Irreversible Monoamine Oxidase Research Articles

Comparative Studies of the Effects of RS-8359 and Safrazine on Monoamine Oxidase In-vitro and In-vivo in Mouse Brain

The effect of RS-8359, pyrimidine on monoamine oxidase (MAO) has been compared with a hydrazinic MAO inhibitor, safrazine (beta-piperonylisopropylhydrazine hydrochloride,) which is a MAO inhibitor used clinically. In-vitro radiochemical determination of MAO activity showed that the IC50 of RS-8359 was 0.52 microM for the deamination of 5-hydroxytryptamine (5-HT) in the mouse brain mitochondrial preparation, while beta-phenylethylamine (PEA) deamination was inhibited by only 20% at 100 microM of the drug. 5-HT deamination in the brain homogenate prepared from mice killed 60 min after administration of RS-8359 was inhibited significantly by 14 and 48%, at 30 and 100 mg kg-1 (p.o.), respectively, while deamination of PEA was little affected at the same doses. On the other hand, safrazine strongly inhibited both 5-HT and PEA deaminations, but showed no selectivity toward the substrate used. The extent of MAO inhibition by RS-8359, measured fluorometrically with kynuramine as a substrate in the brain homogenate, was independent of preincubation up to 80 min. In contrast, the inhibitory potency of safrazine was strengthened by preincubation in a time-dependent manner. Oral administration of RS-8359 (3-30 mg kg-1) caused a dose-dependent increase in endogenous monoamines in mouse brain, which disappeared a few hours after its administration. Increase in monoamine content caused by safrazine lasted for at least 24 h. These results indicate that RS-8359 is a reversible and specific inhibitor of MAO-A, while safrazine is an irreversible and non-specific MAO inhibitor, in-vivo and in-vitro in mouse brain.

A model for the selective mode of action of the irreversible monoamine oxidase inhibitors clorgyline and deprenyl, based on studies of their ability to activate a Ca2+--Mg2+ ATPase in defined lipid environments.

Abstract Clorgyline and deprenyl activated the pure Ca2+-Mg2+ ATPase from rabbit muscle sarcoplasmic reticulum when it was in a defined lipid environment of either dimyristoyl lecithin or dipalmitoyl lecithin, apparently by fluidizing the phospholipid that surrounds the protein (the phospholipid annulus). Activation was only significant at temperatures when the annulus placed rigid constraints upon the protein. There was a two order of magnitude difference in the concentration at which the drugs achieved their effect which is thought to be related to their abilities to perturb the phospholipid annulus since it could not be attributed simply to the small differences in their partition coefficients. Clorgyline, which was more potent than deprenyl at effecting fluidization of the phospholipid annulus of the Ca2+-Mg2+ ATPase in the defined lipid environments, activated species ‘B’ monoamine oxidase at concentrations at which it began to inhibit the species ‘A’ enzyme. Deprenyl did not activate the species ‘A’ enzyme at any concentration tested. It is suggested that, in tissues where there are multiple forms of mitochondrial monoamine oxidase, the selective action of clorgyline and deprenyl arises from a modification of the single inhibitor binding site on a protein species to yield species ‘A’ enzyme and species ‘B’ enzyme. One form of this modification to give the species ‘A’ monoamine oxidase would be a masking of the inhibitor binding site by lipid such that it could be readily penetrated by clorgyline but less readily so by deprenyl. The other form of the modification would yield the species ‘B’ enzyme, which like the ‘chaotrope-treated’ enzyme and presumably ‘nascent’ monoamine oxidase, would expose the inhibitor binding site to the aqueous environment in which deprenyl would be the more efficacious inhibitor.

