Irreversible Monoamine Oxidase Inhibitors Research Articles

Hydrogen peroxide production by monoamine oxidase during ischemia/reperfusion

Reactive oxygen species have been postulated to play a crucial role in the pathogenesis of renal ischemia-reperfusion injury. However, the intracellular sources of reactive oxygen species during ischemia-reperfusion are still unclear. In the present study, we examined whether catecholamine-degrading enzymes monoamine oxidases contribute to hydrogen peroxide (H 2O 2) generation during ischemia-reperfusion using an in vivo rat model of unilateral renal ischemia. The monoamine oxidases were characterized in homogenates of renal cortex by enzyme assay and by Western blot analysis. The monoamine oxidase-dependent H 2O 2 production was measured by luminol-amplified chemiluminescence assay. Renal monoamine oxidase activity and H 2O 2 generation by monoamine oxidases were suppressed during ischemia. The monoamine oxidase-dependent H 2O 2 production was observed during the first 15 min of reperfusion. In addition, enzyme assays showed that monoamine oxidase is also activated in this period. Rat pre-treatment with the irreversible inhibitor of monoamine oxidase, pargyline, prevented H 2O 2 production. These data suggest that monoamine oxidases are a potential source of H 2O 2 generation in the early reperfusion following ischemia, which could be involved in renal ischemia-reperfusion injury.

Characterization of the discriminable stimulus produced by 2-BFI: effects of imidazoline I(2)-site ligands, MAOIs, beta-carbolines, agmatine and ibogaine.

1. The molecular nature and functions of the I(2) subtype of imidazoline binding sites are unknown but evidence suggests an association with monoamine oxidase (MAO). Rats can distinguish the selective imidazoline I(2)-site ligand 2-BFI from vehicle in drug discrimination, indicating functional consequences of occupation of these sites. We have used drug discrimination to investigate the nature of the discriminable stimulus, especially in relation to MAO inhibition. 2. Following training to distinguish 2-BFI 7 mg kg(-1) i.p. from saline vehicle in two-lever operant-chambers, male Hooded Lister rats underwent sessions where test substances were given instead and the proportion of lever presses on the 2-BFI-associated lever (substitution) recorded. 3. 2-BFI; its cogeners BU216, BU224, BU226 and LSL60101; the reversible MAO-A inhibitors moclobemide and RO41-1049; the beta-carbolines harmane, norharmane and harmaline which also reversibly inhibit MAO-A, and the anti-addictive substance ibogaine exhibited potent, dose-dependent substitution for 2-BFI. 4. Agmatine, and LSL60125 substituted at one dose only. The reversible MAO-B inhibitors lazabemide and RO16-1649; the sigma(2)-site ligand SKF10,047 and the I(2A)-site ligand, amiloride, failed to substitute. The irreversible inhibitor of MAO, deprenyl, substituted for 2-BFI while clorgyline did not. 5. These results suggest imidazoline I(2) site ligands produce a common discriminable stimulus that appears associated with reversible inhibition of MAO-A rather than MAO-B, possibly through increases in extracellular concentration of one or more monoamines. Ibogaine exhibits a commonality in its subjective effects with those of I(2)-site ligands.

Post-traumatic stress disorder: a review of psychobiology and pharmacotherapy.

To review the literature on the psychobiology and pharmacotherapy of PTSD. Relevant studies were identified by literature searches (Pub-med, Web of Science) and through reference lists. The search was ended by May 2001. There is evidence of involvement of opioid, glutamatergic, GABAergic, noradrenergic, serotonergic and neuroendocrine pathways in the pathophysiology of PTSD. Medications shown to be effective in double-blind placebo-controlled trials includes selective serotonin reuptake inhibitors, reversible and irreversible MAO-inhibitors, tricyclic antidepressants and the anticonvulsant lamotrigine. Still more agents appear promising in open-label trials. The complexity of the psychobiology is reflected by the difficulties in treating the disorder. According to the present knowledge, suggestions for drug treatment of PTSD are made.

