Pargyline Pretreatment Research Articles

Monoamine oxidase-dependent histamine catabolism accounts for post-ischemic cardiac redox imbalance and injury

Monoamine oxidase (MAO), a mitochondrial enzyme that oxidizes biogenic amines generating hydrogen peroxide, is a major source of oxidative stress in cardiac injury. However, the molecular mechanisms underlying its overactivation in pathological conditions are still poorly characterized.Here, we investigated whether the enhanced MAO-dependent hydrogen peroxide production can be due to increased substrate availability using a metabolomic profiling method. We identified N1-methylhistamine -the main catabolite of histamine- as an important substrate fueling MAO in Langendorff mouse hearts, directly perfused with a buffer containing hydrogen peroxide or subjected to ischemia/reperfusion protocol. Indeed, when these hearts were pretreated with the MAO inhibitor pargyline we observed N1-methylhistamine accumulation along with reduced oxidative stress. Next, we showed that synaptic terminals are the major source of N1-methylhistamine. Indeed, in vivo sympathectomy caused a decrease of N1-methylhistamine levels, which was associated with a marked protection in post-ischemic reperfused hearts. As far as the mechanism is concerned, we demonstrate that exogenous histamine is transported into isolated cardiomyocytes and triggers a rise in the levels of reactive oxygen species (ROS). Once again, pargyline pretreatment induced intracellular accumulation of N1-methylhistamine along with decrease in ROS levels. These findings uncover a receptor-independent mechanism for histamine in cardiomyocytes.In summary, our study reveals a novel and important pathophysiological causative link between MAO activation and histamine availability during pathophysiological conditions such as oxidative stress/cardiac injury.

A systematic microdialysis study of dopamine transmission in the accumbens shell/core and prefrontal cortex after acute antipsychotics.

The only systematic in vivo studies comparing antipsychotic (AP) effects on nucleus accumbens (NAc) shell and core dopamine (DA) transmission are voltammetric studies performed in pargyline-pretreated, halothane-anaesthetized rats. Studies in freely moving rats not pretreated with pargyline are not available. This study was intended to fill this gap by the use of in vivo microdialysis in freely moving rats. Male Sprague-Dawley rats were implanted with microdialysis probes in the NAc shell and core and medial prefrontal cortex (PFCX). The next day, rats were administered intravenously with two or three doses of APs, and dialysate DA was monitored in 10-min samples. Some rats were pretreated with pargyline (75mg/kg i.p.) and after 1h were given clozapine or risperidone. Clozapine, risperidone, quetiapine, raclopride, sulpiride and amisulpride increased DA preferentially in the NAc shell. Such preferential effect on shell DA was not observed after haloperidol, chlorpromazine and olanzapine. In contrast to voltammetric studies, a preferential effect on NAc core DA was not observed after any dose of AP. Pargyline pretreatment did not reduce but actually amplified the preferential effect of clozapine and risperidone on NAc shell DA. Apart from raclopride and olanzapine, the APs with lower extrapyramidal effects could be distinguished from typical APs on the basis of their ability to preferentially stimulate DA transmission in the NAc shell. There was no relationship between stimulation of PFCX DA and atypical APs profile. The differences between this study and voltammetry studies were not attributable to pargyline pretreatment.

Effects of the neurotoxin MPTP and pargyline protection on extracellular energy metabolites and dopamine levels in the striatum of freely moving rats

