60 Years of Combining Tranylcypromine: A Systematic Review of Available Evidence.

BACKGROUND: Tranylcypromine is the only irreversible monoamine oxidase inhibitor that is approved in the United States and in Europe for the management of treatment-resistant major depressive disorder. Comprehensive data in the literature regarding the efficacy and tolerability of tranylcypromine (TCP) combination strategies have not been systematically investigated yet. METHODS: We conducted a systematic review of available literature based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Study types considered eligible for inclusion were studies that reported information on efficacy and/or tolerability/adverse effects of pharmacological TCP add-on or coadministration strategies among people with psychiatric disorders. RESULTS: Ninety-six articles were included in qualitative analyses. A relevant body of evidence shows that TCP combined with first- and second-generation antipsychotics seems relatively safe and might have beneficial effects in some patients with depressive disorders, although caution is needed with some second-generation antipsychotics that have proserotonergic activity. Although evidence is not entirely consistent, amitriptyline as add-on agent might be efficacious and associated with a low rate of severe adverse events. Although available data from case reports are scarce, certain other agents, such as trazodone, but also lithium, seem to have a good risk-benefit profile with regard to TCP that should be further investigated in the context of high-quality studies. CONCLUSIONS: Any combination of a psychotropic with TCP should be preceded by an evaluation of drug-to-drug interaction and an informed consent process and followed by close monitoring. Before any combination strategy, doctors should reevaluate factors of pseudo-treatment resistance, such as rapid-metabolizing status, noncompliance, trauma, alternative diagnosis, or drug abuse.

Cardiovascular Effects of Combining Subcutaneous or Intravenous Esketamine and the MAO Inhibitor Tranylcypromine for the Treatment of Depression: A Retrospective Cohort Study.

BACKGROUND: (Es)ketamine and monoamine oxidase inhibitors (MAOIs), e.g., tranylcypromine, are therapeutic options for treatment-resistant major depression. Simultaneous administration is currently not recommended because of concern about hypertensive crises. OBJECTIVE: Our objective was to evaluate whether changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) during esketamine administration differed between patients who concomitantly received tranylcypromine and those who did not. METHODS: This was a retrospective cohort study utilizing cardiovascular monitoring data from inpatients treated for severe depression in unipolar, bipolar, and schizoaffective disorder. Primary outcomes were change in mean BP and HR during the first hour after intravenous or subcutaneous esketamine administration compared with baseline, controlled for confounders. Secondary analyses quantify differences in absolute BP during esketamine treatment and comparisons of BP peaks, temporal effects, and intraindividual comparisons before and after tranylcypromine initiation. RESULTS: Our analysis included 509 esketamine administrations in 43 patients, 14 of whom concomitantly received tranylcypromine. Controlling for creatinine and age, mean ± standard deviation (SD) BP changes were significantly increased by concomitant tranylcypromine treatment (ΔSBP: F[1,503] = 86.73, p < 0.001; ΔDBP: F[1,503] = 55.71, p < 0.001), but HR remained unaffected. Mean SBP change during esketamine administration was 2.96 ± 18.11 mmHg in patients receiving tranylcypromine (TCP+) and -8.84 ± 11.31 mmHg in those who did not (TCP-). Changes in DBP were -2.81 ± 11.20 mmHg for TCP+ and -10.77 ± 9.13 mmHg for TCP-. Moreover, we found a significant dose-response relationship between tranylcypromine dose and BP (SBP: B = 0.35, standard error [SE] = 0.12, 95% confidence interval [CI] 0.12-0.60, p = 0.004; adjusted R2 = 0.11, p = 0.008; DBP: B = 0.21, SE = 0.08, 95% CI 0.06-0.36, p = 0.007; adjusted R2 = 0.08; p = 0.023). CONCLUSIONS: Although statistically significant changes in BP were identified in patients receiving tranylcypromine and esketamine, these changes were clinically insignificant. Thus, combining esketamine and this MAOI appears to be safe at standard doses. The dose-response relationship calls for caution with higher doses of tranylcypromine.

Clinical Responsiveness to All-trans Retinoic Acid Is Potentiated by LSD1 Inhibition and Associated with a Quiescent Transcriptome in Myeloid Malignancies.