Rasagiline protects against alpha-synuclein induced sensitivity to oxidative stress in dopaminergic cells

Rasagiline is a propargylamine and irreversible monoamine oxidase (MAO) B inhibitor used for the treatment of Parkinson's disease (PD). It has demonstrated neuroprotective properties in laboratory studies. Current concepts of PD aetiopathogenesis include the role of alpha-synuclein, protein aggregation, free radical metabolism and mitochondrial dysfunction in contributing to cell death. We have used a combination of alpha-synuclein and free radical mediated toxicity in a dopaminergic cell line to provide a model of nigral toxicity in order to investigate the potential molecular mechanisms that mediate rasagiline protection. We demonstrate that rasagiline protects against cell death induced by the combination of free radicals generated by paraquat and either wild-type or A53T mutant alpha-synuclein over-expression. This protection was associated with a reduction in caspase 3 activation, a reduction in superoxide generation and a trend to ameliorate the fall in mitochondrial membrane potential. Rasagiline induced an increase in cellular glutathione levels. The results support a role for rasagiline in protecting dopaminergic cells against free radical mediated damage and apoptosis in the presence of alpha-synuclein over-expression. The data are of relevance to the interpretation of the potential mechanisms of action of rasagiline in explaining the results of disease modification trials in PD.

The role of rasagiline in the treatment of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting 1% to 2% of people older than 60 years. Treatment of PD consists of symptomatic therapies while neuroprotective strategies have remained elusive. Rasagiline is a novel, potent, and irreversible monoamine oxidase type B (MAO-B) inhibitor which has been approved for treatment of PD. Rasagiline inhibits MAO-B more potently than selegiline and has the advantage of once-daily dosing. In several large, randomized, placebo-controlled trials, rasagiline has demonstrated efficacy as monotherapy in early PD and as adjunctive therapy in advanced PD. In addition, rasagiline has been shown to have neuroprotective effects in in vitro and in vivo studies. The recently completed delayed-start ADAGIO (Attenuation of Disease Progression with Azilect Given Once-daily) trial suggests a potential disease-modifying effect for rasagiline 1 mg/day, though the clinical import of this finding has yet to be established.

Current Prescription Patterns and Safety Profile of Irreversible Monoamine Oxidase Inhibitors

To determine the prescription pattern and safety profile for irreversible monoamine oxidase inhibitors (MAOIs) in older adults over the past decade. A population-based observational cohort study of older adults was conducted from January 1, 1997, to April 14, 2007, utilizing large administrative health care databases in Ontario, Canada. We examined the prevalence and incidence of irreversible MAOI use, as well as the frequency of coprescribing of MAOIs with contraindicated medications such as serotonergic and sympathomimetic drugs. We reviewed the most responsible diagnosis of emergency department (ED) visits and acute care admissions to assess for serious adverse events that may occur during MAOI treatment (ie, serotonin syndrome and hypertensive crisis). Over a 10-year period, there were 348 new users of irreversible MAOIs. The majority of patients showed a previous treatment pattern consistent with recurrent major depressive disorder, including prior use of antidepressant treatment and electroconvulsive therapy. The yearly incidence of MAOI prescriptions remained low and decreased from a rate of 3.1/100,000 to 1.4/100,000. Concomitant exposure to at least 1 serotonergic drug occurred in 18.1% of patients treated with an MAOI. No ED visits or acute care admissions for serotonin syndrome or hypertensive crisis were identified. The low prescription rate of MAOIs is not consistent with the continued recommendation of MAOIs by expert opinion leaders and consensus guidelines for use in atypical depression and treatment-refractory depression. While their use appeared safe, heightened awareness of the potential risk of concomitant use of serotonergic agents is necessary. Relative underuse of the MAOIs for a significant subgroup of depressed patients with atypical and treatment-refractory depression remains a concern.