The neurotoxin MPTP is known to induce dopamine release and depletion of ATP in the striatum of rats. Therefore, we studied the changes induced by MPTP and pargyline protection both on striatal dopamine release and on extracellular energy metabolites in freely moving rats, using dual asymmetric-flow microdialysis. A dual microdialysis probe was inserted in the right striatum of rats. MPTP (25mg/kg, 15mg/kg, 10mg/kg) was intraperitoneally administered for three consecutive days. MAO-B inhibitor pargyline (15mg/kg) was systemically administered before neurotoxin administration. The first MPTP dose induced an increase in dialysate dopamine and a decrease of DOPAC levels in striatal dialysate. After the first neurotoxin administration, increases in striatal glucose, lactate, pyruvate, lactate/pyruvate (L/P) and lactate/glucose (L/G) ratios were observed. Subsequent MPTP administrations showed a progressive reduction of dopamine, glucose and pyruvate levels with a concomitant further increase in lactate levels and L/P and L/G ratios. At day 1, pargyline pre-treatment attenuated the MPTP-induced changes in all studied analytes. Starting from day 2, pargyline prevented the depletion of dopamine, glucose and pyruvate while reduced the increase of lactate, L/P ratio and L/G ratio. These in vivo results suggest a pargyline neuroprotection role against the MPTP-induced energetic impairment consequent to mitochondrial damage. This neuroprotective effect was confirmed by TH immunostaining of the substantia nigra.

Stimulation by noradrenaline of inositol phospholipid breakdown in the rat hippocampus: effect of the ambient potassium concentration.

The stimulation by noradrenaline (NA) of inositol phospholipid (PI) breakdown has been studied using rat hippocampal miniprisms. Pretreatment with the monoamine oxidase inhibitor, pargyline, potentiated the stimulation produced by NA. On the other hand, pargyline pretreatment did not affect the stimulation of PI breakdown by the alpha 1-adrenoceptor agonist phenylephrine. NA- and phenylephrine-stimulated PI breakdown were enhanced by increasing the ambient potassium concentration in the assay from 5.88 to 18.2 mM. This enhancement did not, in the case of NA, change either the EC50 value for this agonist (2-3 microM) or the pA2 value for the competitive antagonism of the stimulation by the alpha 1-antagonist prazosin (pA2 value 9.2). Time-courses of the NA-stimulated PI turnover in different brain regions indicated that the rate of stimulation was in the order frontal cortex greater than hypothalamus greater than or equal to hippocampus much greater than cerebellum.

P.1.d.007 Effects of 6-hydroxydopamine lesioning of the medial prefrontal cortex on social interactions in rats

This experiment examined the effects on locomotor activity of intraventricular 6-hydroxydopamine (6-OHDA) administered to developing and adult rats. 6-OHDA was administered subsequent to parygline desmethylimipramine (DMI) treatmen(6-OHDA/DMI) at 3 and 6 days of age, 11 and 14 days of age, 20 and 23 days of age, or 46 and 48 days of age. Locomotor activity of vehicle-treated rats assessed in stabilimeter cages peaked between 14 and 16 days of age and subsequently declined to levels characteristic of the adult. Treatment with pargyline and 6-OHDA at 3 days of age, or 6-OHDA/DMI at 3 and 6 or 11 and 14 days of age, did not alter the early rise in locomotor activity but prevented the decline in activity normally seen during the third and fourth weeks of life. When tested as adults, locomotor activity was greater in rats that had been treated with 6-OHDA/DMI at 3 and 6 and at 11 and 14 days of age than in those that had been treated at 20 and 23 days of age. Treatment with 6-OHDA/DMI at 46 and 48 days of age was without significant effect on locomotor activity. 6-OHDA (with pargyline pretreatment) produced large decreases in NE content in telencephalon and diencephalon and in dopamine (DA) content in striatum. 6-OHDA/DMI also produced large decreases in DA content in striatum and, in some of the treatment groups, only small decreases in norepinephrine (NE) content in telencephalon, diencephalon, and brain stem. These data suggest that the maturation of neuronal systems utilizing dopamine as a neurotransmitter is essential for the suppression of locomotor activity normally seen during development. The data further suggest that dopamine depletion per se does not lead to increased locomotor activity, but rather it is the destruction of dopamine-containing fibers prior to the normal period of locomotor suppression that increases locomotor activity.

