Pargyline Pretreatment Research Articles

Effect of monoamine oxidase inhibition on catecholamine levels: evidence for synthesis but not storage of epinephrine in rat spinal cord

Epinephrine levels in the intermediolateral cell group in the rat spinal cord are very low, although there is a dense projection to this region from cells containing all the enzymes required for epinephrine biosynthesis. One explanation for this finding is that epinephrine in the nerve terminals is degraded as soon as it is synthesized, so that no epinephrine is actually stored in synaptic vesicles. To test this hypothesis, epinephrine levels were measured in spinal cord of rats pretreated with an inhibitor of monoamine oxidase, the major enzyme involved in epinephrine degradation. Selected other tissues (i.e. brainstem, hypothalamus, adrenal gland, superior cervical ganglion) were examined for comparison. Pargyline treatment (75 mg/kg i.p., 4 h prior to sacrifice) increased catecholamine levels in spinal cord, hypothalamus, and brainstem. However, the percent increase in epinephrine in the spinal cord and brainstem was much larger than that for dopamine and norepinephrine in the 3 central nervous system regions studied, as well as larger than that for epinephrine in the hypothalamus. These results suggest that phenylethanolamine N-methyltransferase (PNMT)-containing terminals in the rat spinal cord can synthesize epinephrine, but that little if any epinephrine is stored in synaptic vesicles due to the rapid metabolism of cytoplasmic catecholamines by monoamine oxidase. In contrast, pargyline pretreatment had no effect on catechol levels in the adrenal gland, suggesting that little metabolism of catecholamines takes place in those epinephrine-synthesizing cells. Furthermore, since pargyline pretreatment increased norepinephrine levels but decreased dopamine levels in the superior cervical ganglion, it is suggested that most of the dopamine in that sympathetic ganglion is present as a precursor to norepinephrine in noradrenergic postganglionic sympathetic neurons. Additional studies were performed using neonatal rats, since it has been reported that spinal cord epinephrine levels are much higher in neonates than in adults. Epinephrine levels were found to be higher in the spinal cords of neonates compared to adults, but were increased to a lesser extent by monoamine oxidase inhibition. These results suggest that the interaction of monoamine oxidase with epinephrine synthesis is such that high monoamine oxidase activity can prevent the storage of epinephrine in certain nerve terminals containing the enzymes required to synthesize epinephrine. This raises the possibility that PNMT-containing catecholamine neurons may not necessarily be adrenergic.

Effects of Transient Forebrain Ischemia and Pargyline on Extracellular Concentrations of Dopamine, Serotonin, and Their Metabolites in the Rat Striatum as Determined by In Vivo Microdialysis

Striatal microdialysis was performed in rats subjected to 20 min of transient forebrain ischemia produced by occlusion of the carotid arteries during hemorrhagic hypotension. Extracellular changes of dopamine, serotonin, and their metabolites were monitored before, during, and after the ischemic insult at 10-min intervals by on-line HPLC analysis. During ischemia, extracellular dopamine increased dramatically (156 times baseline), as did 3-methoxytyramine (3-MT), whereas 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) decreased (15-25% of baseline). Upon reperfusion, dopamine was cleared from the extracellular fluid within 40 min and reached a stable level (70% of baseline). DOPAC and HVA increased (250-330%) transiently and reached their maximum 1 h following reperfusion, whereas 3-MT decreased to undetectable levels within 20 min. Although baseline levels of serotonin were not detectable, serotonin and 5-hydroxyindoleacetic acid showed a qualitatively similar temporal pattern to dopamine and its acid metabolites. Killing rats by cervical dislocation produced changes in extracellular dopamine, serotonin, and their metabolites that were almost identical to those seen during ischemia. Pargyline pretreatment 2 h before ischemia had marginal effects on the postischemic clearing of dopamine. The pargyline pretreatment, however, did increase the survival rate of rats subjected to ischemia, and this protective effect might be due to the pargyline-induced blockade of the post-ischemic monoamine oxidase-mediated increase in dopamine metabolism and the concurrent production of the potentially neurotoxic molecule, hydrogen peroxide.

