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==Mechanism of Action==
==Mechanism of Action==
Selegiline is a selective monoamine oxidase (MAO) type B inhibitor (I). Monoamine Oxidase (MAO) is the main enzyme responsible for breakdown of the monoamine neurotransmitters (adrenaline, nor-adrenaline, serotonin, histamine and dopamine).
Selegiline is a selective monoamine oxidase (MAO) type B inhibitor (I), also commonly known as L-deprenyl. Monoamine Oxidase (MAO) is the main enzyme responsible for breakdown of the monoamine neurotransmitters (adrenaline, nor-adrenaline, serotonin, histamine and dopamine). Selegiline has a high specificity for dopamine. MAO-Is function by preventing oxidative deamination of brain amines, increasing levels of these substances.
Two forms exist:
Two forms exist, these are different in terms of their distribution in tissues and substrate specificity:
*MAOA:Catabolises serotonin, adrenaline, nor-adrenaline.
*MAOA: Catabolises serotonin, adrenaline, nor-adrenaline.
*MAOB:Catabolises dopamine and histamine.
*MAOB: Catabolises dopamine and histamine.
Selegiline therefore increases the availability of dopamine for inclusion into secretory vesicles by the vesicular monoamine transporter (VMAT) proteins on the surface of cytoplasmic vesicles in dopaminergic neurons.
Selegiline therefore increases the availability of dopamine for inclusion into secretory vesicles by the vesicular monoamine transporter (VMAT) proteins on the surface of cytoplasmic vesicles in dopaminergic neurons.
MAOA inhibitory drugs require dietary modification since they can become toxic in the presence of excess dietary tyramine. This is not the case with relatively selective MAOB inhibitors like selegiline. MAOA inhibitory drugs are NOT suitable alternatives to selegiline.
MAOA inhibitory drugs require dietary modification since they can become toxic in the presence of excess dietary tyramine. This is not the case with relatively selective MAOB inhibitors like selegiline. MAOA inhibitory drugs are NOT suitable alternatives to selegiline.
Selegiline reduces anxiety and depression mainly through its effect on dopamine Although a selective inhibitor of MAOB, there is evidence that selegiline does also partially inhibit MAOA, so some of those anti-depressant and anti-anxiety effects probably do occur.
Selegiline reduces anxiety and depression mainly through its effect on dopamine. Although a selective inhibitor of MAOB, there is evidence that selegiline does also partially inhibit MAOA, so some of those anti-depressant and anti-anxiety effects probably do occur. In addition there is some further evidence that it could possibly increase dopaminergic activity by other mechanisms, these include increased synthesis and release of dopamine into the synapse and interference with re-uptake of dopamine from the synapse. (Heinonen EH, Lammintausta R: A review of the pharmacology of selegiline. Acta Neurol Scand 84:(suppl. 136):44-59, 1991 and Heikkila RE, Cabbat FS, Manzino L, et al: Potentiation by deprenil of l-dopa induced circling in nigral-lesioned rats. Pharmacol Biochem Behav 15:75-79, 1981.)
The exact mechanism of action of selegiline is not fully understood.
*There is a direct antidepressant effect via increased dopamine [not understood].
The exact mechanism of action of selegiline is not fully understood, but the following points summarise its supposed action.
*There may be some reduction in anxiety due to MAOA effects, but this will be small.
*There is a direct antidepressant effect via increased dopamine.
*There may be some reduction in anxiety due to MAOA effects, but this is thought to be relatively small.
*Dopamine level is associated with playfulness. Increased dopamine levels are linked to increased playfulness.
*Dopamine level is associated with playfulness. Increased dopamine levels are linked to increased playfulness.
*Dopaminergic neurons are concentrated in the mesocorticolimbic dopamine system of the midbrain. This is thought to be part of the reward system that somehow assigns value to adaptive behaviours. Recent experiments have shown that normal dogs treated with the drug improve their performance in certain learned tasks and it is believed that this is due to improved function of the reward system.
*Dopaminergic neurons are concentrated in the mesocorticolimbic dopamine system of the midbrain. This is thought to be part of the reward system that somehow assigns value to adaptive behaviours. D<sub>1</sub> receptors are affected in mood disorders and stereotypes and manifest their post-synaptic inhibition in the limbic system. Recent experiments have shown that normal dogs treated with the drug improve their performance in certain learned tasks and it is believed that this is due to improved function of the reward system.
????In the Miller model this could raise the height and perhaps increase the gradient of the approach line, whilst also lowering the avoidance line????
????In the Miller model this could raise the height and perhaps increase the gradient of the approach line, whilst also lowering the avoidance line????
*In mood disorders and stereotypies D<sub>2</sub>, D<sub>3</sub> and D<sub>4</sub> receptors are all also affected.