Analysis of hepatic reduced glutathione, 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.

Pargyline pretreatment prevents immunological changes induced by MPTP in mice

The relationship between the central dopaminergic and the immune system is poorly understood. Experimental work suggest that damage of the nigrostriatal system may influence immunity. Immunological abnormalities have been described in Parkinson's disease and in a mouse model of this disorder induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this report, we present evidence that reduced numbers of L3T4 T cells in blood, and diminished primary antibody response to sheep erythrocytes in MPTP treated mice can be restored by pargyline pretreatment. Since pargyline prevents dopamine depletion in the striatum in MPTP treated animals, our data extend previous experimental observations and support a possible role for dopamine in immune regulation.

Dopamine produced from l-DOPA is degraded by endogenous monoamine oxidase in neurons of the dorsal raphe nucleus of the rat: an immunohistochemical study

The aim of the present study is to examine by immunohistochemistry whether dopamine produced from l-DOPA in serotonin neurons of the rat brain is degraded by endogenous monoamine oxidase (MAO). In rats that received intraperitoneally l-DOPA plus a peripheral decar☐ylase inhibitor, carbidopa, a cluster of dopamine-immunoreactive neurons was found in the dorsal raphe nucleus (DR). In l-DOPA/carbidopa-injected rats that were pretreated with an intraperitoneal injection of a MAO inhibitor, pargyline, when compared with the l-DOPA/carbidopa-injected rats without the pargyline pretreatment, neurons of the cluster of the DR became much darker in dopamine staining. The distribution of dopamine-stained neurons in the DR of these rats corresponded very closely to the previously reported distribution of serotonin-immunoreactive neurons of normal rats. In normal or only pargyline-injected rats, dopamine-stained neurons were scarcely observed in the DR. We previously showed that serotonin neurons of the rat DR were induced to contain dopamine by the injection of l-DOPA plus carbidopa. These findings suggest that the newly produced dopamine from l-DOPA in serotonin neurons of the rat DR is degraded by endogenous MAO.

Electrical stimulation-induced release of dopamine and noradrenaline in human blood vessels

Noradrenaline (NA), dopamine (DA) and DA metabolites levels, as well as their ratios, have been compared in various human vessels. In the same tissue we have also studied the influence of electrical stimulation in the presence or absence of pargyline, or pargyline plus cocaine. Catecholamines and DA metabolites have been measured by HPLC with electrochemical detection. The highest levels of NA and DA were found in the splenic artery and the lowest in the pulmonary artery and saphenous vein. Appreciable concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) were found in splenic, gastric, mesenteric and uterine arteries, whereas homovanillic acid (HVA) was not measurable in any tissue. However, the vascular segments showed a different DA/NA ratio, which was significantly higher in the mesenteric artery. The electrical stimulation increased this ratio, especially in the mesenteric artery. The ratio increased still more after treatment with pargyline plus cocaine. After pargyline pretreatment and in the presence of cocaine, electrical stimulation significantly increased NA and DA release from all blood vessels, except pulmonary artery and saphenous vein. During a second period of electrical stimulation only the DA release remained high. The results suggest that DA is coreleased with NA from the nerve endings of the vascular wall, and after neuronal uptake it is metabolized to DOPAC. Moreover, deamination is more important than methylation. When the sympathetic nerve endings are depleted of NA, the synthesis of DA increases. The DA/NA ratio differs between the various vessels, suggesting different roles for DA. Since this ratio was higher in the mesenteric artery, DA probably works as a cotransmitter in this vessel.