Effects of l‐Methyl‐4‐Phenyl‐l,2,3,6‐Tetrahydropyridine in the Dog: Effect of Pargyline Pretreatment

Adult beagle dogs of either sex were injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-HCl (2.5 mg/kg, i.v.) alone or after pretreatment with pargyline (5.0 mg/kg, s.c., twice), with pargyline alone, or were uninjected. Groups were killed 2 h, 3 weeks, or 3 months after injection, and several brain areas were assayed for biogenic amines and their synthetic and degradative enzymes. MPTP caused a massive and permanent loss of striatal dopamine, tyrosine hydroxylase, and 3,4-dihydroxyphenylalanine decarboxylase activities and the loss of cells within the substantia nigra pars compacta. Dopamine and norepinephrine also were depleted to various degrees in cortex, olfactory bulb, and hypothalamus; however, dopamine beta-hydroxylase activity in cortex was normal. There was no cell loss in the ventral tegmental area or locus ceruleus. The activities of monoamine oxidase (MAO)-A and MAO-B in cortex and caudate were not affected by MPTP. Despite a permanent loss of the nigrostriatal system, the dogs exhibited only a transient hypokinesia lasting 1-2 weeks. Pargyline pretreatment prevented the loss of striatal dopamine and cells from the substantia nigra, but did not prevent a prolonged but reversible decrease in the concentration of dopamine metabolites. It is argued that this apparent inhibition of MAO is due not to suicide inactivation of the enzyme by MPTP, but to reversible inhibition by accumulation of the pyridinium metabolite, 1-methyl-4-phenylpyridinium, selectivity in aminergic terminals.

The neurotoxicant MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) increases glial fibrillary acidic protein and decreases dopamine levels of the mouse striatum: Evidence for glial response to injury

The neurotoxicant MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), administered to male or female mice, decreased striatal dopamine content and increased the levels of the astrocyte intermediate filament protein, glial fibrillary acidic protein (GFAP). The rise in GFAP was evident as early as two days following the last dose of MPTP, was maximal 7 days after the toxicant and returned to control levels by two months, post MPTP. Striatal dopamine content was decreased post-MPTP administration, showing a slight recovery between one and two months after the toxicant. No differences were observed among male and female mice in their responses to the toxicant. Hippocampal noradrenaline content was not affected by the toxicant, neither was the GFAP content altered by MPTP in this structure. Additionally, pargyline pretreatment prevented both the rise in GFAP and the decrease in dopamine in striatum. MPTP produced a smaller elevation in GFAP levels within a midbrain section of tissue containing the substantia nigra, without significantly decreasing the dopamine content of this structure, suggesting neurotoxic involvement at the level of dopamine perikarya. The toxicant did not affect the molecular radius of the protein detected by the antibody to GFAP, as determined by immunoblot analysis.

Serotonergic projections to the spinal cord but not those to the olfactory bulb also contain substance P. A combined immunocytochemical and autoradiographic study following retrograde axonal transport of [ 3H]serotonin labeled products

Co-localization of substance P with serotonin in raphe projection neurons was studied by combining substance P immunocytochemistry and autoradiography following uptake and retrograde axonal transport of [ 3H]serotonin and/or its products from target areas. In this study, two central pathways in the rat were investigated: the serotonergic projections of the midbrain raphe to the olfactory bulb and those of the medullary raphe that innervate the thoracic spinal cord. Two hours after pargyline pretreatment, injections of 10 −4M [ 3H]serotonin were made either into the olfactory bulb or into the spinal cord and respectively 24 or 60 h thereafter, rats were administered with colchicine. After a 24 h survival time, the paraformaldehyde fixed brains were investigated for substance P immunocytochemistry and then treated for light and electron microscopy autoradiography. Combining both methods, we can define on the same tissue sections at least three labeled neuronal populations: substance P immunolabeled neurons, radiolabeled neurons and doubly immuno-radiolabeled neurons. In the midbrain raphe cells as well as in the olfactory bulb nerve terminals, two kinds of labeled profiles were detected: substance P immunoreactive profiles and radiolabeled ones. The radiolabeled cell bodies of the midbrain raphe (403 counted cells) were never reactive to substance P antibodies. Moreover, they were distributed caudally to substance P stained perikarya. In contrast, in the medullary raphe, of the 336 radiolabeled cell bodies 162 were stained after substance P antibody treatment. They represent about 48% of the serotonin radiolabeled neurons projecting to the thoracic spinal cord, where a great number of varicosities were observed immunolabeled, radiolabeled and doubly immuno-radiolabeled in the dorsal horn. At the ultrastructural level, cell bodies and dendritic processes were also doubly labeled. Both labelings were observed over the cytoplasm and some organelles or perikarya. These observations provide a morphological basis to support the hypothesis that substance P can occur within some but not all serotonergic neurons and raise questions about the expression of this peptide in these systems as well as the modes of interaction of these transmitter molecules.