Role of rasagiline in treating Parkinson’s disease: effect on disease progression

Rasagiline is a second generation, selective, irreversible monoamine oxidase type B (MAO-B) inhibitor. It has demonstrated efficacy in monotherapy for early Parkinson's disease (PD) patients in one large randomized, placebo-controlled trial (TVP-1012 in Early Monotherapy for Parkinson's Disease Outpatients), and has shown ability to reduce off time in more advanced PD patients with motor fluctuations in two large placebo-controlled trials (Parkinson's Rasagiline: Efficacy and Safety in the Treatment of "Off", and Lasting Effect in Adjunct Therapy With Rasagiline Given Once Daily). Preclinical data abound to suggest potential for neuroprotection by this compound against a variety of neurotoxic insults in cell cultures and in animals. The lack of amphetamine metabolites provides an advantage over the first generation MAO-B inhibitor selegiline. One large trial has investigated the potential for disease modification in PD patients (Attenuation of Disease progression with Azilect Given Once-daily) and preliminary results maintain some possible advantage to earlier initiation of the 1 mg/day dose. The clinical significance of the difference detected remains a consideration.

Antioxidant and antiapoptotic activities of deprenyl and estradiol co-administration in aged rat kidney

Aging is a progressive degeneration process in living organisms. Deprenyl is an irreversible monoamine-oxidase B inhibitor which has antioxidant, antiapoptotic and neuroprotective effects. Estradiol is also a neuroprotective and antioxidant hormone. The objective of this study was to determine whether the antioxidative effects of deprenyl can suppress apoptotic activity, with or without estradiol, in aged female rat kidney. Wistar Albino female rats were divided into six groups as follows; young (3 months old) control, aged (24 months old) control, aged deprenyl treated, aged estradiol treated, aged deprenyl plus estradiol treated and sham. All rats except for the sham group were injected for 21 days. Determination of oxidative stress parameter was performed spectrophotometrically. To detect apoptotic cells, TUNEL staining and caspase-3 immunohistochemistry were performed. Deprenyl and estradiol administration, alone or in combination, decreased significantly the levels of lipid peroxidation relative to aged control and sham-injected rats. The number of TUNEL positive cells decreased significantly in deprenyl and estradiol-treated rats compared with aged control and sham rats. Deprenyl and estradiol replacement attenuated age-related changes in renal morphology. The results indicate that deprenyl treatment alone, or in combination with estradiol, may modulate age-related apoptotic changes in rat kidney by decreasing oxidative stress.

Inhibition of Monoamine Oxidases Desensitizes 5-HT1AAutoreceptors and Allows Nicotine to Induce a Neurochemical and Behavioral Sensitization

Although nicotine is generally considered to be the main compound responsible for addictive properties of tobacco, experimental data indicate that nicotine does not exhibit all the characteristics of other substances of abuse. We recently showed that a pretreatment with mixed irreversible monoamine oxidases inhibitors (MAOIs), such as tranylcypromine, triggers a locomotor response to nicotine in mice and allows maintenance of behavioral sensitization to nicotine in rats. Moreover, we showed by microdialysis in mice that behavioral sensitization induced by compounds belonging to main groups of drugs of abuse, such as amphetamine, cocaine, morphine, or alcohol, was underlain by sensitization of noradrenergic and serotonergic neurons. Here, this neurochemical sensitization was tested after nicotine, tranylcypromine, or a mixture of both compounds. Data indicate that, whereas neither repeated nicotine nor repeated tranylcypromine alone has any effect by itself, a repeated treatment with a mixture of nicotine and tranylcypromine induces both behavioral sensitization and sensitization of noradrenergic and serotonergic neurons. The development of neurochemical and behavioral sensitizations is blocked by prazosin and SR46349B [(1Z,2E)-1-(2-fluoro-phenyl)-3-(4-hydroxyphenyl)-prop-2-en-one-O-(2-dimethylamino-ethyl)-oxime hemifumarate], two antagonists of alpha1b-adrenergic and 5-HT(2A) receptors, respectively, but not by SCH23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride], a D(1) receptor antagonist. Finally, we found that pretreatments with WAY 100635 [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclo-hexane carboxamide trihydrochloride], a 5-HT(1A) receptor antagonist, can also induce a behavioral and neurochemical sensitization to repeated nicotine. Complementary experiments with 8-OHDPAT (8-hydroxy-dipropylamino-tetralin), a 5-HT(1A) receptor agonist, and analysis of 5-HT(1A) receptors expression in the dorsal raphe nucleus after a tranylcypromine injection indicate that MAOIs contained in tobacco desensitize 5-HT(1A) autoreceptors to trigger the strong addictive properties of tobacco.