A physiological role of brain histamine during energy deficiency

Histaminergic activation in the rat hypothalamus was investigated under a deficit in energy supply. Fasting of rats for 24 h increased hypothalamic histamine (HA) content. Intraperitoneal (IP) injection of insulin (2 U/kg) increased pargyline-induced accumulation of tele-methylhistamine ( t-MH) leaving steady-state HA and t-MH levels unaffected, which implies enhancement of HA turnover rate. The insulin infusion induced hypoglycemia both in rats with and without pargyline pretreatment. Infusion of 2-deoxy- D-glucose (2-DG) into the third cerebroventricle also produced an increase in pargyline-induced accumulation of t-MH and no change in steady-state HA and t-MH levels. The 2-DG infusion induced hyperglycemia. Hypothalamic glycogen content decreased after 24 h starvation, but this decrease was prevented by depletion of HA by α-fluoromethylhistidine. Absolute glycogen contents in the cortex were lower than those in the hypothalamus, and were not affected by fasting or depletion of HA. The results indicate that activation of hypothalamic HA in response to glucoprivation may modulate homeostatic control of energy supply in the brain.

Dopamine metabolism and free-radical related mitochondrial injury during transient brain ischemia in gerbils

Regional extracellular release of dopamine (DA) and its metabolites, 3,4-dihydroxy-phenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) was measured in gerbils (with or without pargyline pretreatment) subjected to bilateral carotid artery occlusion (15 min) and various periods of recirculation (up to 6 hr), utilizing intracerebral microdialysis and high-performance liquid chromatography (HPLC) with electrochemical detection. Mitochondrial monoamine oxidase (MAO) and superoxide dismutase (SOD) activities and in vitro stimulated lipid peroxidation (TBARM) were determined in separate experimental groups of animals. The ischemically induced DA release, decrease of MAO-derived DA metabolites DOPAC and HVA, and accumulation of 3-MT were potentiated and prolonged by pargyline pretreatment. Mitochondrial MAO and SOD activities were significantly reduced during ischemia alone and up to 1 hr of reperfusion, whereas TBARM was enhanced during reflow only. The data suggest that reduced activity of mitochondrial antioxidative enzyme(s) but not DA metabolism by MAO may contribute to free radical-mediated injury of (mitochondrial) membranes.

Different effects of methylxanthines on central serotonergic postsynaptic neurons in a mouse behavioral model

Effects of the four methylxanthines (100 mg/kg, IP)—caffeine, theophylline, theobromine, and pentoxifylline—on the central serotonergic neuron were studied in mice using a behavioral model, the head-twitch response. The four methylxanthines potentiated the head twitches induced by 5-hydroxytryptophan (5-HTP) in pargyline-pretreated mice; pentoxifylline was the most potent. The potentiating effect of pentoxifylline was increased by paroxetine, the selective inhibitor of uptake of 5-hydroxytryptamine (5-HT), but those of the other drugs were not. In nontreated animals, caffeine directly induced head-twitch responses, which were not affected by pargyline pretreatment but were increased by prior treatment with 5,7-dihydroxytryptamine (5,7-DHT). The number of head twitches produced by caffeine in 5,7-DHT-treated mice was increased twofold by p-chlorophenylalanine ( p-CPA), the tryptophan hydroxylase inhibitor. In mice treated with both 5,7-DHT and p-CPA, theophylline induced the responses, although much less potently than caffeine. Theobromine and pentoxifylline produced even fewer responses. From the results of the present study, it may be concluded that the methylxanthines possess qualitatively different actions on the central serotonergic neuron; caffeine and theophylline appear to have direct effects on the postsynaptic neuron, but theobromine and pentoxifylline do not.

Distribution of catecholamine-containing nerves on blood vessels of the rat trachea.

