Dopamine inactivation

Inhibitors of monoamine oxi-dase-B (MAOb). This isoenzyme breaks down dopamine in the corpus striatum and can be selectively inhibited by selegiline. Inactivation of norepinephrine, epinephrine, and 5-HT via MAOa is unaffected. The antiparkinsonian effects of selegiUne may result from decreased dopamine inactivation (enhanced levodopa response) or from neuroprotective mechanisms (decreased oxyradical formation or blocked bioactivation of an unknown neurotoxin). 

In medical practice, four types of dopaminergic drags are used, and they can be characterized as dopamine precursors (levodopa), dopamine-releasing drugs (amantadine), dopamine receptor agonists (bromocriptine), and dopamine inactivation inhibitors (selegiline). 

This drug is a selective inhibitor of monoaminooxidase B, which suppresses dopamine-inactivation processes and facilitates an increase of its level in the brain. In treating Parkinsonism, selegiline is usually used in combination with levodopa. The most common synonyms of selegiline are deprenyl, eldepryl, eldopal, and others. 

Amalric M, Baunez C, Nieoullon A (1995a) Does the blockade of excitatory amino acid transmission in the basal ganglia simply reverse reaction time deficits induced by dopamine inactivation Behav Pharmacol 55 508-519. 

Monoamine Oxidase Inhibitors. MAOIs inactivate the enzyme MAO, which is responsible for the oxidative deamination of a variety of endogenous and exogenous substances. Among the endogenous substances are the neurotransmitters, norepinephrine, dopamine, and serotonin. The prototype MAOI is iproniazid [54-92-2] (25), originally tested as an antitubercular dmg and a close chemical relative of the effective antitubercular, isoniazid [54-85-3] (26). Tubercular patients exhibited mood elevation, although no reHef of their tuberculosis, following chronic administration of iproniazid. In... 

The transporters for 5HT, noradrenaline and dopamine, biogenic monoamines, are genetically related, exist as single isoforms and are expressed on the surface of nerve cells, which use monoamines as (or convert them into) their cognate neurotransmitter. The single-isoform monoamine transporters fulfil all three fundamental functions (reuptake, limiting synaptic transmission, and control of the extracellular neurotransmitter concentration). Inactivation of DAT, NET, or SERT results in an increased extracellular lifetime and level of monoamine neurotransmitter, but decreased intracellular storage and evoked release (Fig. 3). 

There are numerous transmitter substances. They include the amino acids glutamate, GABA and glycine acetylcholine the monoamines dopamine, noradrenaline and serotonin the neuropeptides ATP and NO. Many neurones use not a single transmitter but two or even more, a phenomenon called cotransmission. Chemical synaptic transmission hence is diversified. The basic steps, however, are similar across all neurones, irrespective of their transmitter, with the exception of NO transmitter production and vesicular storage transmitter release postsynaptic receptor activation and transmitter inactivation. Figure 1 shows an overview. Nitrergic transmission, i.e. transmission by NO, differs from transmission by other transmitters and is not covered in this essay. 

Reserpine inhibits the synaptic vesicular storage of the monoamines dopamine, serotonin and noradrenaline. As a result they leak out into the cytoplasm where they are inactivated by monoamine oxidase this causes their long-lasting depletion. The resulting low levels of dopamine underlie the antipsychotic actions of reserpine (Chapter 11), whereas the reduced noradrenaline levels underlie its antihypertensive actions. Finally, the resulting low levels of serotonin and noradrenaline mean that reserpine also induces depression. These severe side effects mean that reserpine is no longer used clinically as a treatment for schizophrenia (Chapter 11). 

Many neurotransmitters are inactivated by a combination of enzymic and non-enzymic methods. The monoamines - dopamine, noradrenaline and serotonin (5-HT) - are actively transported back from the synaptic cleft into the cytoplasm of the presynaptic neuron. This process utilises specialised proteins called transporters, or carriers. The monoamine binds to the transporter and is then carried across the plasma membrane it is thus transported back into the cellular cytoplasm. A number of psychotropic drugs selectively or non-selectively inhibit this reuptake process. They compete with the monoamines for the available binding sites on the transporter, so slowing the removal of the neurotransmitter from the synaptic cleft. The overall result is prolonged stimulation of the receptor. The tricyclic antidepressant imipramine inhibits the transport of both noradrenaline and 5-HT. While the selective noradrenaline reuptake inhibitor reboxetine and the selective serotonin reuptake inhibitor fluoxetine block the noradrenaline transporter (NAT) and serotonin transporter (SERT), respectively. Cocaine non-selectively blocks both the NAT and dopamine transporter (DAT) whereas the smoking cessation facilitator and antidepressant bupropion is a more selective DAT inhibitor. 

