (-)deprenyl in antagonizing tetrabenazine induced inhibition of performance. (+/-)BPAP protected cultured hippocampal neurons from the neurotoxic effect of beta-amyloid in 10(-14)-10(-15)M concentration.

The action of single and repeated doses of p-bromo-methamphetamine on the monoamine content and turnover rate in rat brain

Abstract The effect of p-bromo-methamphetamine (pBrMA) on serotonergic and catecholaminergic neurones in the rat brain was studied. Acute (15 mg/kg, s.c.) and chronic (30 × 15 mg/kg, s.c.) administration of the drug caused a long-lasting decrease in serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) content of whole brain. In contrast the catecholamine (CA) levels remained unchanged. Detailed studies of the 5-HT and CA content of brain regions showed a time-dependent decrease in 5-HT after acute injection, and a marked and persistent reduction in 5-HT and 5-HIAA after chronic treatment. In both injection regimens the content of noradrenaline (NA) was enhanced in the cortex. The turnover rate of 5-HT, dopamine (DA) and NA was reduced after acute treatment. Repeated injections caused a decrease in 5-HT turnover, while that of NA remained unchanged. However, the turnover rate of DA was enhanced. The present data appears to confirm the previous suggestion that after chronic treatment, when the rats show improvement in their learning performances, the serotonergic tone of the brain is decreased while dopaminergic tone is increased.

EFFECT OF p-BROMO-METHAMPHETAMINE /V-lll/ ON SEROTONERGIC AND CATECHOLAMINERGIC MECHANISMS

Publisher Summary This chapter discusses a study to examine the effect of p-bromo-methamphetamine (V-111) on serotonergic and catecholaminergic mechanisms. The focus in the study was directed toward the change of the activity of 5HT neurons and the effect of V-111 on striatal DA metabolites. 15 mg/kg s.c. single and 30 × 15 mg/kg s.c. daily dose of the drug produced a long lasting reduction of 5HT and 5HIAA in the brain. The turnover rate of 5HT was calculated from the elimination of 5HIAA, the accumulation of 5HT after pargyline, and the 5HIAA accumulation after probenecid. Results showed that the activity of 5HT neurons were markedly reduced in acute and chronic experiments. Striatal HVA and DOPAC content decreased while that of DA and NA remained unchanged. After chronic administration, DA and NA content did not change but the level of DA metabolites increased significantly. Results present further information about the effect of V-111 on the serotonergic mechanism and show that the response of catecholaminergic neurons is different to acute and chronic injection of the drug.