This study was performed to determine the distribution of catecholamine-containing sympathetic nerves on blood vessels of the rat trachea. The glyoxylic acid method was used to visualize catecholamine-containing axons in tracheal whole mounts, and silicone vascular casts were used to elucidate the architecture of the vasculature. We also examined the relationship of these axons to the trachea's plexus of cholinergic nerves and ganglia, using tracheal whole mounts stained for acetylcholinesterase activity. We found that most catecholamine-containing axons were associated with arterioles located between cartilaginous rings or in the posterior membrane. In both regions, catecholamine-containing nerves were most abundant at the origin of terminal arterioles, which supplied the airway mucosa and smooth muscle. At the origin of these vessels, the fluorescent axons changed their orientation from longitudinal to circumferential. Few fluorescent axons were present beyond this region of the terminal arterioles, and none was found on capillaries or venules or on smooth muscle cells of the posterior membrane. Fluorescent axons were present in some tracheal ganglia but non enveloped neuronal cell bodies or had varicosities, and no ganglion cells had glyoxylic acid-induced fluorescence. Catecholamine-fluorescence was also present in clusters of small intensely fluorescent (SIF) cells, which were located in the adventitia of the posterior membrane and in the longitudinal nerve trunks which ran the length of the trachea. Pargyline pretreatment increased the fluorescence of axons and SIF cells but did not reveal a different distribution of these structures.(ABSTRACT TRUNCATED AT 250 WORDS)

Prejunctional actions of tacrine on autonomic neuroeffector transmission in rabbit isolated pulmonary artery and rat isolated atria.

1. This study investigated the effects of tacrine (1,2,3,4-tetrahydro-9-aminoacridine) on the resting and stimulation-induced (SI) release of radioactive substances from isolated preparations of rat atria and rabbit pulmonary artery in which the noradrenergic transmitter stores had been labelled with [3H]-noradrenaline, and from rat atrial preparations in which cholinergic transmitter stores had been labelled with [3H]-acetylcholine. In addition, the effect of tacrine on the uptake of [3H]-noradrenaline by noradrenergic nerves in rat atria was determined. 2. Tacrine produced concentration-dependent increases in the resting efflux of radioactivity from both the [3H]-noradrenaline-loaded artery and atrial preparations. Blockade of neuronal amine transport with desipramine reduced the release of radioactivity evoked by tacrine from atria but not that evoked from artery preparations. Inhibition of monoamine oxidase by pargyline pretreatment markedly reduced the tacrine-evoked release of radioactivity in both atrial and artery preparations. 3. The radioactivity released from [3H]-noradrenaline-labelled rat atrial preparations by 30 mumol/L tacrine consisted entirely of the deaminated metabolite [3H]-DOPEG. The evoked release of [3H]-DOPEG from atria was reduced by approximately 50% by desipramine (1 mumol/L). When atrial monoamine oxidase had been inhibited by pargyline treatment in vivo and in vitro, 30 mumol/L tacrine evoked the release of [3H]-noradrenaline instead of [3H]-DOPEG. However, the amounts of [3H]-noradrenaline released by tacrine when monoamine oxidase was inhibited were only about 25% of the amounts of [3H]-DOPEG released in untreated atria. 4. Tacrine, in concentrations of 1 and 10 mumol/L, enhanced the release of radioactivity evoked by field stimulation of [3H]-noradrenaline-loaded rabbit pulmonary artery preparations. This effect was unaltered by desipramine or pretreatment with pargyline. However, in artery preparations pretreated with pargyline, a high concentration of tacrine (100 mumol/L) markedly reduced SI efflux. In contrast to the findings with artery preparations, tacrine (1-30 mumol/L) did not alter SI efflux in rat atrial preparations. 5. It is concluded that tacrine displaces noradrenaline from intraneuronal transmitter stores of sympathetically-innervated tissues, and that the displaced amine is totally metabolized by monoamine oxidase before leaving the nerve terminals. When deamination of neuronal cytoplasmic noradrenaline is prevented, only a portion of the noradrenaline displaced from storage vesicles passes to the extracellular space. It is likely that the transfer of cytoplasmic noradrenaline out of the terminals is limited by the activity of the amine transport mechanism.