PURPOSE: In preclinical studies, the lysine-specific histone demethylase 1A (LSD1) inhibitor tranylcypromine (TCP) combined with all-trans retinoic acid (ATRA) induces differentiation and impairs survival of myeloid blasts in non-acute promyelocytic leukemia acute myeloid leukemia (AML). We conducted a phase I clinical trial (NCT02273102) to evaluate the safety and activity of ATRA plus TCP in patients with relapsed/refractory AML and myelodysplasia (MDS). PATIENTS AND METHODS: Seventeen patients were treated with ATRA and TCP (three dose levels: 10 mg twice daily, 20 mg twice daily, and 30 mg twice daily). RESULTS: ATRA-TCP had an acceptable safety profile. The MTD of TCP was 20 mg twice daily. Best responses included one morphologic leukemia-free state, one marrow complete remission with hematologic improvement, two stable disease with hematologic improvement, and two stable disease. By intention to treat, the overall response rate was 23.5% and clinical benefit rate was 35.3%. Gene expression profiling of patient blasts showed that responding patients had a more quiescent CD34+ cell phenotype at baseline, including decreased MYC and RARA expression, compared with nonresponders that exhibited a more proliferative CD34+ phenotype, with gene expression enrichment for cell growth signaling. Upon ATRA-TCP treatment, we observed significant induction of retinoic acid-target genes in responders but not nonresponders. We corroborated this in AML cell lines, showing that ATRA-TCP synergistically increased differentiation capacity and cell death by regulating the expression of key gene sets that segregate patients by their clinical response. CONCLUSIONS: These data indicate that LSD1 inhibition sensitizes AML cells to ATRA and may restore ATRA responsiveness in subsets of patients with MDS and AML.

Suppression of LSD1 enhances the cytotoxic and apoptotic effects of regorafenib in hepatocellular carcinoma cells.

Regorafenib has been approved to treat patients who have HCC progression after sorafenib failure, however, regorafenib also faces the risk of drug resistance and subsequent progression of HCC patients. As LSD1 inhibitors can alleviate acquired resistance to sorafenib, in this context, we are interested to investigate the role of LSD1 in regorafenib treatment. Firstly, over-expressed LSD1 was observed in HCC patients and predicted poor prognosis. However, regorafenib failed to suppress the expression of LSD1 in HCC cells. Thus, we hypothesized that LSD1 inhibition could enhance the anti-HCC activity of regorafenib. As expected, LSD1 knockdown could enhance anti-proliferation effect of regorafenib in HCC cells. LSD1 inhibitor SP2509 could enhance the cytotoxic and apoptotic effects of regorafenib in HCC cells. In addition, clinically used LSD1 inhibitor tranylcypromine also enhanced anti-HCC effect of regorafenib. Furthermore, LSD1 suppressed by SP2590 or tranylcypromine could alleviate the activated p-AKT (ser473) induced by regorafenib in HCC cells. Thus, inhibiting LSD1 might be an attractive target for regorafenib sensitization and clinical HCC therapy, our findings could help to elucidate more effective therapeutic options for HCC patients.

Combined Applications of Repurposed Drugs and Their Detrimental Effects on Glioblastoma Cells.

BACKGROUND/AIM: Glioblastoma multiforme (GBM) is a malignant primary brain tumor with high rates of recurrence. This study aimed to investigate the effect of repurposed drug combinations on GBM. MATERIALS AND METHODS: Viability of U87 MG and 11ST patient-derived GMB cell lines, after valproic acid, tranylcypromine or riluzole alone, in different combinations, as well as combined with standard temozolomide chemotherapy was examined using the MTT assay. Proliferation, mRNA level of tissue factor pathway inhibitor 2 (TFPI2), and cell invasion were evaluated using anti-Ki-67 antibody staining, reverse transcriptase-polymerase chain reaction and xCELLigence system. RESULTS: The strongest effect on cell viability was achieved by the combination of riluzole with valproic acid (U87MG: 27.2%, 11ST: 25.99%). Tranylcypromine significantly enhanced the effect of temozolomide when used in combination, as did valproic acid. The normally high proliferation of GBM significantly declined under treatment with valproic acid with tranylcypromine (p=0.01). Finally, we observed reduction of invasion comparing single tranylcypromine to its combination with valproic acid or riluzole. CONCLUSION: These results support the idea that combinations of drugs could increase the treatment efficiency of GBM.