The first two antidepressants, iproniazid and imipramine, were developed in the same decade. They were shown to reverse the behavioural and neurochemical effects of reserpine in laboratory rodents, by inhibiting the inactivation of these monoamine transmitters (Leonard, 1985). Iproniazid inhibits MAO (monoamine oxidase), an enzyme located in the presynaptic neuronal terminal which breaks down NA, 5-HT and dopamine into physiologically inactive metabolites. Imipramine inhibits the reuptake of NA and 5-HT from the synaptic cleft by their transporters. Therefore, both of these drugs increase the availability of NA and 5-HT for binding to postsynaptic receptors and, therefore, result in enhanced synaptic transmission. Conversely, lithium, the oldest but still most frequently used mood stabiliser (see below), decreases synaptic NA (and possibly 5-HT) activity, by stimulating their reuptake and reducing the availability of precursor chemicals required in the biosynthesis of second messengers. 

Catechol-O-methyltransferase (COMT) An enzyme that inactivates dopamine and noradrenaline. 

Endocannabinoids are endogenous ligands for the CB1 receptor. The best established are anandamide (N-arachidonoylethanolamine) and 2-AG (2-arachidonoyl-glycerol). Others may also exist. Pathways involved in the formation and inactivation of anandamide and 2-AG are shown in Figure 56-6. Some steps in their formation are Ca2+-dependent. This explains the ability of neuronal depolarization, which increases postsynaptic intracellular Ca2+ levels, to stimulate endocannabinoid formation and release. Some neurotransmitter receptors (e.g. the D2 dopamine receptor) also stimulate endocannabinoid formation, probably by modulating postsynaptic Ca2+ levels or signaling pathways (e.g. PLC) that regulate endocannabinoid formation. 

Milner, H. E., Beliveau, R., and Jarvis, S. M. (1994) The in situ size of the dopamine transporter is a tetramer as estimated by radiation inactivation. Biochim. Biophys. Acta 1190,185-187. 

Itiee, J. M., et ah. Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum Mol Genet, 2003, 12(18), 2277-91. 

Kulak JM, Nguyen TA, Olivera BM, McIntosh JM (1997) Alpha-conotoxin Mil blocks nicotine-stimulated dopamine release in rat striatal synaptosomes. J Neurosci 17 5263-5270 Kuryatov A, Gerzanich V, Nelson M, Olale F, Lindstrom J (1997) Mutation causing autosomal dominant nocturnal frontal lobe epilepsy alters Ca + permeabihty, conductance, and gating of human a4 32 nicotinic acetylcholine receptors, J Neurosci 17 9035-9047 Kuryatov A, Olale FA, Choi C, Lindstrom J (2000) Acetylchohne receptor extracellular domain determines sensitivity to nicotine-induced inactivation, Eur J Pharmacol 393 11-21 Langley JN (1880) On the antagonism of poisons. J Physiol 3 11-21... 

The process of RGS recruitment to the membrane-bound receptor, however, seems to be constitutive—it appears to be independent of the state of activation of the receptor or G protein. This recruitment may facilitate signal quenching because the combination of 30 RGS proteins and 20 Ga subunits allows for a diverse pattern of inactivation. RGS proteins, therefore, are recruited to the plasma membrane in cells expressing either Ga subunits (Gsa) or linked GPCRs (e.g., Dj-dopamine receptor) in preparation for the GAP activity that quenches G protein signaling (104,105). 

The desensitization motifs in the dopamine Dj receptor, as an example, may be at least partly located in the proximal carboxyl tail of the receptor f/22). This region may interact with portions of the third intracellular loop to promote desensitization. These structures may also be involved in recycling and trafficking of inactivated receptors (147). 

---