Disposition of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice before and after monoamine oxidase and catecholamine reuptake inhibition.

The distribution of radioactivity in pigmented mice after a single intravenous injection of 1-(3H) methyl-4-phenyl-1,2,3,6-tetrahydropyridine (3H-MPTP) was studied by quantitative whole body autoradiography and liquid scintillation counting. Pretreatment with the monoamine oxidase inhibitors clorgyline, pargyline and deprenyl, or the catecholamine reuptake inhibitor nomifensine was performed 30 min. prior to the 3H-MPTP administration. A high uptake of radioactivity was observed in the striatum, nucleus accumbens, midbrain area and locus coeruleus, and also in the adrenal medulla. This uptake was inhibited by deprenyl or pargyline pretreatment, but not after clorgyline or nomifensine pretreatment. An extensive uptake which was not influenced by deprenyl or pargyline treatment was found in the melanin-containing tissues of the eye. This accumulation is due to the melanin affinity of MPTP and its metabolites. A comparatively rapid elimination from the brain of MPTP and its metabolites was observed, which may be due to the lack of neuromelanin in mice.

Chronic alterations in jejunal myoelectric activity in rats due to MPTP.

Parkinsonian patients may have symptoms consistent with intestinal pseudo-obstruction, but a primary intestinal abnormality has not been shown. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), after conversion to a toxic metabolite via the monoamine oxidase system, can induce Parkinson's disease by destroying dopaminergic neurons in the substantia nigra in humans and primates. Rodents have some catecholamine depletion but much less so than primates. Using chronic bipolar electrodes on the proximal jejunum of Wistar rats, we show significant, chronic migrating myoelectric complex disruption (P less than 0.001) and prolongation of irregular spike activity (P less than 0.001). Pargyline (a monoamine oxidase inhibitor) pretreatment significantly blocked these myoelectric changes. Sinemet (L-dopa and carbidopa), given after MPTP to replete dopamine, decreased the MPTP-induced migrating myoelectric complex disruption. Jejunal myenteric plexus dopamine levels were significantly decreased (to 61% of control) after MPTP but after much higher doses than were required to disrupt migrating myoelectric complex activity (180 mg/kg total vs. 30 mg/kg). Dopamine in the central nervous system was not depleted. We conclude that MPTP causes intestinal myoelectric disruption (which can be blocked by pargyline and decreased by Sinemet) possibly through enteric, but not central, nervous system effects.

The aziridinium derivative of DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) accelerates the beating rate of isolated rat atria by enhancing the spontaneous release of noradrenaline