Region-dependent effects of acute and chronic tranylcypromine in vivo on [ 3H]2-BFI binding to brain imidazoline I 2 sites

An imidazoline I 2 site has been localised to monoamine oxidase. However, in vitro studies of the effect of monoamine oxidase inhibitors on imidazoline I 2-site radioligand binding have produced conflicting findings. Using the technique of autoradiography, we examined the effect of in vivo administration of the irreversible monoamine oxidase inhibitor tranylcypromine on binding of the imidazoline I 2 site-specific ligand [ 3H]2-(-2-benzofuranyl)-2-imidazoline ([ 3H]2-BFI) in four rat brain nuclei which are known to possess a high density of imidazoline I 2 sites, together with cerebral cortex and cerebellum which show weaker binding. A single acute pre-treatment with tranylcypromine significantly increased imidazoline I 2 site-specific binding in four regions: arcuate nucleus, interpeduncular nucleus, pineal gland and area postrema, but effects in cortical areas and cerebellum were not significant. The extent of the increase was proportional to the control binding in each region. In contrast, five daily treatments with the same dose of tranylcypromine significantly reduced [ 3H]2-BFI binding in these same areas. The potential role of monoamine oxidase isoforms in these changes is discussed.

A Reevaluation of Dietary Restrictions for Irreversible Monoamine Oxidase Inhibitors

A Reevaluation of Dietary Restrictions for Irreversible Monoamine Oxidase Inhibitors

Assessing the comparative effectiveness of antidepressant therapies: a prospective clinical practice study.

Although efficacy studies suggest equal potency among antidepressant treatments, their effectiveness in clinical practice appears more variable, particularly in that the newer antidepressants may be less effective in either more severe depression or the melancholic subtype of depression. We pursue some factors that may impact the effectiveness of antidepressant treatments in a clinical sample. A sample of 182 patients with DSM-IV major depressive disorder was assessed at baseline and 12 months later to establish treatments provided, identify patients who had recovered from the index episode, and quantify likely treatment determinants. Four systems for distinguishing patients with melancholic and non-melancholic depression were examined to assess for differential effects of the antidepressant strategies across those subtypes. Multimodal therapy (commonly, psychotherapy combined with an antidepressant drug) and patients' frequent attribution of recovery to spontaneous improvement made for difficulty in disentangling recovery determinants. After excluding a spontaneous improvement component, electroconvulsive therapy (ECT) and the irreversible monoamine oxidase inhibitors (MAOIs) appeared to be the most effective therapies across the sample, while the reversible inhibitor of monoamine oxidase-A (RIMA) appeared to be the least effective. The distinct gradient of suggested effectiveness of various strategies appeared to be contributed to principally by the varied effectiveness of alternate treatments across the melancholic subtype, whereby ECT, tricyclic antidepressants, and MAOIs were the most effective, and the selective serotonin reuptake inhibitors (SSRIs), RIMAs, and antipsychotic drugs were much less effective. For the nonmelancholic disorders, the effectiveness of SSRIs appeared to be comparable with that of older antidepressants. Although most patients received a physical treatment, they commonly judged psychotherapy and spontaneous improvement to be influential in their recovery. Reasons for such attributions are worthy of clarifying studies. Despite patients' concerns about the side effects and stigma of ECT as well as the side effects associated with the older antidepressants, these therapies were rated as more helpful by patients-and were more strongly associated with recovery-than the newer antidepressant drugs. Such overall results are compatible with an earlier study undertaken by us involving an independent sample and retrospective data. The overall gradient is clarified by studying depressive subtypes, allowing an important conclusion. Although the newer and older antidepressant drugs may be of similar effectiveness in nonmelancholic depression, the newer agents appear comparatively inferior for the treatment of melancholia, findings that have clinical implications and perhaps inform us about the pathogenesis of melancholia.

Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B.

