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The rima moclobemide: More than an effective antidepressant?
5-51 MAO lsoforms as Targets for Psychotropic and Neuroprotective Drugs
164
laboratory the possible role of endogenous opioids in experimental addiction including studies of local infusions of naltrexone in brain regions. The pioneering human work on naltrexone for alcoholism treatment was carried out at the University of Pennsylvania. Dr. Charles O 'Brien will present data from their studies as well as new post-antagonist 6-month follow-up results. There has been increasing interest in a process that could speed up narcotic detoxification and increase its success rate. Dr. Herbert Kleber, from Columbia University, will discuss the original ultra-rapid antagonist-precipitated opioid detoxification as well as newer techniques that reduce the length of time down to less than 24 hours, emphasizing safety and outcome issues. Dr. Marian Fischman from Columbia University will discuss the use of narcotic antagonists in narcotic addiction, focusing especially on the low acceptance rate of the drug by addicts and methods to improve it. Finally, Dr. Enrico Tempesta, University Cattolica S. Cuore, Rome. will discuss the European experience with narcotic antagonists in the treatment both of opioids and. more recently. alcohol dependence. Dr. Tempesta will review the available data from various countries.
I5-51 I MAO Isoforms as Targets for Psychotropic and Neuroprotective Drugs
about 80% of total MAO activity in the human basal ganglia. This isoform is mainly localized to the glial cells with one or two specific locations in the brain, e.g. raphe nucleus. MAO-A is present in the extraneuronal compartment and within the aminergic terminals, where it is involved in metabolism intraneuronal neurotransmitter. Selegiline, a selective inhibitor of MAO-B has been widely used in treatment of Parkinson's disease (PD). In Parkinsonian brains obtained at autopsy from 2 weeks or 4 years of l- selegiline treated subjects, a highly significant increase in brain phenylethylamine and dopamine. There were no changes in serotonin. noradrenaline or their metabolite contents. By contrast, clorgyline (MAO-A inhibitor) increases both noradrenaline and serotonin highly significantly with a slight increase in dopamine in human basal ganglia. So far little attention has been paid to MAO-A inhibition in PD. even though dopamine is equally metabolized by MAO-A and MAO-B in the striatum. There is no indication as to what is the contribution of MAO-A inhibition to human brain amine metabolism. In a recent study, we have examined the effects of a selective reversible inhibitor of MAO-A (RIMA) moclobemide, when added to the standard therapy with levodopa and dopaminergic agonists, on motor performance of patients with idiopathic PD. We shall report on the comparison of selegiline and moclobemide.
I8-51 -31
The Rima Moclobemide: Morethan an Effective Antidepressant?
R. Amrein. F. Hoffmann-La Roche LId., Swit zerland
I8-51-1 I Mo?~lation of Cerebral Monoamine Release by Mao InhIbitors 1. Finberg, I. Larnensdorff, I. Kopin I . :\1. Youdim. Pharmacology Unit, Rappaport Faculty of Medicine. Technion. Haifa, Israel: I NINDS, NIH, Bethesda. MD. USA
Concentration of amine neurotransmitter in extracellular fluid of CNS is dependent on rate of release from the neuron, activity of uptake system. and rate of removal by capillary flow. Net neuronal uptake is governed by activity of active transporter and cytoplasmatic amine level. The latter is ruled by activity of M.-\O for the specific amine, together with vesicular transport. A single administration of clorgyline in rats. sufficient to inhibit brain MAO-A by 95Q. did not affect conical extracellular noradrenaline concentration I:'\A"cr) in microdialysate, whereas 3 weeks inhibition of MAO-A increased :'\A"cr by threefold. An effect of MAO-A inhibition on cortical NA,~ .. is consistent with the location of MAO-A in CNS noradrenergic nerves. and the difference between acute and chronic MAO-A inhibition could be the result of more extensive (ic > 95%) enzyme inhibition [I] . Return of locus coeruleus firing rate, depressed by MAO inhibition, to predrug levels is not thought to occur [2]. On the other hand, a single administration of clorgyline increased striatal extracellular dopamine (DA" , ! following intrastriatal L-DOPA administration. although a single administration of the selective MAO-B inhihitors selegiline or TVP- 101 2 lRc +lN-propargyl- l-aminoindan] did not. Although dopaminergic nerves of the nigro-striatal tract contain MAO-A, a chronic treatment with selective MAO-B-inhibitory doses of selegiline and TVP- 1012 did enhance basal DArer. This could be the result of an effect of the MAO-B inhibitors on the DA transporter. or on accumulation of endogenous bera-phenylethylamine. In primates. however. inhibition ofMAO-B may exert a greater initial effect on DA" r, because of the different synaptic architecture. [1] Cassis L, Ludwig J, Grohmann M. Trendelenburg C, Naunyn Schrniedeberg's Arch. Pharmaca l. 333 ( \ 986) 253-26 1.
[2) Blier P. De Mantigny C. Neuroscience 16 C19&5, 9-19- 955.
