How drugs impact the neurotransmitter life cycle

Neurons interact with each other through electrical events called action potentials and the release of chemical signals called neurotransmitters (Lodish et al., 2000). The neurotransmitter life cycle can be broken down into six component processes: synthesis, storage, release, receptor interaction, reuptake, and degradation (Beckstead, 1996). Each of these steps can be impacted by drugs in a clinical setting to assist in the treatment of diseases and disorders or to promote physical and mental well-being.

First, neurotransmitter molecules are synthesised from precursors under the influence of enzymes. This process called Synthesis takes place in the presynaptic terminal (Purves et al., 2001). Clinically useful drugs that can act on synthesis include L-DOPA, also known as Levodopa, which is used in the treatment of Parkinson’s disease (Cotzias & Papavasiliou, 1967).

Parkinson’s disease is a movement disorder which is common in the elderly (Hughes et al., 2002), and where 80% of dopamine innervations are reduced in the basal ganglia (Kostrzewa et al., 2005). L-DOPA, which is still considered the gold standard treatment today (Ovallath & Sulthana, 2017), works by enhancing the synthesis of dopamine in patients with Parkinson’s disease (Dorszewska et al., 2014). This process is most effective in the presence of enzyme aromatic L-amino acid decarboxylase (Lovenberg, 1962), also known as DOPA decarboxylase.

The second component process is Storage: neurotransmitters are stored in organelles called synaptic vesicles (Kelly, 1993), via proteins called vesicular transporters (Edwards, 1992). Reserpine is one of the drugs that have historically been used to act on this process. Reserpine inhibits the storage of catecholamines—dopamine, norepinephrine, and epinephrine—into vesicles by blocking the vesicular monoamine transporters (Henry, 1989). Reserpine was long employed for the control of high blood pressure, but because of numerous side effects, including depression, it is now rarely used (Shamon & Perez, 2009).

The next step in the neurotransmitter life cycle is called Release, where action potentials cause vesicles to fuse with the presynaptic membrane, and neurotransmitters are released into the synapse (Zbili et al., 2016). The synapse is the junction where communication happens between neurons, and is constituted of the presynaptic terminal and the postsynaptic region (Foster & Sherrington, 1897).

By acting on the presynaptic membrane to facilitate release of dopamine into the synapse, the drug Amantadine has been used as an adjuvant to L-DOPA in the treatment of Parkinson’s disease (Bandini et al, 2002). While Amantadine has been shown to be useful in clinical practice with positive short-term effects on symptoms of Parkinson’s disease (Singer et al., 2006), a systematic review questions the long-term efficacy and safety of the drug (Crosby et al, 2003).

Next, neurotransmitters interact with receptors, which are divided in two major types: ionotropic receptors, which are neurotransmitter-gated ion channels, and metabotropic receptors, which are G-protein coupled receptors without ion channels (Snyder, 2009). N-methyl-D-aspartate (NMDA) receptors, for example, are ionotropic glutamate receptors, called this way because the agonist molecule NDMA binds selectively to them and not to other glutamate receptors such as AMPA and kainate receptors; the binding of NMDA or glutamate and glycine opens the channel and allows positively charged ions to flow through the cell membrane (Furukawa, 2005).

An example of drug acting on this process is Ketamine, an NMDA receptor antagonist (Anis et al., 1983). Rather than preventing the binding of glutamate to NDMA receptors, it inhibits them by blocking activated channels (MacDonald, 1987). Still used today as an anesthetic, Ketamine has shown psychotomimetic effects which have spurred new research into glutamate-based antidepressants (Abdallah et al., 2015).

Reuptake is the subsequent process by which released neurotransmitters can be reabsorbed either by the neuron or by glia (Masson et al., 1999). Reuptake inhibitors slow the reabsorption of neurotransmitter into the presynaptic neuron, thus increasing the concentration of neurotransmitter in the synapse (Iversen, 2006).

Such example of reuptake inhibitor is Tiagabine, which interferes with GABA reuptake by blocking GAT transporters, and is used in the treatment of epilepsy and anxiety disorders (Pollack et al., 2005).

The last step in the neurotransmitter lifecycle is Degradation, which can happen in parallel to reuptake, and where neurotransmitters are deactivated by enzymes in the synaptic cleft. Vigabatrin, for example, is a suicide inhibitor—causing an irreversible form of enzyme inhibition—of the enzyme GABA-T and is used as an anticonvulsant (Chadwick et al., 1999).

Despite many current applications of drugs targeting various neurotransmitter systems, the understanding of these mechanisms is still partial. For example, Memantine, a drug used for the treatment of Alzheimer’s disease targeting the glutamatergic system, while initially considered a promising treatment (Lipton, 2006), has only shown clinically marginal effectiveness, and additional research needs to be conducted to better understand the role of neurotransmitters in Alzheimer’s disease Reddy, 2017).