1. Rasagiline [N-propargyl-1R(+)-aminoindan], was examined for its monoamine oxidase (MAO) A and B inhibitor activities in rats together with its S(-)-enantiomer (TVP 1022) and the racemic compound (AGN-1135) and compared to selegiline (1-deprenyl). The tissues that were studied for MAO inhibition were the brain, liver and small intestine. 2. While rasagiline and AGN1135 are highly potent selective irreversible inhibitors of MAO in vitro and in vivo, the S(-) enantiomer is relatively inactive in the tissues examined. 3. The in vitro IC(50) values for inhibition of rat brain MAO activity by rasagiline are 4.43+/-0.92 nM (type B), and 412+/-123 nM (type A). The ED(50) values for ex vivo inhibition of MAO in the brain and liver by a single dose of rasagiline are 0.1+/-0.01, 0.042+/-0.0045 mg kg(-1) respectively for MAO-B, and 6.48+/-0.81, 2.38+/-0.35 mg kg(-1) respectively for MAO-A. 4. Selective MAO-B inhibition in the liver and brain was maintained on chronic (21 days) oral dosage with ED(50) values of 0.014+/-0.002 and 0.013+/-0.001 mg kg(-1) respectively. 5. The degree of selectivity of rasagiline for inhibition of MAO-B as opposed to MAO-A was similar to that of selegiline. Rasagiline was three to 15 times more potent than selegiline for inhibition of MAO-B in rat brain and liver in vivo on acute and chronic administration, but had similar potency in vitro. 6. These data together with lack of tyramine sympathomimetic potentiation by rasagiline, at selective MAO-B inhibitory dosage, indicate that this inhibitor like selegiline may be a useful agent in the treatment of Parkinson's disease in either symptomatic or L-DOPA adjunct therapy, but lack of amphetamine-like metabolites could present a therapeutic advantage for rasagiline.

Activation of I(2)-imidazoline receptors enhances supraspinal morphine analgesia in mice: a model to detect agonist and antagonist activities at these receptors.

This work investigates the receptor acted upon by imidazoline compounds in the modulation of morphine analgesia. The effects of highly selective imidazoline ligands on the supraspinal antinociception induced by morphine in mice were determined. 2. Intracerebroventricular (i.c.v.) or subcutaneous (s.c.) administration of ligands selective for the I(2)-imidazoline receptor, 2-BFI, LSL 60101, LSL 61122 and aganodine, and the non selective ligand agmatine, increased morphine antinociception in a dose-dependent manner. Neither moxonidine, a mixed I(1)-imidazoline and alpha(2)-adrenoceptor agonist, RX821002, a potent alpha(2)-adrenoceptor antagonist that displays low affinity at I(2)-imidazoline receptors, nor the selective non-imidazoline alpha(2)-adrenoceptor antagonist RS-15385-197, modified the analgesic responses to morphine. 3. Administration of pertussis toxin (0.25 microg per mouse, i.c.v.) 6 days before the analgesic test blocked the ability of the I(2)-imidazoline ligands to potentiate morphine antinociception. 4. The increased effect of morphine induced by I(2)-imidazoline ligands (agonists) was completely reversed by idazoxan and BU 224. Identical results were obtained with IBI, which alkylates I(2)-imidazoline binding sites. Thus, both agonist and antagonist properties of imidazoline ligands at the I(2)-imidazoline receptors were observed. 5. Pre-treatment (30 min) with deprenyl, an irreversible inhibitor of monoamine oxidase B (IMAO-B), produced an increase of morphine antinociception. Clorgyline, an irreversible IMAO-A, given 30 min before morphine did not alter the effect of the opioid. At longer intervals (24 h) a single dose of either clorgyline or deprenyl reduced the density of I(2)-imidazoline receptors and prevented the I(2)-mediated potentiation of morphine analgesia. 6. These results demonstrate functional interaction between I(2)-imidazoline and opioid receptors. The involvement of G(i)-G(o) transducer proteins in this modulatory effect is also suggested.

Comparison of neurochemical effects of the monoamine oxidase inhibitors phenelzine, moclobemide and brofaromine in the rat after short- and long-term administration