Rapid changes in ascorbate and dopamine release in rat nucleus accumbens after intracerebroventricular administration of NMDA

In vivo voltammetry at electrochemically pretreated carbon fibre electrodes was used to investigate the effect of intracerebroventricular (i.c.v.) administration of N- methyl- d-aspartic acid (NMDA) on neuronal activity in rat nucleus accumbens. Infusion of a low dose of NMDA (1 nmol) was followed a few minutes later by rapid changes in both Peak 1 and Peak 2 heights indicating large but short-lived increases in the extracellular concentrations of ascorbate and catecholamines, respectively. These responses did not seem to be dependent on the dose infused since infusion of NMDA for a longer time period neither changed the amplitude nor the time-course of these effects. The increase in Peak 2 height was resistant to pargyline pretreatment indicating that this response mainly reflected the release of dopamine. The administration of NMDA was followed by behavioural activation in the animals but not convulsions. Co-administration of the competitive NMDA receptor antagonist, CPP (1 nmol), completely blocked these effects while the acetylcholine receptor antagonist, atropine (1.5 nmol), and the GABA receptor antagonist, picrotoxin (1 nmol), failed in this respect. The phenomenon spreading depression is discussed as a possible explanation of these results.

Effect of atrial natriuretic peptide on DOPA potentiation in mice

The effect of rat atrial natriuretic peptide (ANP 1–28) on the pargyline-DOPA potentiation test was studied following its administration into the lateral brain ventricle in mice. Thirty minutes after pargyline pretreatment, three doses of ANP (200, 500, or 1,000 ng/mouse) were administered simultaneously with DOPA and animals were then observed for 2 h. ANP in doses of 500 and 1,000 ng markedly enhanced the effect of DOPA. The maximum intensity of the effect was registered 30–45 min following administration of the peptide. The data suggest that ANP might be regarded as a dopaminergic-modulating agent in the CNS.

Regional effects of ceruletide, a cholecystokinin-8 analog, on the striatal monoaminergic systems in food-deprived mice

To clarify the pharmacological mechanism by which ceruletide affects involuntary movements, we used 20-h food-deprived mice to examine the acute effects of ceruletide (600 μg/kg, i.p.) on the histochemistry of striatal dopaminergic and serotonergic systems. The latter was unchanged but a reduction in catecholamine fluorescence was seen which was restricted to the ventrolateral (VL) portion of the striatum. Biochemical assays also indicated decreased levels of dopamine (DA) and its metabolites in this restricted region of the striatum with little or no change in noradrenaline, serotonin or their metabolites. In all regions examined, except the dorsomedial part of the mid-striatum, the ration of dopamine metabolites to dopamine was higher in the ceruletide-treated group than in controls, suggesting increased DA release. Further pharmacological experiments showed that, compared to results in mice receiving only ceruletide: the ceruletide-induced decreases in DA and dihydroxyphenylacetic acid (DOPAC) in VL were less after α-methyl- p-tyrosine treatment; ceruletide caused no significant decrease in either DA or DOPAC after pargyline pretreatment, although the low levels of homovanillic acid (HVA) were still further significantly reduced; and the ceruletide-induced decrease of DA was reduced, that of DOPAC was abolished and that of HVA enhanced by nomifensine pretreatment. These results suggested that ceruletide might induce a more rapid degradation of DA in VL and increased efflux of HVA through the blood-brain barrier. This evidence suggests that ceruletide has a regionally specific effect on the striatal dopaminergic system which may relate to the amelioration of involuntary movements.