The aziridinium derivative of the compound N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (az-DSP4) depletes endogenous noradrenaline stores and exerts neurotoxic actions on noradrenergic neurons. These effects are persistent in the central nervous system and transient in the periphery. To determine if transmitter release plays a role in the noradrenaline depletion caused by az-DSP4, the action of the compound was studied in isolated and spontaneously beating rat atria. 1. az-DSP4 enhanced atrial beating rate when present in the incubation medium at concentrations ranging from 10(-7) M to 10(-4) M but at 10(-3) M decreased that rate below basal levels. 2. Preincubation of atria for 30 min with the noradrenaline uptake blocker desimipramine (DMI, 10(-6) M) or with the beta-blocker propranolol (10(-7) M), abolished the positive chronotropic action of az-DSP4. 3. The rate-accelerating effect of az-DSP4 could be prevented by pretreating the rats with reserpine (5 mg/kg i.p. 24 h) or enhanced by pargyline pretreatment (100 mg/kg i.p. 18 h). 4. az-DSP4 stimulated the spontaneous efflux of tritium from the isolated atria previously labeled with 3H-noradrenaline (4 X 10(-7) M), an increase that was mainly accounted for by DOPEG. 5. COMT and MAO activities in atria homogenates were inhibited by az-DSP4 in a concentration-dependent manner. However, MAO inhibition did not result in a change of the metabolic pattern as could be expected. 6. The results obtained indicate that az-DSP4 enhances the rate of spontaneous beating of isolated rat atria.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of deuterium substitution on the catabolism of beta-phenylethylamine: an in vivo study.

beta-Phenylethylamine (PE) hydrochloride injected intraperitoneally into rats was distributed evenly throughout the various regions of rat brain. Similarly, when a mixture of PE and alpha, alpha, beta, beta-deuterated PE [( 2H4]PE) was injected, no regional differences were observed in the ratios of the amounts of [2H4]PE and PE present; however, significantly more [2H4]PE than PE was present, although a 1:1 mixture had been administered. Further experiments in which the amounts of [2H4]PE and PE in whole rat brain, liver, and plasma were quantified confirmed this finding. The maximum [2H4]PE-to-PE ratios observed were 67 in whole brain 1 h after injection and 8 in liver and in plasma 45 min after injection. The whole brain [2H4]PE-to-PE ratios were decreased by pargyline pretreatment. Subsequent experiments showed that more alpha, alpha-[2H2]PE than PE was present in whole brain, liver, and plasma of rats injected with an equimolar mixture of alpha, alpha-[2H2]PE and PE. In contrast, beta, beta-[2H2]PE was not enriched in comparison to PE under the same experimental conditions. We concluded that the basis for the enrichment of [2H4]PE and alpha, alpha-[2H2]PE compared to PE was due to protection of the deuterated analogs from the actions of monoamine oxidase and perhaps aldehyde dehydrogenase; this protection led to pronounced deuterium substitution effects in vivo especially in the brain.

Locomotor response of nialamide pretreated old rats to intraaccumbens dopamine

The objective of this study was to determine the locomotor activity response of young (6 month), mature (15 month), and old (26 month) rats to bilateral intraaccumbens injections of dopamine after pretreatment with nialamide. Young and mature rats responded to dopamine with high rates of activity, while old rats either did not respond at all or responded with a lower intensity of activity. In contrast, the response of old rats to dopamine or ergometrine alone or to dopamine after pargyline pretreatment was not less than that of mature and young rats. These results suggest that the attenuated response of old rats to dopamine after nialamide pretreatment is not due to a decrease in dopamine receptor activity, but appears to be due to some unique property of nialamide in these animals. However, the reduced response of old rats to dopamine was not due to the inability of nialamide to inhibit monoamine oxidase, since nialamide completely inhibited the activity of this enzyme in the nucleus accumbens of old rats.

IX. Neurochemical and functional consequences following 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) and methamphetamine

The neurochemical and functional consequences following MPTP administration to the rat were evaluated and compared to similar effects following methamphetamine administration. It was observed that MPTP induced long lasting depletions of striatal dopamine concentrations and this neurotoxic effect could be prevented by pargyline pretreatment. The MPTP-induced neuronal damage produced a tolerance to the disruptive effects of amphetamine and a supersentivitity to the disruptive effects of apomorphine in rats responding in a schedule controlled paradigm. Methamphetamine, like MPTP, produced depletions of striatal dopamine but these actions were potentiated by pargyline pretreatment. These observations are discussed in reference to possible deleterious effects following the administration of pargyline to patients with Parkinson's Disease.