Background: Chronic administration of several irreversible monoamine oxidase (MAO) inhibitors induces a down-regulation of tryptamine and 5-hydroxytryptamine 2 receptors in rat brain, but there is a paucity of information available on the effects of reversible MAO-A inhibitors on these receptors. Methods: Acute and chronic experiments were conducted in rats and the effects of the irreversible monoamine oxidase inhibitor, phenelzine and the reversible MAO type-A inhibitors, moclobemide and brofaromine, on tryptamine and 5-hydroxytryptamine 2 receptors were analysed using radioligand binding techniques. In addition, activities of MAO-A and -B were determined radiochemically and brain and/or urine levels of tryptamine, 5-hydroxytryptamine, 3-methoxy-4-hydroxyphenylglycol (MHPG), β-phenylethylamine, brofaromine and moclobemide were determined by chromatographic procedures. Results: After 30 days of administration, moclobemide and brofaromine selectively inhibited brain MAO-A activity and phenelzine inhibited MAO-A and -B to equal extents. All three drugs caused a significant down-regulation of tryptamine receptors, whereas only phenelzine significantly down-regulated 5-hydroxytryptamine 2 receptors. In a comparison of phenelzine and brofaromine, both caused marked elevations of urinary tryptamine and decreases of urinary MHPG levels, while only phenelzine increased β-phenylethylamine levels. After 14 days of administration, phenelzine, but not moclobemide or brofaromine, significantly increased levels of tryptamine in brain; all three drugs significantly increased 5-HT levels. Limitations: 24-h urine samples were not collected for moclobemide-treated animals and brain levels of tryptamine were not measured after 30-day administration. Conclusions: These studies revealed marked neurochemical differences among phenelzine, moclobemide and brofaromine which could contribute to their actions in the clinical setting.

Modulation of dihydroxyphenylacetaldehyde extracellular levels in vivo in the rat striatum after different kinds of pharmacological treatment

We recently identified the direct product of dopamine (DA) by monoamine-oxidase (MAO) activity, dihydroxyphenylacetaldehyde (DOPALD) in the trans-striatal dialysate. Based on these findings, in this work, we directly measured the variations in DOPALD levels after various kinds of pharmacological treatment in rat striatal extracellular fluid. Using both reversible and irreversible MAO inhibitors, we found that MAO-A inhibition suppressed, whereas MAO-B inhibition did not modify DOPALD levels in the dialysate. The vesicular DA uptake blocker Ro 4-1284 led to an increase in extracellular DA and DOPALD, whereas the increase in extracellular DA obtained after administration of the plasma membrane DA uptake blocker GBR-12909 occurred without concomitant changes in DOPALD extracellular levels. Microinfusions of DA through the dialysis probe or systemic administration of l-DOPA increased striatal DOPALD to a greater extent compared with other DA metabolites, both in intact and in 6-hydroxydopamine (6-OHDA)-lesioned striatum. This study indicates that the direct product of MAO activity within the rat striatum derives from the activity of the isoenzyme MAO-A. The assay of DOPALD, together with DOPAC, represents a reliable tool to measure directly, in freely moving animals, DA oxidative metabolism. As recent studies have shown that microinfusions of exogenous DOPALD might induce cell death, pharmacological modulation of DOPALD levels might also be relevant for an understanding of the mechanisms involved in DA neurotoxicity.

Rasagiline, a novel monoamine oxidase-B inhibitor with neuroprotective effects under ischemic conditions in PC12 cells

Rasagiline (N-propargyl-1R-aminoindan) is a novel, potent, selective, and irreversible inhibitor of monoamine oxidase B (MAO-B), currently in Phase III trials for the treatment of Parkinson disease (PD). Rasagiline was shown to have neuroprotective properties in various in vitro and in vivo models independently of MAO-B inhibition. Recently, we developed an in vitro oxygen-glucose deprivation (OGD) model of time-course dependent neuronal cell death in nerve growth factor (NGF)-differentiated PC12 cultures. OGD was accompanied by activation of the arachidonic acid cascade and a decrease in ATP content, changes typical of ischemic conditions. OGD for 3 h followed by reoxygenation for 18 h caused about 30–40% cell death. These conditions are suitable for testing the effect of potential neuroprotective compounds on neuronal cell death. Rasagiline markedly reduced OGD-induced cell death independently of MAO-B inhibition, reducing OGD-induced cell death even when added after the OGD insult. The compound also inhibited OGD-induced prostaglandin E2 (PGE2) release in a dose-dependent manner. At present, selegiline remains the only drug approved for PD therapy based on MAO-B inhibition. However, in contrast to selegiline, rasagiline is not metabolized to amphetamine-like products, which cause adverse side effects and neuronal cell death. Therefore, rasagiline, whose neuroprotective properties are uncomplicated by the production of neurotoxic metabolites, may have an advantage over selegiline in the treatment of PD. Drug Dev. Res. 50:285–290, 2000. © 2000 Wiley-Liss, Inc.