Tranylcypromine Plus Amitriptyline for Electroconvulsive Therapy-Resistant Depression: A Long-Term Study.

BACKGROUND: Few therapeutic options are available for patients with electroconvulsive therapy-resistant major depressive disorder (ECT-r MDD), leaving a substantial proportion of this population beyond treatment possibilities. The combination of monoamine oxidase inhibitors and tricyclic antidepressants could be a potential strategy for managing ECT-r MDD, and the specific association of amitriptyline and tranylcypromine may offer additional tolerability advantages. Although promising, in our knowledge, no studies have examined until now the effectiveness of this combination in ECT-r MDD. METHODS: We report a retrospective cohort of 31 patients with ECT-r MDD treated in an open-label fashion with the combination of amitriptyline and tranylcypromine. RESULTS: Overall, 80.6% of the sample met response criteria at the end of the first 12 weeks of treatment. Seventy-six percent (19 of 25) of the responders were followed for a mean of 9.37 ± 3.86 years. During this follow-up period, none of the patients had a recurring depressive episode. The combination was well tolerated, whereas minor adverse effects were common, and no severe or life-threatening events were reported throughout the study. CONCLUSIONS: These findings indicate that the combination tranylcypromine and amitriptyline is a potentially safe and effective candidate for future investigation in the treatment and long-term maintenance of ECT-r MDD.

Effects of Monoamine Oxidase Inhibition on the Reinforcing Properties of Low-Dose Nicotine.

The Food and Drug Administration (FDA) has the authority to regulate cigarette smoke constituents, and a reduction in nicotine content might benefit public health by reducing the prevalence of smoking. Research suggests that cigarette smoke constituents that inhibit monoamine oxidase (MAO) may increase the reinforcing value of low doses of nicotine. The aim of the present experiments was to further characterize the impact of MAO inhibition on the primary reinforcing and reinforcement enhancing effects of nicotine in rats. In a series of experiments, rats responded for intravenous nicotine infusions or a moderately-reinforcing visual stimulus in daily 1-h sessions. Rats received pre-session injections of known MAO inhibitors. The results show that (1) tranylcypromine (TCP), a known MAO inhibitor, increases sensitivity to the primary reinforcing effects of nicotine, shifting the dose-response curve for nicotine to the left, (2) inhibition of MAO-A, but not MAO-B, increases low-dose nicotine self-administration, (3) partial MAO-A inhibition, to the degree observed in chronic cigarette smokers, also increases low-dose nicotine self-administration, and (4) TCP decreases the threshold nicotine dose required for reinforcement enhancement. The results of the present experiments suggest cigarette smoke constituents that inhibit MAO-A, in the range seen in chronic smokers, are likely to increase the primary reinforcing and reinforcement enhancing effects of low doses of nicotine. If the FDA reduces the nicotine content of cigarettes, then variability in constituents that inhibit MAO-A could impact smoking.

Discovery of a Novel Inhibitor of Histone Lysine-Specific Demethylase 1A (KDM1A/LSD1) as Orally Active Antitumor Agent.

We report the stereoselective synthesis and biological activity of a novel series of tranylcypromine (TCPA) derivatives (14a-k, 15, 16), potent inhibitors of KDM1A. The new compounds strongly inhibit the clonogenic potential of acute leukemia cell lines. In particular three molecules (14d, 14e, and 14g) showing selectivity versus MAO A and remarkably inhibiting colony formation in THP-1 human leukemia cells, were assessed in mouse for their preliminary pharmacokinetic. 14d and 14e were further tested in vivo in a murine acute promyelocytic leukemia model, resulting 14d the most effective. Its two enantiomers were synthesized: the (1S,2R) enantiomer 15 showed higher activity than its (1R,2S) analogue 16, in both biochemical and cellular assays. Compound 15 exhibited in vivo efficacy after oral administration, determining a 62% increased survival in mouse leukemia model with evidence of KDM1A inhibition. The biological profile of compound 15 supports its further investigation as a cancer therapeutic.

Combination of intravenous S-ketamine and oral tranylcypromine in treatment-resistant depression: A report of two cases.

