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→Mechanism of Action
==Mechanism of Action==
==Mechanism of Action==
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, augmenting levels of these substances<ref name="Overall">Overall, K.L., 2001. Pharmacological Treatment in Behavioural Medicine: The Importance of Neurochemistry, Molecular Biology and Mechanistic Hypotheses. The Veterinary Journal, 162, 9-23</ref>.
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 the oxidative deamination of the monoamine neurotransmitters (adrenaline, nor-adrenaline, serotonin, histamine and dopamine)<ref name="Overall">Overall, K.L., 2001. Pharmacological Treatment in Behavioural Medicine: The Importance of Neurochemistry, Molecular Biology and Mechanistic Hypotheses. The Veterinary Journal, 162, 9-23</ref>.
Two forms exist, these are different in terms of their distribution in tissues and substrate specificity:
Two forms of MAO exist, which differ in 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 has a high specificity for inhibiting MAOB, and 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.
Most MAOI antidepressants are mixed or selective inhibitors of MAOA. These have very similar effects on serotonergic and nor-adrenergic neurotransmission to SRI/SSRI drugs, and lead to almost identical postsynaptic receptor regulation. MAOA inhibitors also increase dopaminergic transmission, which has a recognised but not fully understood effect on depression.
Most MAOI antidepressants are mixed or selective inhibitors of MAOA. These have very similar effects on serotonergic and nor-adrenergic neurotransmission to SRI/SSRI drugs, and lead to almost identical postsynaptic receptor regulation. 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 therefore 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.
Although a selective inhibitor of MAOB, there is evidence that selegiline does also partially inhibit MAOA, potentially leading to some MAOAi-like anti-depressant and anti-anxiety effects . 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<ref>Heinonen EH, Lammintausta R: A review of the pharmacology of selegiline. Acta Neurol Scand 84:(suppl. 136):44-59, 1991</ref> <ref>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.</ref>.
The exact mechanism of action of selegiline is not fully understood, but the following points summarise its supposed action.
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 is thought to be relatively small.
*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.
*There is a dopaminergic-related increase in playfulness and exploratory behaviour (which is sometimes confused with an anti-depressant effect).
*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. 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.
*D<sub>1</sub> receptors are affected in mood disorders and stereotypes and manifest their post-synaptic inhibition in the limbic system<ref name="Overall"/>. In mood disorders and stereotypies D<sub>2</sub>, D<sub>3</sub> and D<sub>4</sub> receptors are all also affected.
*D<sub>1</sub> receptors are affected in mood disorders and stereotypes and manifest their post-synaptic inhibition in the limbic system<ref name="Overall"/>. In mood disorders and stereotypies D<sub>2</sub>, D<sub>3</sub> and D<sub>4</sub> receptors are all also affected.