Are the Newer Antidepressant Drugs as Effective as Established Physical Treatments? Results from an Australasian Clinical Panel Review

The aim of this study was to determine, in a clinical panel sample, the extent to which patients with depression (and melancholic and non-melancholic subtypes) judged the effectiveness of previously received antidepressant treatments, particularly the comparative effectiveness of the older and newer antidepressant drugs. Twenty-seven Australasian psychiatrists assessed 341 non-psychotic depressed patients and rated the extent to which previous antidepressant treatments had been effective. Patients were assigned to 'melancholic' and residual 'non-melancholic' categories by two processes (DSM-IV decision rules, and a cluster analysis-derived allocation) and treatment effectiveness examined within each category. Electroconvulsive therapy (both bilateral and unilateral) was judged as highly effective by both melancholic and non-melancholic patients. Antipsychotic medication similarly rated highly (but was judged as more effective by the non-melancholic than melancholic patients). The tricyclics and irreversible monoamine oxidase inhibitors (MAOIs) were rated as more effective by the whole sample than several newer antidepressant classes (including the selective serotonin re-uptake inhibitors [SSRIs], venlafaxine, mianserin and moclobemide), whether effectiveness was examined dimensionally or categorically. Comparison of the overall tricyclic and SSRI classes indicated that any superior tricyclic effectiveness was specific to the melancholic subjects. Despite methodological limitations intrinsic to such clinical panel data, the judged greater effectiveness of the older antidepressants (tricyclics and irreversible MAOIs) for melancholic depression is of importance. If valid, such data are of intrinsic clinical relevance but also have the potential to inform us about the neurobiological determinants of 'melancholia' and pharmacological actions which contribute to its effective treatment.

Reduction of Oral Ethanol Self-Administration in Rats by Monoamine Oxidase Inhibitors

Evidence for a role of dopamine and serotonin in the control of ethanol intake in animals suggests that monoamine oxidase (MAO) inhibitors, which increase the synaptic availability of serotonin and dopamine by blocking their metabolism, might have efficacy in the treatment of alcohol dependence. The aim of the present study was, therefore, to evaluate several MAO inhibitors for their capacity to affect ethanol self-administration in rats trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task. The nonselective and irreversible MAO inhibitors, phenelzine (3–10 mg/kg), tranylcypromine (1–3 mg/kg), and nialamide (30 mg/kg), decreased rates of responding maintained by ethanol reinforcement. The reversible MAO-A inhibitor, befloxatone (0.3–3 mg/kg), and the irreversible MAO-A inhibitor, clorgyline (10–30 mg/kg), also reduced ethanol self-administration. However, befloxatone-induced effects leveled off at a 50% decrease. The irreversible MAO-B inhibitors, pargyline (30 mg/kg) and l-deprenyl (3–10 mg/kg) also decreased responding maintained by ethanol reinforcement; these results are consistent with previous findings that both drugs decreased ethanol intake in mice. In conclusion, the present results showing that several MAO inhibitors decreased ethanol self-administration in rats are consistent with previous findings that synaptic levels of serotonin and dopamine play a critical role in the control of ethanol self-administration.

Undesirable Blood Pressure Changes Under Naturalistic Treatment with Moclobemide, a Reversible MAO-A Inhibitor - Results of the Drug Utilization Observation Studies

Blood pressure decrease, associated with postural hypotension, as well as spontaneous hypertension are considered to be typical side-effects of conventional, irreversible and nonselective MAO (A+B) inhibitors. The new generation of reversible MAO-A inhibitors is, however, expected to have negligible cardiovascular effects and low propensity to induce either blood pressure increases or decreases. But, the true incidence of such changes is largely unknown since observation studies, specifically assessing the frequency of blood pressure changes, in unselected population of patients treated in the practice, are lacking.