Ketamine, a rapid-acting antidepressant and anti-suicidal agent, is thought to increase brain monoamine levels by enhancing monoamine release or inhibiting presynaptic monoamine-reuptake. Here we present two female inpatients suffering from treatment-resistant depression with recurrent severe suicidal crises receiving a combination of intravenous S-ketamine and oral tranylcypromine, which is a well-known irreversible monoamine oxidase (MAO) inhibitor. Since inhibition of monoamine-reuptake with concurrent blockade of MAO might trigger sympathomimetic crisis, this combination is considered hazardous. Nonetheless, cardiovascular parameters remained stable in both patients, while good anti-suicidal effects were observed. Hence, we put serious doubt on whether monoamine-reuptake inhibition is a relevant pharmacological effect of ketamine in humans.

Preclinical activity of combined HDAC and KDM1A inhibition in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most common and aggressive form of brain cancer. Our previous studies demonstrated that combined inhibition of HDAC and KDM1A increases apoptotic cell death in vitro. However, whether this combination also increases death of the glioma stem cell (GSC) population or has an effect in vivo is yet to be determined. Therefore, we evaluated the translational potential of combined HDAC and KDM1A inhibition on patient-derived GSCs and xenograft GBM mouse models. We also investigated the changes in transcriptional programing induced by the combination in an effort to understand the induced molecular mechanisms of GBM cell death. METHODS: Patient-derived GSCs were treated with the combination of vorinostat, a pan-HDAC inhibitor, and tranylcypromine, a KDM1A inhibitor, and viability was measured. To characterize transcriptional profiles associated with cell death, we used RNA-Seq and validated gene changes by RT-qPCR and protein expression via Western blot. Apoptosis was measured using DNA fragmentation assays. Orthotopic xenograft studies were conducted to evaluate the effects of the combination on tumorigenesis and to validate gene changes in vivo. RESULTS: The combination of vorinostat and tranylcypromine reduced GSC viability and displayed efficacy in the U87 xenograft model. Additionally, the combination led to changes in apoptosis-related genes, particularly TP53 and TP73 in vitro and in vivo. CONCLUSIONS: These data support targeting HDACs and KDM1A in combination as a strategy for GBM and identifies TP53 and TP73 as being altered in response to treatment.

How treatable is refractory depression?

INTRODUCTION: Patients who do not remit following one or more attempts at treatment present a clinical challenge, as well as prolonged suffering and disability. Discouragement is common, so knowledge of likelihood of eventual remission as well as which treatments might ultimately be effective would help patient and clinician alike. METHOD: Thirty-one patients with major depression were recruited, 28 beginning study treatment. All had remained significantly depressed following adequate (4 weeks taking ≥ PDR maximum dose) trials on ≥ two antidepressants having different presumed mechanisms. Patients were begun on tranylcypromine to 60 mg/d, were then treated with up to 120 mg/d and then had dextroamphetamine added. Following two week wash-out, patients were then treated with nortriptyline+lithium, and then phenelzine was added. Each successive phase was entered only if remission had not been achieved, and phases could be skipped. RESULTS: Eighteen of the 28 patients (65%) remitted in one of the five phases of the study, plus 5 additional patients with open post-study treatment (total remitting, 82%). By study phase, Eight of 27 (30%) patients remitted with initial dosing of tranylcypromine up to 60 mg/d, 6/18 (33%) remitted with above PDR dosing of tranylcypromine up to 120 mg/d, and 1/6 (17%) to adding dextroamphetamine. With nortriptyline, 1/10 (10%) remitted with nortriptyline+lithium, and 1/5 (20%) when phenelzine was added. Eighteen of the 28 patients (64%), or 78% of those who remitted, maintained their good benefit for at least six months. DISCUSSION: The majority of depressed patients refractory to two or more adequately utilized differently acting antidepressant medications can still remit and about half may maintain remission for extended periods. "Refractory depression" appears to be a relative description for many unresponsive depressed patients.

The effects of chronic administration of tranylcypromine and rimonabant on behaviour and protein expression in brain regions of the rat.