Inhibitory GABAergic influence on striatal serotonergic transmission exerted in the dorsal raphe as revealed by in vivo voltammetry

In vivo differential pulse voltammetry with electrochemically treated carbon fiber microelectrodes has been used to investigate the anatomical nature of the GABAergic influence on striatal serotonergic transmission in the rat. Lesion studies and pharmacological treatments demonstrated that the electrochemical signal recorded at 300 mV in the striatum probably correspondes to the oxidation of extracellularly released 5-hydroxyindoleacetic acid. Thus, dorsal raphe´lesions or systemic administration of α-propyldopacetamide, NSD 1015, pargyline and MK212 decreased, whereas reserpine injection increased the amplitude of the signal. Moreover, l-5-hydroxytryptophan administration caused an increase in the signal which was almost completely prevented by pargyline pretreatment. Acute administration of dipropylacetamide (150 mg/kg i.p.) reduced the amplitude of the signal from the striatum, while injection of γ-acetylenic GABA (200 mg/kg i.p.) was without effect. Repeated (but not acute) treatment with the GABA receptor agonist, progabide (400 mg/kg i.p. b.i.d. for 14 days), led to a pronounced decrease in the amplitude of the signal from the striatum. A similar effect was observed after intradorsal raphe´infusion of GABA (10 and 100 μg), γ-vinyl GABA (100 μg) and SL 75102 (10 μg), a principal metabolite of progabide. In contrast, local injection of the GABA receptor antagonists, bicuculline (1 and 10 μg) or R5135 (0.05 μg), failed to affect the peak amplitude in the striatum. When infused into the dorsal raphe´, R5135 (0.05–0.1 μg) antagonized the diminution of the signal induced by intradorsal raphe´infusion of GABA (100 μg) or SL 75102 (10 μg). Finally, electrolytic lesion of the habenular nuclei completely blocked the diminution of the signal from striatum induced by an intradorsal raphe´infusion of GABA (100 μg). These results indicate that the inhibitory GABAergic control of striatal serotonergic transmission is exerted at the level of the dorsal raphe´cells and depends upon the integrity of the habenulo-dorsal pathway.

Analysis of hepatic reduced glutathine, cysteine and homocysteine by cation-exchange high-performance liquid chromatography with electrochemical detection

A high-performance liquid chromatographic method employing a mercury-based electrochemical detector and a cation-exchange column is described for the simultaneous measurement of reduced glutathione, cysteine, and homocysteine in liver homogenates. Sample preparation involves precipitation of protein with perchloric acid, removal of perchlorate by precipitation as its potassium salt and dilution with mobile phase. Mercaptoethylglycine is used as the internal standard. Using this procedure, the sum of the individual hepatic thiols agreed well with the total thiols determined with Ellman's reagent. Comparisons were made with (a) control rats, (b) rats depleted of hepatic thiols by pargyline pretreatment, and (c) rats administered l-cysteine.

Nigral dopaminergic mechanisms in drug-induced circling

Unilateral injections of dopamine into the substantia nigra pars reticulata of pargyline-pretreated rats caused a prolonged, contralateral circling, similar in magnitude to that elicited by the injection of the same amount of dopamine intrastriatally. Contralateral circling was also elicited by the unilateral intranigral injection of amphetamine (after pargyline pretreatment), or by the dopamine agonists ergometrine and SKF 38393. In contrast, bilateral intranigral injection of the dopamine antagonist haloperidol greatly reduced the amphetamine-induced circling of rats with unilateral 6-hydroxydopamine-induced nigrostriatal lesions. These results support the hypothesis that dopaminergic mechanisms in the substantia nigra are involved in motor behavior.

Alterations in brain 5HT and tryptamine content during indoleamine-induced myoclonus in guinea pigs

l-5-Hydroxytryptophan (5HTP) (with or without carbidopa pretreatment), l-tryptophan (plus pargyline pretreatment), or tryptamine (plus pargyline pretreatment) all induced dose-dependent myoclonus in guinea pigs. At the time of maximal behavioural response animals were killed for determination of brain indoleamine content. Administration of 5HTP (50–200 mg/kg) to naive guinea pigs, or of 5HTP (20–80 mg/kg) to carbidopa- (25 mg/kg 1 hr previously) pretreated animals, markedly elevated brain 5-hydroxytryptamine (5HT) concentrations but depressed whole brain tryptamine content. l-Tryptophan (50–200 mg/kg) administration to pargyline- (75 mg/kg 30 min previously) pretreated animals also increased cerebral 5HT levels. l-Tryptophan (200 mg/kg plus pargyline), elevated whole brain tryptamine content. Administration of tryptamine (40mg/kg) to pargyline-pretreated guinea pigs caused a small increase in brain 5HT levels, but markedly elevated cerebral tryptamine content. 5HT appears to be the indoleamine mainly responsible for 5HTP-induced myoclonus but tryptamine predominates in tryptamine-induced myoclonus. Both 5HT and tryptamine may contribute to myoclonus induced by l-tryptophan.