Neuronal Sparing and Behavioral Effects of the Antiapoptotic Drug, (−)Deprenyl, Following Kainic Acid Administration

(−)Deprenyl is an irreversible inhibitor of monoamine oxidase B (MAO-B) frequently used as an adjunct therapy in the treatment of Parkinson’s Disease. Recent evidence, however, has found that deprenyl’s metabolites are associated with an antiapoptotic action within certain neuronal populations. Interestingly, deprenyl’s antiapoptotic actions appear not to depend upon the inhibition of MAO-B. Due to a paucity of information surrounding (−)deprenyl’s ability to spare neurons in vivo, a series of studies was conducted to further investigate this phenomenon within an apoptotic neuronal death model: kainic acid induced excitotoxicity. Results indicated that (−)deprenyl increased hippocampal neuronal survival compared to saline-matched controls following kainic acid insult. Furthermore, it was discovered that (−)deprenyl treatment could be stopped 14 days following CNS insult by kainate, with evidence of neuronal sparing still present by day 28. In open-field locomotor activity testing of kainate-treated animals, those given subsequent (−)deprenyl treatment showed habituation curves similar to control subjects, while saline-treated animals did not. Given deprenyl’s antiapoptotic actions, it is proposed that (−)deprenyl may be beneficial in the treatment of a variety of neurodegenerative diseases where evidence of apoptosis exists, such as Parkinson’s and Alzheimer’s Disease, by slowing the disease process itself.

Effect of selegiline on dopamine concentration in the striatum of a primate

Monoamine oxidase (MAO) has two subtypes, A and B, that have different distributions between the rodent and the human. In the striatum, dopamine (DA) of the rat seems to be metabolized by MAO A, and DA of the human is largely deaminated by MAO B. MAO in the striatum of common marmosets is also type B. Using in vivo microdialysis, we investigated the pharmacological activity of selegiline, a selective irreversible inhibitor of MAO B, in the striatum of marmosets. Intraperitoneal co-administration of selegiline (1 mg kg −1, i.p.) with levodopa/carbidopa (10/2.5 mg kg −1, i.p.) did not significantly increase extracellular concentration of DA in the striatum of common marmosets compared with control animals receiving levodopa/carbidopa alone. Daily pretreatment with 0.1 mg kg −1 (i.p.) selegiline for two weeks, however, dramatically increased extracellular concentration of DA to about seven times that of control animals treated with levodopa/carbidopa alone in marmosets. Such an increase in extracellular concentrations of DA could not be observed in a similar study with Wistar rats. This study showed that chronic administration of a small dose of selegiline caused a marked increase in extracellular DA concentration in the striatum of primates, but not in the rodents.

Stimulation of locus coeruleus neurons by non-I1/I2-type imidazoline receptors: an in vivo and in vitro electrophysiological study.

1. Imidazoline binding sites have been reported to be present in the locus coeruleus (LC). To investigate the role of these sites in the control of LC neuron activity, we studied the effect of imidazolines using in vivo and in vitro single-unit extracellular recording techniques. 2. In anaesthetized rats, local (27 pmoles) and systemic (1 mg kg(-1), i.v.) administrations of 2-(2-benzofuranyl)-2-imidazoline (2-BFI), a selective I-imidazoline receptor ligand, increased the firing rate of LC cells (maximal increase: 22+/-5%, P<0.001 and 16+/-7%, P<0.001 respectively). Chronic pretreatment with the irreversible monoamine oxidase inhibitor clorgyline (3 mg kg(-1), i.p., every 12 h for 14 days) abolished this effect. 3. In rat midpontine brain slices containing the LC, bath application (1 mM) of the imidazolines 2-BFI, 2-(4,5-dihydroimidaz-2-yl)-quinoline (BU224), idazoxan, efaroxan, phentolamine and (2-2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline (RX821002) reversibly stimulated LC cells. The maximal effect was approximately 90% except for RX821002 and efaroxan which induced smaller maximal effects (approximately 58% and approximately 35% respectively). Simultaneous application of idazoxan and 2BFI did not lead to additive effects. 4. Bath application of the alpha2-adrenoceptor antagonists, yohimbine (1 - 10 microM) and N-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) (10 microM), failed to modify LC activity. The irreversible blockade of alpha2-adrenoceptors with EEDQ (10 microM) did not alter the effect of idazoxan or that of efaroxan. Previous application of clorgyline (10 microM) did not modify the excitatory effect of 2-BFI or efaroxan. 5. Changes in the pH of the bathing solution (6.84-7.84) did not influence the effect caused by idazoxan. Bath application of 2-BFI (1 mM) reversed the inhibition induced by diazoxide (300 microM), an ATP-sensitive K+ channel opener, whereas application of glibenclamide (3 microM), an ATP-sensitive K+ channel blocker, partially blocked the effect of 2-BFI. 6. This study shows that imidazoline compounds stimulate the firing rate of LC neurons. This effect is not mediated by alpha2-adrenoceptors nor by I1 or I2-imidazoline receptors but involves a different subtype of imidazoline receptor. Our results indicate that this receptor is located extracellularly and modulates ATP-sensitive K+ channels.