Recent Advances in Understanding and Treating Social Anxiety Disorder

The common occurrence and high level of morbidity and burden associated with social anxiety disorder (SAD) are gaining widespread recognition. Interest in understanding and treating the disorder has also grown in response to large-scale investigations that have demonstrated high levels of efficacy with both pharmacologic and nonpharmacologic treatments. Such trials indicate that many patients with generalized SAD (roughly 40% to 60%) respond (eg, Clinical Global Impressions-Improvement rating 1 or 2) after an adequate treatment trial, despite having suffered with disabling symptoms for most of their adult lives. First-line therapy options include the selective serotonin reuptake inhibitors and the dual-acting serotonin-norepinephrine reuptake inhibitor venlafaxine. Second-line options consist of anticonvulsants (gabapentin, pregabalin, valproic acid) and benzodiazepines (clonazepam). Reversible and irreversible monoamine oxidase inhibitors (moclobemide and phenelzine, respectively), while effective, are not widely used. Nonpharmacologic approaches, such as cognitive-behavioral therapy (CBT), are also effective for SAD. Newer treatment strategies such as levetiracetam, atypical antipsychotics, or D-cycloserine in combination with CBT appear promising but require further investigation. Finding a well-tolerated, safe, and effective treatment for each individual patient is crucial as most will require ongoing treatment in order to maintain benefits, prevent SAD relapse, and to experience optimal outcomes in the long term.

Safety of High-intensity Treatment with the Irreversible Monoamine Oxidase Inhibitor Tranylcypromine in Patients with Treatment-resistant Depression

Because the irreversible monoamine oxidase inhibitor tranylcypromine (TCP) was introduced nearly 50 years ago, only few studies exist on today's clinical prescribing practice together with 2nd and 3rd generation psychotropic drugs. We performed a practice-based observational study of patients with depression treated with TCP in two psychiatric departments in Berlin to assess side effects, effectiveness, comedication and acceptance of the low-tyramine diet. We identified thirty-two patients treated with TCP at a mean dose of 51.9 mg/day after an average of 3.3 pre-treatments in the current episode. Dosing of TCP and the use of multiple psychotropic comedications indicate a high-intensity treatment. The most frequent side effects resulted from arterial hypotonia (28%). Dietary restrictions were mainly rated as moderate. 59% of patients remitted (HAMD- (21)<9 or CGI-I=1) and 22% responded (HAMD- (21) reduction >50% or CGI-I=2). A high-intensity treatment of inpatients with TCP is clinically feasible, i.e., the use of high doses and multiple comedications with a good benefit-risk-ratio. Prospective data aiming at comparisons with modern antidepressants and clarifying further safety issues are warranted.

MAO-B Inhibition by a Single Dose of l-Deprenyl or Lazabemide Does Not Prevent Neuronal Damage Following Focal Cerebral Ischaemia in Rats

The present study investigated the effect of postischaemic infusion of an irreversible monoamine oxidase B (MAO-B) inhibitor, l-deprenyl, an equipotent dose of a reversible MAO-B inhibitor, lazabemide, or 0.9% NaCl on infarct volumes following focal cerebral ischaemia in rats. The drug doses (0.3 mg/kg) were selected to induce selective MAO-B inhibition (45–55%), but not MAO-A inhibition. The infarct volumes in the cortex or in the striatum did not differ between the experimental groups 72 hr after transient occlusion of the middle cerebral artery, which suggests that during ischaemia/reperfusion, suppressed oxidative stress by partial MAO-B inhibition or MAO-B independent mechanisms such as induction of trophic factors, does not protect against ischaemia/reperfusion damage.