The role of catecholamines, 5-hydroxytryptamine and m-tyramine in the behavioural effects of m-tyrosine in the rat

The behavioural and neurochemical effects of m-tyrosine and a monoamine oxidase inhibitor in the rat are described. Systemic injections of m-tyrosine (50–150 mg/kg) 30 min after the administration of pargyline (75 mg/kg) produced intense behavioural stimulation which was not evident after injection of either compound alone. The behavioural syndrome induced consisted of forepaw padding, headweaving, backward walking, splayed hindlimbs, wet dog shakes, hyperactivity and hyperreactivity. m-Tyrosine alone or in combination with pargyline caused a significant increase in brain m-tyramine levels and a significant depletion of catecholamines. 5-Hydroxytryptamine (5-HT) levels, however, were unaffected by the administration of m-tyrosine at most of the times studied. The increase in levels of m-tyramine produced by m-tyrosine plus pargyline was 10 times greater than that produced by m-tyrosine alone, whereas the depletion in levels of the more abundant amines was not potentiated by pargyline pretreatment. The biochemical results suggest that an increased formation of m-tyramine may have been responsible for the observed behavioural stimulation and that a threshold level of m-tyramine in the brain appears to be necessary to produce an overt behavioural effect. The behavioural components observed indicate that m-tyramine could act by releasing newly synthesized catecholamines or 5-HT. Alternatively, m-tyrosine may function as a direct agonist at 5-HT or dopamine receptors, although an action on a specific tyraminergic receptor cannot be ruled out at present.

Improved catecholamine histofluorescence in the developing brain based on the magnesium and aluminum (ALFA) perfusion techniques: Methodology and anatomical observations

Detailed protocols for the application of two different metal salt perfusion procedures are described for the production of superior catecholamine histofluorescence in the brains of immature rats up to 2 weeks of age. As in the adult, both magnesium and aluminum salts are highly advantageous for catecholamine histofluorescence in developing animals, and yield marked increases in sensitivity. In the magnesium-perfusion technique, animals are perfused in a simple one-step process using a hand-held syringe with cold buffer containing magnesium sulphate, formaldehyde and glyoxylic acid. The aluminum-perfusion (ALFA) technique provides even greater sensitivity and richness of detail, but requires a controlled-pressure perfusion system and a two-step perfusion process. Animals are first perfused with a room-temperature buffer containing magnesium sulphate and procain (to prevent vasoconstriction) followed by cold buffer containing aluminum sulphate and formaldehyde. In both methods, tissue pieces are subsequently freeze-dried, reacted with formaldehyde vapour and paraffin-sectioned according to the standard Falck-Hillarp procedure. Tissue pieces can also be taken from aluminum-perfused brains for simultaneous catecholamine assay using radioenzymatic methods, thereby permitting correlated histochemical and neurochemical analyses on the same brains. Many catecholamine terminal systems can be visualized in the rat brain even at birth with the ALFA procedure following pargyline pretreatment. However, the endogenous intraaxonal catecholamine concentration is so low in immature brains that the full anatomical extent of these systems cannot be reliably seen without recourse to pre-loading with an exogenously administered amine. For this purpose systemic injections of α-methyl-noradrenaline were extensively investigated. In combination with the ALFA procedure, such pretreatment was found to cause a dramatic increase in both the intensity and number of terminal and preterminal fibers throughout the brain. Control experiments with 6-hydroxydopamine and the catecholamine uptake blocker, nomifensine, indicate that this loading is specific for catecholamine systems. This approach has indicated that certain of the forebrain noradrenergic and dopaminergic systems are very extensive at birth, and in some regions an intermediate stage of hyperinnervation is a normal feature of ontogeny. Some of these findings are illustrated here and will also be presented in greater detail in further reports.