Mechanism-based inhibition of monoamine oxidase by 3-aryl-Delta3-pyrrolines.

The compound 1-methyl-3-phenyl-Delta3-pyrroline and its 4-chlorophenyl analogue appear to act as irreversible inhibitors of monoamine oxidase B (MAO B) in mitochondria of rat liver. The compounds are metabolized by MAO B and concomitantly inhibit the enzyme in what seems to be a two-step process. The metabolic end product of this process is the corresponding pyrrole. This inhibition process is considered in the light of possible intermediates formed during the enzymic oxidation, and comparisons are made with the structurally analogous neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Serotonin syndrome: history and risk.

This review focuses on the history of investigations into the behavioural reaction resulting from excess stimulation of post-synaptic 5-hydroxytryptamine receptors and the relative risk of this occurring with different combinations of drugs. Other aspects, particularly treatment with 5-hydroxytryptamine receptor antagonists, are reviewed in a recent separate paper [44]. The first human case was in 1955 and animal work had defined the characteristic features by 1958, and established they were lessened by chlorpromazine. Substantial evidence of a 'dose-effect' relationship existed by 1984. The relative risk with different drug combinations is assessed from available evidence and argued to be strongly associated with the degree of elevation of 5-hydroxytryptamine, which is greatest following combinations of irreversible inhibitors of monoamine oxidase A and B with potent serotonin reuptake inhibitors. The various serotonergic drugs that may be implicated in serotonin syndrome are tabulated and discussed in relation to the relative risk. It is suggested that the proposed 'diagnostic criteria' for serotonin syndrome are inappropriate since there is a continuous spectrum from side effects to toxicity. The term 'serotonin syndrome' may encourage the presumption that it is an idiosyncratic response, as neuroleptic malignant syndrome is usually considered to be. The terms 'toxic serotomimetic reaction' or 'toxic serotonin syndrome' may be preferable alternatives. The differences between serotonin syndrome and neuroleptic malignant syndrome are highlighted with examples from difficult or questionable cases in the recent literature. It is proposed that more systematic national collection of toxicity data is essential in order to quantify the relative risk of serotonin syndrome with various combinations of serotonergic drugs.

Selegiline prevents long-term changes in dopamine efflux and stress immobility during the second and third weeks of abstinence following opiate withdrawal

Selegiline is an irreversible inhibitor of monoamine oxidase B with trophic and neuroprotective effects. Because of evidence for decreased dopaminergic function during the withdrawal syndromes associated with opiates and other medications with potential for abuse, we investigated effects of treatment with selegiline on in vitro measures of dopamine efflux following opiate withdrawal. Treatment with 2.0 mg/kg/day of selegiline did not modify the severity of opiate withdrawal, as assessed by weight loss over the first 3 days of abstinence. Opiate withdrawal increased immobility in response to a forced warm water swim test performed during the second and third weeks of abstinence following the onset of withdrawal. Brain slices obtained from the nucleus accumbens of opiate-withdrawn animals immediately following swim stress testing displayed diminished efflux of tritiated dopamine after two in vitro exposures to cocaine or amphetamine. Cocaine increases neurotransmitter efflux through blockade of dopamine reuptake, while amphetamine augments efflux by stimulating release of dopamine from intracellular storage vesicles. Although slices from opiate withdrawal subjects showed decreases in efflux after in vitro treatment with these agents, no differences were observed after exposure to 4-aminopyridine, which increases neurotransmitter release by prolonging action potential duration. These findings indicate mechanisms of action that are specific for catecholamine neurotransmitter systems are important for demonstrating long-term changes in dopaminergic function following opiate withdrawal. Selegiline prevented decreases in the efflux of tritiated dopamine in slices obtained from opiate-withdrawn subjects. In addition, selegiline decreased withdrawal-induced immobility during warm water swim testing. In conclusion, treatment with selegiline can prevent long-term changes in stress-induced immobility and deficits in presynaptic dopaminergic function that occur following the opiate withdrawal syndrome.