Selegilin Exerts Antidepressant-Like Effects During the Forced Swim Test in Adrenocorticotropic Hormone–Treated Rats

In the present study, we investigated the effect of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test after the administration of selegiline, a selective and irreversible monoamine oxidase (MAO)-B inhibitor. Single and repeated administration of selegiline significantly decreased the duration of immobility in normal rats. When selegiline was administered for 15 days, we observed a significant decrease in immobility in rats treated with ACTH for 14 days. The immobility-decreasing effect of selegiline was blocked by nafadotride, a selective dopamine D3–receptor antagonist in normal and ACTH-treated rats. Selegiline may be useful in an animal model of depressive conditions resistant to tricyclic antidepressant treatment via the dopamine D3receptor.

Rasagiline improves freezing in a patient with primary progressive freezing gait

We herein report the case of a 84-year-old man with a 4-year history of freezing of gait (FOG) consistent with the diagnosis of primary progressive freezing gait. Single photon emission tomography (SPECT) with a radiolabeled ligand of the dopamine transporter (DAT-SPECT) showed integrity of striatal dopaminergic terminals, whereas brain perfusion SPECT disclosed multiple areas of decreased perfusion in frontal and parietal lobes, as well as in the subcortical gray nuclei of both sides. Treatment with the new irreversible monoamine oxidase B inhibitor rasagiline at standard doses resulted in a rapid, dramatic, and sustained improvement of the frequency and duration of FOG episodes. In addition, brain perfusion SPECT after treatment showed a marked increase of the activity in all cortical areas as well as in the basal ganglia and thalamus. Rasagiline may prove to be an effective and safe treatment for this disabling condition.

Selegiline transdermal system in the treatment of depressive disorders

Selegiline is a selective irreversible inhibitor of monoamine oxidase (MAO)-B during low-dose oral treatment. Additional MAO-A inhibition occurs in higher dose ranges. Selegiline transdermal system (STS) shows a more potent MAO inhibition in comparison with orally administered selegiline, and at minimum doses of 20 mg/20 cm2 patch delivering 6 mg/24 h, no dietary restrictions, including low-tyramine food, are necessary. While oral selegiline has been used for years in the treatment of Parkinson’s disease, the US FDA recently approved the STS for use in treating major depression. Data from three randomized controlled trials showed a significantly better efficacy of STS in the treatment of unipolar major depression in comparison with placebo during 6–8 weeks of treatment. In addition, one long-term randomized controlled trial demonstrated the efficacy of the STS in relapse prevention of unipolar depression over 1 year. A total number of 515 depressed patients received STS during these studies. The tolerability profile of STS without dietary restrictions was excellent. The only side effects that were more frequent than with placebo were application-site reactions. No change in vital parameters and no hypertensive crisis have been recorded. Comparative studies including treatment with established antidepressants and the investigation of bipolar depressed patients and of specific patient subgroups (e.g., anergic and atypical depression) have to follow. The combination of the well-known effectiveness of irreversible MAO inhibitors with a good tolerability profile and a new pharmaceutical form, possibly enhancing compliance, represents a promising further expansion of the pharmacotherapeutic repertoire in the treatment of depression.

Suppression of apoptosis and oxidative stress by deprenyl and estradiol in aged rat liver