*Dopamine is also important in the putative ‘seeking’ circuit, which is involved in reinforcement of search, exploratory and investigatory behaviours. Animals that have an enhancement of the ‘seeking’ system become immensely interested in what is around them and become excited when they anticipate the arrival of things that they want.
*Dopamine is also important in the putative ‘seeking’ circuit, which is involved in reinforcement of search, exploratory and investigatory behaviours. Animals that have an enhancement of the ‘seeking’ system become immensely interested in what is around them and become excited when they anticipate the arrival of things that they want.
*Two of the main metabolites of selegiline, L-amphetamine and L-methamphetamine may also play a role in its effects, however the extent to which this is the case is uncertain.
*A decrease in the concentration of catecholamines in the CNS and reduced level of neurotransmission are thought to be the pathogenesis behind the clinical signs associated with cognitive decline.
Remembering that in veterinary medicine depression, anxiety and the inhibitory effects of fear are measured by observing behaviour, a drug that increases exploratory behaviour, activity, playfulness and response to appetitive events would, by definition, reduce observed levels of depression. So the effect of selegiline may in some way be to reduce fear and anxiety, whilst at the same time increasing the tendency to explore and then enhancing reward for behaviours.
Remembering that in veterinary medicine depression, anxiety and the inhibitory effects of fear are measured by observing behaviour, a drug that increases exploratory behaviour, activity, playfulness and response to appetitive events would, by definition, reduce observed levels of depression. So the effect of selegiline may in some way be to reduce fear and anxiety, whilst at the same time increasing the tendency to explore and then enhancing reward for behaviours.
==Use==
==Use==
The main uses for selegiline are the treatment of fears and phobias, and cognitive decline where reduced dopamine levels are implicated [of the type that resembles dementia of the Alzheimer’s type, DAT].
The main uses for selegiline are the treatment of fears and phobias, and cognitive decline where reduced dopamine levels are implicated [of the type that resembles dementia of the Alzheimer’s type, DAT]. Selegiline should be administered for a minimum of 4 weeks before a reliable evaluation of efficacy is possible.
*Licensed [dog]
*Licensed [dog]
:*Cognitive decline [hypothetically of DAT].
:*Cognitive decline [hypothetically of DAT].
*Unlicensed
*Unlicensed
:*Other fear related problems [including aggression]
:*Other fear related problems [including aggression] - have also read that can cause an increase in aggression? - does this depend on the cause of aggression as to whether appropriate?
:*Spraying [fear related in cats]
:*Spraying [fear related in cats]
:*Hyperactivity
:*Hyperactivity
:*Compulsive/stereotypical disorders [predominantly involving fear]
:*Compulsive/stereotypical disorders [predominantly involving fear]
==Adverse Effects==
==Adverse Effects==
'''Care should be taken if used in conjunction with any of the following drugs, which may interact and cause adverse effects:'''
'''Care should be taken if used in conjunction with any of the following drugs, which may interact and cause adverse effects:'''
*TCA/SSRI: serotonin syndrome.
*TCA/SSRI: severe CNS toxicity and risk of serotonin syndrome.
*Benzodiazepines: Effects of benzodiazepines potentiated by selegiline. Isolated [human] problems with MAOA inhibitors, probably not relevant to selegiline.
*Benzodiazepines: Effects of benzodiazepines potentiated by selegiline. Isolated [human] problems with MAOA inhibitors, probably not relevant to selegiline.
*Buspirone: isolated [human] cases of non-fatal hypertension.
*Buspirone: isolated [human] cases of non-fatal hypertension.
*Pethidine: some serious [fatal] adverse reactions seen in man. Hyperpyrexia, respiratory failure, impaired consciousness, neurological signs.
*Pethidine: some serious [fatal] adverse reactions seen in man. Hyperpyrexia, respiratory failure, impaired consciousness, neurological signs.
*Phenylpropanolamine, Phenylephrine, ephedrine, pseudoephedrine: life-threatening hypertension seen in man.
*Phenylpropanolamine, Phenylephrine, ephedrine, pseudoephedrine: extreme fluctuations of blood pressure and life-threatening hypertension seen in man.
A minimum of a 2 week gap should be allowed between withdrawal of selegiline and initiation of treatment with a tricyclic antidepressant or selective serotonin reuptake inhibitor. Due to the long half-life of fluoxetine and its active metabolites, at least 5 weeks should elapse between discontinuation of fluoxetine and initiation of treatment with selegiline.
Note that most of the potential interactions relate to mixed and selective MAOA inhibitors in man, but it is sensible to be aware of these interactions when using a drug, like selegiline, that has a short history of use in veterinary medicine. Any adverse reaction should be reported via the NOAH reporting system.
Note that most of the potential interactions relate to mixed and selective MAOA inhibitors in man, but it is sensible to be aware of these interactions when using a drug, like selegiline, that has a short history of use in veterinary medicine. Any adverse reaction should be reported via the NOAH reporting system.