Characterization of monoamine release in the lateral hypothalamus of awake, freely moving rats using in vivo microdialysis

Extracellular levels of serotonin (5-HT), dopamine (DA) and their major metabolites 5-hydroxyindoleacetic acid (5-HIAA), 3, 4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), were measured in the lateral hypothalamus of awake, freely moving rats using microdialysis combined with HPLC and electrochemical detection. To characterized the factors which control 5-HT release, the effects of various drugs were assessed. TTX had a reversible inhibitory effect on the basal levels of 5-HT, 5-HIAA, DOPAC and HVA. Infusion of K + concomitantly increased 5-HT and DA and decreased 5-HIAA and HVA. Imipramine increased extracellular levels of 5-HT and DA and decreased 5-HIAA levels; this effect was TTX-sensitive. Systemic pargyline increased extracellular 5-HT and markedly decreased the metabolite levels. Pargyline pretreatment in the presence of imipramine, infused through the dialysis probe, slowly increased 5-HT levels above that produced by the reuptake blocker alone. Infusion with AMPH produced a dramatic, TTX-insensitive, increase in 5-HT and DA and a decrease in the metabolite levels. These results provide evidence that (1) basal release of 5-HT in the lateral hypothalamus results from neuronal activity, (2) the metabolites in the extracellular fluid derive primarily from intracellular monoamine oxidase (MAO) activity, (3) 5-HT is mainly removed from the extracellular space by a reuptake mechanism, with minimal contribution of an extracellular MAO, and (4) the AMPH-evoked release of 5-HT and DA is a Na + channel-independent process.

Effects of Selective Monoamine Oxidase Inhibitors on the In Vivo Release and Metabolism of Dopamine in the Rat Striatum

Brain microdialysis was used to examine the in vivo efflux and metabolism of dopamine (DA) in the rat striatum following monoamine oxidase (MAO) inhibition. Relevant catecholamines and indoleamines were quantified by HPLC coupled with a electrochemical detection system. The MAO-B inhibitor selegiline only affected DA deamination at a dose shown to inhibit partially type A MAO. Alterations in DA and metabolite efflux were not observed when using the MAO-B-selective dose of 1 mg/kg of selegiline. At 10 mg/kg, selegiline reduced the efflux of DA metabolites to approximately 70% of basal values without affecting DA efflux. K(+)- and veratrine-stimulated DA efflux was not affected by selegiline. Experiments using amphetamine and the DA uptake inhibitor nomifensine demonstrated that the effect of selegiline on DA metabolism was unlikely to be mediated either by inhibition of DA uptake or by an indirect effect of its metabolite amphetamine. The possibility that the effect of selegiline is mediated via a nonspecific inhibition of MAO is discussed. In contrast, the MAO-A inhibitor clorgyline inhibited basal DA metabolism and increased basal and depolarisation-induced DA efflux. A 1 mg/kg dose of clorgyline reduced basal DA metabolite efflux (40-60% of control values) without affecting DA efflux. At 10 mg/kg of clorgyline, DA efflux increased to 253 +/- 19% of basal values, whereas efflux of DA metabolites was reduced to between 15 and 26% of control values. The release of DA induced by K+ and veratrine was not affected by 1 mg/kg of clorgyline but was increased by approximately 200% following pretreatment with 10 mg/kg of clorgyline. The nonselective MAO inhibitor pargyline caused similar but more pronounced alterations in these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Pargyline increases 6-hydroxydopamine levels in the neostriatum of methamphetamine-treated rats

Neostriatal 6-hydroxydopamine (6-OHDA) was detected in 6 of 13 rats pretreated 2 or 4 hr earlier with methamphetamine (MA; 100 mg/kg, SC) and pargyline (25 mg/kg, IP, 30 min before MA injection). Neostriatal 6-OHDA was detected in 2 of 16 rats treated 2 or 4 hr earlier with MA. These results suggest that pargyline pretreatment may enhance formation of 6-OHDA from endogenous stores of dopamine (DA) following MA administration. Alternatively, these results suggest that pargyline pretreatment may protect endogenously formed 6-OHDA from oxidative deamination by monoamine oxidase. Enhancement of MA-induced neostriatal 6-OHDA levels may be the mechanism by which pargyline enhances the long-term neurotoxic effects of MA upon dopaminergic nerve terminals. These observations support the hypothesis that MA toxicity to DA-containing fibers is caused by the conversion of released DA into 6-OHDA.