Aging is accompanied by significant structural and functional transformations of all organs and systems. Age-associated increase in apoptotic behavior may cause disease. Older cells are more susceptible to endogenous oxidative damage, and oxidative stress is a potent inducer of apoptosis. Deprenyl is an irreversible monoamine-oxidase B inhibitor which has anti-oxidant, anti-apoptotic and neuroprotective effects. Estrogen is also a neuroprotective and anti-oxidant hormone. The objectives of this study were to determine whether the anti-oxidative effects of deprenyl can suppress apoptotic activity, with or without estradiol, in aged female rat livers. In this study, ovariectomized female Wistar albino rats were divided into six groups as follows; young (3 months old) saline-treated control, aged (24 months old) saline-treated control, aged deprenyl treated, aged estradiol treated, aged deprenyl plus estradiol treated and aged sham controls. All rats except for the sham group were treated for 21 days. Determination of oxidative stress parameters was performed spectrophotometrically. To detect apoptotic cells, TUNEL staining was performed. The results were analyzed by one-way ANOVA post hoc Bonferroni test. Deprenyl and estradiol administration, alone or in combination, decreased significantly the levels of lipid peroxidation and increased superoxide dismutase activity in the liver relative to aged control and sham rats (P<0.05). The number of TUNEL positive cells decreased significantly in deprenyl and estradiol-treated rats compared with aged control and sham rats. The results indicate that deprenyl treatment alone, or in combination with estradiol, may modulate age-related apoptotic changes in rat liver by decreasing oxidative stress.

Involvement of brain serotonin 5-HT1A receptors in genetic predisposition to aggressive behavior

Experiments were performed on Norwegian rats selected over more than 59 generations for high and low levels of high-affective defensive aggressivity and on highly aggressive (offensive) Tg8 mice with irreversible monoamine oxidase A knockout. There were significant differences in the functional state and expression of 5-HT(1A) receptors between highly aggressive and non-aggressive animals. Functional activity assessed in terms of hypothermia evoked by a 5-HT(1A) agonist was significantly greater in non-aggressive rats and mice than in aggressive animals. The high level of functional activity in non-aggressive rats coincided with a greater level of expression of 5-HT(1A) receptors in the midbrain. The level of 5-HT(1A) receptor mRNA in aggressive mice was unchanged in the midbrain and hypothalamus and was increased in the frontal cortex and amygdaloid complex. These results led to the conclusion that 5-HT(1A) receptors play a significant role in the mechanisms of genetic predisposition to aggressive behavior.

Aminoindan and hydroxyaminoindan, metabolites of rasagiline and ladostigil, respectively, exert neuroprotective properties in vitro

The anti-Parkinson, selective irreversible monoamine oxidase B inhibitor drug, rasagiline (Azilect), recently approved by the US Food and Drug Administration, has been shown to possess neuroprotective-neurorescue activities in in vitro and in vivo models. Recent preliminary studies indicated the potential neuroprotective effect of the major metabolite of rasagiline, 1-(R)-aminoindan. In the current study, the neuroprotective properties of 1-(R)-aminoindan were assessed employing a cytotoxic model of human neuroblastoma SK-N-SH cells in high-density culture-induced neuronal death. We show that aminoindan (0.1-1 mumol/L) significantly reduced the apoptosis-associated phosphorylated protein, H2A.X (Ser139), decreased the cleavage of caspase 9 and caspase 3, while increasing the anti-apoptotic proteins, Bcl-2 and Bcl-xl. Protein kinase C (PKC) inhibitor, GF109203X, prevented the neuroprotection, indicating the involvement of PKC in aminoindan-induced cell survival. Aminoindan markedly elevated pPKC(pan) and specifically that of the pro-survival PKC isoform, PKCepsilon. Additionally, hydroxyaminoindan, a metabolite of a novel bifunctional drug, ladostigil [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate], combining cholinesterase and monoamine oxidase inhibitor activity, exerted similar neuroprotective properties. Aminoindan and hydroxyaminoindan also protected rat pheochromacytoma PC-12 cells against the neurotoxin, 6-hydroxydopamine. Our findings suggest that both metabolites may contribute to the overall neuroprotective activity of their respective parent compounds, further implicating rasagiline and ladostigil as potentially valuable drugs for treatment of a wide variety of neurodegenerative disorders of aging.