18-51 -21 Potentials of MAO·A and B Inhibitors in the Clinic M.B.H. Youdim. Faculty of Medicine. Technion. Haifa Monoamine oxidase (MAO) is the main enzyme involved in the catabolism of brain monoamines dopamine. noradrenaline, serotonin and phenylethylamine via oxidative deamination, In the brain, the enzyme exists in two isoforms, A and B. with different substrate specifities inhibitor sensitivities and cellular distributions. MAO-B accounts for
Moclobemide a reversible inhibitor of monoamine oxidase type A, is well established as an effective antidepressant in major depression, in endogenous and neurotic depression. in severe forms of depression and also in therapy resistant depression. Recent studies indicate that moclobemide is also effective in dysthymia, panic disorder and social phobia and may be useful in the treatment of brief recurrent depression. Animal data show that in rats with drug induced deficits moclobemide may also ameliorate the cognitive and memory functions. Recent study results in elderly depressed patients with dementia demonstrate that rnoclobemide ameliorates not only the symptoms of depression but in parallel also the symptoms of cognitive deficits. Whether this effect on cognition can be considered to be independent of the effect of moc\obemide on mood. will be discussed in this paper. Moclobemide was successfully used in attention deficit hyperactivity disorder. The usefulness in the treatment of the chronic fatigue syndrome needs further confirmation. In rats with an inborn alcohol preference. the alcohol consumption is decreased with moclobemide and in parallel the water intake is increased, This may be interpretedas a consequence of an elevated synaptic dopamine concentration resulting from MAO-A inhibition due to rnoclobemide. In humans the effect of RIMAs on dopaminergic neurons is less pronounced than in rats. Nevertheless this effect seems to be sufficient to be useful during smoking cessation. Alcohol consumption is frequently increased during depression. There are several anecdotical reports indicating that the treatment of depression by moclobemide often leads to a reduced desire for alcohol and a reduced alcohol consumption in the treatment. In addition positive effects on the symptoms of Parkinson's disease (with or without depression) also indicate the effect of moclobemide on the dopaminergic system. RIMAs exert a biochemical effect on more than one biogenic amine. Theoretical model calculations show, that the concentration of biogenic amines in the synaptic cleft would be normalized under the effect of RIMAs rather than increased above normal levels as with uptake-inhibitors. The principle of reversible inhibition of MAO-A offers the theoretical advantage of a well balanced effect on different biogenic amines. The broad spectrum of clinically useful application of RIMAs is supported by previous experience with the irreversible MAO-inhibitors.
164
laboratory the possible role of endogenous opioids in experimental addiction including studies of local infusions of naltrexone in brain regions. The pioneering human work on naltrexone for alcoholism treatment was carried out at the University of Pennsylvania. Dr. Charles O 'Brien will present data from their studies as well as new post-antagonist 6-month follow-up results. There has been increasing interest in a process that could speed up narcotic detoxification and increase its success rate. Dr. Herbert Kleber, from Columbia University, will discuss the original ultra-rapid antagonist-precipitated opioid detoxification as well as newer techniques that reduce the length of time down to less than 24 hours, emphasizing safety and outcome issues. Dr. Marian Fischman from Columbia University will discuss the use of narcotic antagonists in narcotic addiction, focusing especially on the low acceptance rate of the drug by addicts and methods to improve it. Finally, Dr. Enrico Tempesta, University Cattolica S. Cuore, Rome. will discuss the European experience with narcotic antagonists in the treatment both of opioids and. more recently. alcohol dependence. Dr. Tempesta will review the available data from various countries.
I5-51 I MAO Isoforms as Targets for Psychotropic and Neuroprotective Drugs
about 80% of total MAO activity in the human basal ganglia. This isoform is mainly localized to the glial cells with one or two specific locations in the brain, e.g. raphe nucleus. MAO-A is present in the extraneuronal compartment and within the aminergic terminals, where it is involved in metabolism intraneuronal neurotransmitter. Selegiline, a selective inhibitor of MAO-B has been widely used in treatment of Parkinson's disease (PD). In Parkinsonian brains obtained at autopsy from 2 weeks or 4 years of l- selegiline treated subjects, a highly significant increase in brain phenylethylamine and dopamine. There were no changes in serotonin. noradrenaline or their metabolite contents. By contrast, clorgyline (MAO-A inhibitor) increases both noradrenaline and serotonin highly significantly with a slight increase in dopamine in human basal ganglia. So far little attention has been paid to MAO-A inhibition in PD. even though dopamine is equally metabolized by MAO-A and MAO-B in the striatum. There is no indication as to what is the contribution of MAO-A inhibition to human brain amine metabolism. In a recent study, we have examined the effects of a selective reversible inhibitor of MAO-A (RIMA) moclobemide, when added to the standard therapy with levodopa and dopaminergic agonists, on motor performance of patients with idiopathic PD. We shall report on the comparison of selegiline and moclobemide.