Recent findings indicate that CB1 receptor blockade might be relevant to the action of antidepressant drugs as inhibition of endocannabinoid function can increase synaptic availability of neurotransmitters; an effect also seen with chronic antidepressant drug treatment. Chronic treatments with established antidepressants also lead to raised brain BDNF levels. The aim of this study was to compare the effects of rimonabant (an inverse agonist/antagonist of CB1 receptors) with those of the antidepressant tranylcypromine (TCP), on behaviour and expression of BDNF/CREB signalling pathways in rat brain. Daily (i.p.) injections of vehicle or TCP (10 mg/kg) or rimonabant (2 mg/kg) were given for 14 days. Locomotor activity (LMA) and a conditional emotional response (CER) were measured in addition to levels of BDNF and CREB/phospho-CREB, using immunoblotting, in the frontal cortex, hippocampus, striatum and cerebellum. The velocity of movement was increased significantly on the 3rd, but not 9th, day of TCP treatment versus vehicle-treated rats (p<0.05) while rimonabant had no effect. There were no significant changes in grooming or freezing behaviours after rimonabant or TCP compared to vehicle-treated rats. Rearing was significantly reduced by TCP treatment on the 3rd, but not 9th, day of treatment (p<0.001) while rimonabant had no effect. BDNF levels were significantly increased in the frontal cortex after TCP (p<0.05) but not by rimonabant. Neither TCP nor rimonabant significantly affected CREB or p-CREB expression. In conclusion, chronic administration of TCP to rats increased BDNF expression in the frontal cortex but no similar effect was observed with rimonabant indicating that rimonabant does not show antidepressant drug-like responses after chronic treatment.

Safety of high-intensity treatment with the irreversible monoamine oxidase inhibitor tranylcypromine in patients with treatment-resistant depression.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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). DISCUSSION: 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.

The guinea pig forced swim test as a new behavioral despair model to characterize potential antidepressants.

RATIONALE: Behavioral despair is a model of high predictivity for antidepressant activity in murids. For some drug targets, guinea pigs exhibit a higher homology to their human counterparts compared to murids. OBJECTIVES: In this paper, we established a model of behavioral despair namely, the forced swim test (FST) in guinea pigs. MATERIALS AND METHODS: Male guinea pigs underwent the FST similar to rats. Animals received intraperitoneal injections of either vehicle or drugs 24, 4, and 0.5 h before testing. We tested the tricyclic antidepressants desipramine and amitriptyline, the monoamine oxidase inhibitor tranylcypromine, the selective serotonin reuptake inhibitors fluoxetine and paroxetine, and the neurokinin 1 (NK(1)) receptor antagonist, L-733,060, and for comparison the antipsychotic clozapine and the stimulant methamphetamine. RESULTS: Desipramine (> or =3 mg/kg) and amitriptyline (>10 mg/kg) increased the latency to immobility (LTI) to greater than 230 s, and tranylcypromine (10 mg/kg) it to greater than 190 s. Paroxetine (>0.3 mg/kg) and fluoxetine (>10 mg/kg) also increased LTI significantly but only to greater than 120 s. Methamphetamine (3 mg/kg) completely eliminated immobility, whereas clozapine (5-20 mg/kg) had no effect. L-733,060 (10 mg/kg) increased LTI to 270 s. Doses producing significant effects in FST were investigated in the open field. Antidepressants did not affect locomotion, whereas methamphetamine induced hyperlocomotion. CONCLUSIONS: We demonstrate the suitability of a modified procedure of the FST for a nonmurid species: the guinea pig. Known antidepressants showed similar effects as in rats and mice. It is interesting to note that the NK(1) antagonist L-733,060 increased forced swimming, suggesting its antidepressant potential. Thus, the guinea pig FST allows the study of antidepressant activity also in NK(1) antagonists that cannot be studied appropriately in murids.

Reduced evoked fos expression in activity-related brain regions in animal models of behavioral depression.