Effects of co-administration of antidepressants and monoamine oxidase inhibitors on 5-HT-related behavior in rats

5-hydroxytryptamine (5-HT) syndrome is a dangerous condition of 5-HT excess that can occur during co-administration of a monoamine oxidase (MAO) inhibitor and an antidepressant. We investigated the effects of acute administration of MAO inhibitors and subchronic administration of tricyclic and heterocyclic antidepressants, and a serotonin-noradrenaline reuptake inhibitor (SNRI) on 5-HT syndrome in rats treated with 5-hydroxytryptophan (5-HTP). The irreversible and non-selective MAO inhibitor pargyline, and the reversible and selective MAO-A inhibitor clorgyline, produced increases in 5-HT syndrome in the 5-HTP-treated rats, while subchronic co-administration of imipramine partly intensified and partly attenuated the syndrome, whereas milnacipran only attenuated the syndrome. Co-administration of mianserin partly intensified and partly attenuated the syndrome but the attenuating effect was dominant. Administration of the irreversible and selective MAO-B inhibitor selegiline did not produce any increase in 5-HT syndrome in the 5-HTP-treated rats, compared with the saline control. These data suggest that non-selective MAO and selective MAO-A inhibitors can induce 5-HT syndrome in humans when co-administered with antidepressants. Furthermore, the risk of 5-HT syndrome may be lower with the selective MAO-B inhibitor selegiline.

Tranylcypromine enhancement of nicotine self-administration

Tobacco use has one of the highest rates of addiction of any abused drug. Paradoxically, in animal models, nicotine appears to be a weak reinforcer. We report here that the inhibition of monoamine oxidase (MAO), a major effect of tobacco smoke, increases the reinforcing effect of nicotine. Rats (aged postnatal day 27 and 90) were tested for self-administration, without prior response training, in five daily 3-h sessions. Whereas control rats did not self-administer nicotine, low doses of nicotine (2.5 to 21 μg/kg/injection) were avidly self-administered following a pretreatment with tranylcypromine (3 mg/kg), an irreversible and non-selective MAO inhibitor. Tranylcypromine-enhanced nicotine (10 μg/kg/injection, i.v.) self-administration was reduced by systemic injection of a D1-dopaminergic receptor antagonist, SCH23390 (0.02 mg/kg). Moreover, an increase in extracellular dopamine in the nucleus accumbens was detected, using microdialysis, following nicotine (60 μg/kg) injection in tranylcypromine pre-treated rats. Depending on the time of tranylcypromine pretreatment (20 or 1 h), MAO activity was decreased by 72% and 99% and nicotine intake at day 5 was increased by 619 and 997%, respectively. Taken together, these results indicate that in a stringent self-administration acquisition test, MAO inhibition increases the rewarding effect of low doses of nicotine, possibly via a dopamine-dependent mechanism.

Irreversible blockade of monoamine oxidases reveals the critical role of 5‐HT transmission in locomotor response induced by nicotine in mice

Although nicotine is generally considered as the main compound responsible for addictive properties of tobacco, some experimental data indicate that nicotine does not exhibit all the characteristics of other substances of misuse such as psychostimulants and opiates. For example, nicotine generally fails to induce locomotor response in mice and self-administration of nicotine is difficult to obtain in rats. We have shown recently that a pretreatment with mixed irreversible monoamine oxidase inhibitors (MAOIs), such as tranylcypromine, triggers a locomotor response to nicotine in mice and induces a robust self-administration of nicotine in rats. We show here that when mice were pretreated with enhancers of extracellular levels of noradrenaline, dopamine or serotonin (D-amphetamine, GBR12783 or para-chloro-amphetamine, respectively) and injected with nicotine (1 mg/kg), only those animals pretreated with para-chloro-amphetamine exhibited a specific locomotor response to nicotine. These data indicate a critical role of serotonin in nicotine-induced locomotor activity in mice. This was further confirmed in microdialysis experiments showing that nicotine induces an increase in extracellular serotonin levels in the ventral striatum in mice pretreated with tranylcypromine. This effect of nicotine on extracellular serotonin levels was absent in mice lacking the beta2-subunit of the nicotinic acetylcholine receptor. Our data suggest that mixed irreversible MAOIs contained in tobacco facilitate the effects of nicotine on serotonin release, thus allowing the locomotor and rewarding effects of nicotine.