I8-51 -31
The Rima Moclobemide: Morethan an Effective Antidepressant?
R. Amrein. F. Hoffmann-La Roche LId., Swit zerland
I8-51-1 I Mo?~lation of Cerebral Monoamine Release by Mao InhIbitors 1. Finberg, I. Larnensdorff, I. Kopin I . :\1. Youdim. Pharmacology Unit, Rappaport Faculty of Medicine. Technion. Haifa, Israel: I NINDS, NIH, Bethesda. MD. USA
Concentration of amine neurotransmitter in extracellular fluid of CNS is dependent on rate of release from the neuron, activity of uptake system. and rate of removal by capillary flow. Net neuronal uptake is governed by activity of active transporter and cytoplasmatic amine level. The latter is ruled by activity of M.-\O for the specific amine, together with vesicular transport. A single administration of clorgyline in rats. sufficient to inhibit brain MAO-A by 95Q. did not affect conical extracellular noradrenaline concentration I:'\A"cr) in microdialysate, whereas 3 weeks inhibition of MAO-A increased :'\A"cr by threefold. An effect of MAO-A inhibition on cortical NA,~ .. is consistent with the location of MAO-A in CNS noradrenergic nerves. and the difference between acute and chronic MAO-A inhibition could be the result of more extensive (ic > 95%) enzyme inhibition [I] . Return of locus coeruleus firing rate, depressed by MAO inhibition, to predrug levels is not thought to occur [2]. On the other hand, a single administration of clorgyline increased striatal extracellular dopamine (DA" , ! following intrastriatal L-DOPA administration. although a single administration of the selective MAO-B inhihitors selegiline or TVP- 101 2 lRc +lN-propargyl- l-aminoindan] did not. Although dopaminergic nerves of the nigro-striatal tract contain MAO-A, a chronic treatment with selective MAO-B-inhibitory doses of selegiline and TVP- 1012 did enhance basal DArer. This could be the result of an effect of the MAO-B inhibitors on the DA transporter. or on accumulation of endogenous bera-phenylethylamine. In primates. however. inhibition ofMAO-B may exert a greater initial effect on DA" r, because of the different synaptic architecture. [1] Cassis L, Ludwig J, Grohmann M. Trendelenburg C, Naunyn Schrniedeberg's Arch. Pharmaca l. 333 ( \ 986) 253-26 1.
[2) Blier P. De Mantigny C. Neuroscience 16 C19&5, 9-19- 955.
18-51 -21 Potentials of MAO·A and B Inhibitors in the Clinic M.B.H. Youdim. Faculty of Medicine. Technion. Haifa Monoamine oxidase (MAO) is the main enzyme involved in the catabolism of brain monoamines dopamine. noradrenaline, serotonin and phenylethylamine via oxidative deamination, In the brain, the enzyme exists in two isoforms, A and B. with different substrate specifities inhibitor sensitivities and cellular distributions. MAO-B accounts for
Moclobemide a reversible inhibitor of monoamine oxidase type A, is well established as an effective antidepressant in major depression, in endogenous and neurotic depression. in severe forms of depression and also in therapy resistant depression. Recent studies indicate that moclobemide is also effective in dysthymia, panic disorder and social phobia and may be useful in the treatment of brief recurrent depression. Animal data show that in rats with drug induced deficits moclobemide may also ameliorate the cognitive and memory functions. Recent study results in elderly depressed patients with dementia demonstrate that rnoclobemide ameliorates not only the symptoms of depression but in parallel also the symptoms of cognitive deficits. Whether this effect on cognition can be considered to be independent of the effect of moc\obemide on mood. will be discussed in this paper. Moclobemide was successfully used in attention deficit hyperactivity disorder. The usefulness in the treatment of the chronic fatigue syndrome needs further confirmation. In rats with an inborn alcohol preference. the alcohol consumption is decreased with moclobemide and in parallel the water intake is increased, This may be interpretedas a consequence of an elevated synaptic dopamine concentration resulting from MAO-A inhibition due to rnoclobemide. In humans the effect of RIMAs on dopaminergic neurons is less pronounced than in rats. Nevertheless this effect seems to be sufficient to be useful during smoking cessation. Alcohol consumption is frequently increased during depression. There are several anecdotical reports indicating that the treatment of depression by moclobemide often leads to a reduced desire for alcohol and a reduced alcohol consumption in the treatment. In addition positive effects on the symptoms of Parkinson's disease (with or without depression) also indicate the effect of moclobemide on the dopaminergic system. RIMAs exert a biochemical effect on more than one biogenic amine. Theoretical model calculations show, that the concentration of biogenic amines in the synaptic cleft would be normalized under the effect of RIMAs rather than increased above normal levels as with uptake-inhibitors. The principle of reversible inhibition of MAO-A offers the theoretical advantage of a well balanced effect on different biogenic amines. The broad spectrum of clinically useful application of RIMAs is supported by previous experience with the irreversible MAO-inhibitors.