A previous study showed that two mouse models of behavioral depression, immune system activation and depletion of brain monoamines, are accompanied by marked reductions in stimulated neural activity in brain regions involved in motivated behavior. The present study tested whether this effect is common to other depression models by examining the effects of repeated forced swimming, chronic subordination stress or acute intraventricular galanin injection - three additional models - on baseline or stimulated c-fos expression in several brain regions known to be involved in motor or motivational processes (secondary motor, M2, anterior piriform cortex, APIR, posterior cingulate gyrus, CG, nucleus accumbens, NAC). Each of the depression models was found to reduce the fos response stimulated by exposure to a novel cage or a swim stress in all four of these brain areas but not to affect the response of a stress-sensitive region (paraventricular hypothalamus, PVH) that was included for control purposes. Baseline fos expression in these structures was either unaffected or affected in an opposite direction to the stimulated response. Pretreatment with either desmethylimipramine (DMI) or tranylcypromine (tranyl) attenuated these changes. It is concluded that the pattern of a reduced neural function of CNS motor/motivational regions with an increased function of stress areas is common to 5 models of behavioral depression in the mouse and is a potential experimental analog of the neural activity changes occurring in the clinical condition.

Tyramine pressor sensitivity during treatment with the selegiline transdermal system 6 mg/24 h in healthy subjects.

The oral tyramine pressor test was administered to healthy males during treatment with a selegiline transdermal system (STS; 6 mg/24 h). The tyramine sensitivity factor (TSF) was calculated from the ratio of baseline and on-treatment tyramine pressor doses. The tyramine sensitivity factor value following 9 days of treatment with the selegiline transdermal system was 1.85 +/- 0.10. Extended treatment, 33 days, produced a small, clinically non-meaningful increase in this value. The tyramine sensitivity factor for the selegiline transdermal system was similar to that following treatment with 10 mg/d of oral selegiline capsules but more than 20 times less than observed during tranylcypromine treatment. A larger increase in the tyramine sensitivity factor was observed following extended selegiline transdermal system treatment at a higher dose (12 mg/24 h), which was significantly decreased following coadministration of tyramine capsules with a meal. These results suggest a wide tyramine safety margin for the selegiline transdermal system and provide evidence that the 6-mg/24-h selegiline transdermal system can be administered safely without dietary tyramine restrictions.

The neurochemical and behavioral effects of the novel cholinesterase-monoamine oxidase inhibitor, ladostigil, in response to L-dopa and L-tryptophan, in rats.

The novel drugs, ladostigil (TV3326) and TV3279, are R and S isomers, respectively, derived from a combination of the carbamate cholinesterase (ChE) inhibitor, rivastigmine, and the pharmacophore of the monoamine oxidase (MAO) B inhibitor, rasagiline. They were developed for the treatment of comorbidity of dementia with Parkinsonism. In the present study, we determined the effects of these drugs on both aminergic neurotransmitter levels and motor behavioral activity in naïve and in L-dopa- or L-tryptophan-induced rats. Chronic treatment of rats with ladostigil (52 mg kg(-1) for 21 days) inhibited hippocampal and striatal MAO A and B activities by >90%, increased striatal levels of dopamine and serotonin, and inhibited striatal ChE activity by approximately 50%. Chronic TV3279 (26 mg kg(-1) for 21 days) similarly inhibited approximately 50% of striatal ChE activity, but did not affect MAO activity or amine levels. In sharp contrast to the inductive effect of the MAO A/B inhibitor, tranylcypromine (TCP), on stereotyped hyperactivity in response to L-dopa (50 mg kg(-1)) or L-tryptophan (100 mg kg(-1)), ladostigil completely inhibited these behavioral hyperactivity syndromes. Accordingly, acute rivastigmine (2 mg kg(-1)) and chronic TV3279 abolished the ability of TCP to initiate L-dopa-induced hyperactivity, while scopolamine (0.5 mg kg(-1)) reversed the inhibitory effect of chronic ladostigil on L-dopa-induced hyperactivity, suggesting that ladostigil may attenuate successive locomotion by activating central cholinergic muscarinic receptors.Finally, while chronic ladostigil administration to naïve rats resulted in preserved spontaneous motor behavior, acute treatment with ladostigil decreased motor performance, compared to control animals. In contrast, chronic as well as acute treatments with TV3279 reduced spontaneous motor activity. Thus, the aminergic potentiation by ladostigil may counteract its cholinergic inhibitory effect on spontaneous motor behavior. Our results suggest that potentiation of both aminergic and cholinergic transmission systems by ladostigil contributes equally to motor behavior performance, which is substantially impaired in comorbidity of dementia with Parkinsonism including dementia with Lewy bodies (DLB).