Pharmacological evidence for the existence of a neuronal amine uptake mechanism in the dog liver in vivo.

The possibility of a neuronal uptake mechanism in the liver was studied in dogs anesthetized with sodium pentobarbital. Plasma catecholamine concentrations in hepatic venous blood were determined by a radioenzymatic assay following injections of tyramine (30-1000 micrograms) into either the common hepatic artery or the portal vein. Concomitant changes in hepatic vascular parameters and aortic catecholamine concentrations were also investigated. The mean basal values for hepatic venous and aortic catecholamine concentrations were found to be 0.081 +/- 0.007 ng/mL and 0.433 +/- 0.080 ng/mL, respectively. Injections of tyramine (300 and 1000 micrograms) into the hepatic artery increased hepatic venous catecholamine concentrations significantly to 0.109 +/- 0.017 ng/mL and 0.126 +/- 0.023 ng/mL (P less than 0.05, n = 7), respectively. Hepatic arterial vascular conductance decreased concomitantly by 29.7 and 44.9% (P less than 0.05, n = 7), respectively. Intraportal injections of tyramine did not bring about significant changes in either hepatic venous catecholamine concentrations or portal venous vascular conductance at any dose tested. After inhibition of monoamine oxidase with pargyline (10 mg/kg. i.v.), the effects of tyramine (1000 micrograms) injected into the hepatic artery were potentiated. The duration of action was approximately 10 min after pargyline pretreatment (control duration: 1 min). The effects of tyramine were absent after inhibition of the neuronal uptake mechanism with desipramine (1 mg/kg. i.v.). No drug tested had a significant effect on aortic catecholamine concentrations. The present results support the presence of the neuronal uptake mechanism in the dog liver.

Pharmacological analysis of the myoclonus induced by 5-hydroxytryptophan in the guinea pig suggests the presence of multiple 5-hydroxytryptamine receptors in the brain

Myoclonus induced in guinea pigs by administration of l-5-hydroxytryptophan (5-HTP) appears to be due to stimulation of central 5-HT receptors. Dose-dependent myoclonus was induced by administration of 5-HTP (with carbidopa pretreatment), l-tryptophan and tryptamine (both with pargyline pretreatment). and also by N, N-dimethyltryptamine, 5-metoxy- N, N-dimethyltryptamine and d-lysergic acid diethylamide (LSD). The synthetic 5-HT agonists quipazine, MK-212 and 1-( m-trifluoromethylphenyl) piperazine, however, evoked only occasional myoclonus at toxic doses. Antagonists of 5-HT receptors differed markedly in their ability to inhibit 5-HTP-induced myoclonus; while methergoline and cyproheptadine were potent inhibitors, mianserin, methysergide and BW 501C67 only caused effective inhibition in large doses. Similarly, 5-HT re-uptake blockers showed different activities in potentiating the effects of a threshold dose of 5-HTP; myoclonus was greatly potentiated by chlorimipramine, paroxetine and Org 6582, while femoxetine, fluoxetine and desmethylimipramine were only weakly active. The lack of uniform effects of the 5-HT agonists, antagonists and re-uptake blockers studied is not attributable entirely to their variable actions on central 5-HT mechanisms, to their effects on other brain neuronal pathways, or to differences in cerebral penetration. The data may provide functional evidence for a multiplicity of cerebral 5-HT receptors.

Dopamine depletion by 6-hydroxydopamine prevents conditioned taste aversion induced by methylamphetamine but not lithium chloride

Specific lesions of the central dopaminergic system produced by intraventricular injections of 6-hydroxydopamine with pargyline and desmethylimipramine pretreatment significantly attenuated conditioned taste aversions to a sweetened-condensed milk solution induced by methylamphetamine. Identically treated rats formed an aversion to the milk solution when lithium chloride was utilized. These results suggest that the methylamphetamine-induced aversion is dependent upon intact dopaminergic neurons.