References:

Abdallah, C. G., Sanacora, G., Duman, R. S., & Krystal, J. H. (2015). Ketamine and rapid-acting antidepressants: a window into a new neurobiology for mood disorder therapeutics. Annual review of medicine66, 509-523.

Anis, N. A., Berry, S. C., Burton, N. R., & Lodge, D. (1983). The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate. British journal of pharmacology,79(2), 565-575.

Bandini, F., Pierantozzi, M., & Bodis-Wollner, I. (2002). The visuo-cognitive and motor effect of amantadine in non-Caucasian patients with Parkinson’s disease. A clinical and electrophysiological study. Journal of neural transmission109(1), 41-51.

Beckstead, R. M. (1996). The Life Cycle of Neurotransmitters. In A Survey of Medical Neuroscience (pp. 32-44). Springer, New York, NY.

Chadwick, D., & Vigabatrin European Monotherapy Study Group. (1999). Safety and efficacy of vigabatrin and carbamazepine in newly diagnosed epilepsy: a multicentre randomised double-blind study. The Lancet354(9172), 13-19.

Cotzias, G. C., & Papavasiliou, P. S. (1967). Therapeutic studies of Parkinsonian patients: long term effects of D, L, and L Dopa. Brookhaven National Lab, Upton, NY.

Crosby, N. J., Deane, K., & Clarke, C. E. (2003). Amantadine for dyskinesia in Parkinson’s disease. Cochrane Database of Systematic Reviews, (2).

Dorszewska, J., Prendecki, M., Lianeri, M., & Kozubski, W. (2014). Molecular effects of L-dopa therapy in Parkinson’s disease. Current genomics15(1), 11-17.

Edwards, R. H. (1992). The transport of neurotransmitters into synaptic vesicles. Current opinion in neurobiology2(5), 586-594.

Foster, M.; Sherrington, C.S. (1897). Textbook of Physiology, volume 3 (7th ed.). London: Macmillan. p. 929.

Furukawa, H., Singh, S. K., Mancusso, R., & Gouaux, E. (2005). Subunit arrangement and function in NMDA receptors. Nature438(7065), 185.

Henry, J. P. (1989). Radioligands of the vesicular monoamine transporter and their use as markers of monoamine storage vesicles. Biochemical pharmacology38(15), 2395-2404.

Hughes, A. J., Daniel, S. E., Ben‐Shlomo, Y., & Lees, A. J. (2002). The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain125(4), 861-870.

Iversen, L. (2006). Neurotransmitter transporters and their impact on the development of psychopharmacology. British journal of pharmacology147(S1).

Kelly, R. B. (1993). Storage and release of neurotransmitters. Cell72, 43-53.

Kostrzewa, R. M., Nowak, P., Kostrzewa, J. P., Kostrzewa, R. A., & Brus, R. (2005). Peculiarities of L-DOPA treatment of Parkinson’s disease. Amino Acids28(2), 157-164.

Lipton, S. A. (2006). Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nature reviews Drug discovery5(2), 160.

Lodish H, Berk A, Zipursky SL, et al. (2000) Molecular Cell Biology. 4th edition. New York: W. H. Freeman. Overview of Neuron Structure and Function, Section 21.1.

Lovenberg, W., Weissbach, H., & Udenfriend, S. (1962). Aromatic LAmho acid decarboxylase. J Biol Chem1(237), 89-93.

MacDonald, J. F., Miljkovic, Z., & Pennefather, P. (1987). Use-dependent block of excitatory amino acid currents in cultured neurons by ketamine. Journal of Neurophysiology58(2), 251-266.

Masson, J., Sagne, C., Hamon, M. E., & El Mestikawy, S. (1999). Neurotransmitter transporters in the central nervous system. Pharmacological reviews51(3), 439-464.

Ovallath, S., & Sulthana, B. (2017). Levodopa: History and therapeutic applications. Annals of Indian Academy of Neurology20(3), 185.

Pollack, M. H., Roy-Byrne, P. P., Van Ameringen, M., Snyder, H., Brown, C., Ondrasik, J., & Rickels, K. (2005). The selective GABA reuptake inhibitor tiagabine for the treatment of generalized anxiety disorder: results of a placebo-controlled study. Journal of Clinical Psychiatry66(11), 1401-1408.

Purves, D., Augustine, G. J., Fitzpatrick, D., Katz, L. C., LaMantia, A. S., McNamara, J. O., & Williams, S. M. (2001). Neuroscience 2nd Edition. Sunderland (MA) Sinauer Associates.

Reddy, P. H. (2017). A critical assessment of research on neurotransmitters in Alzheimer’s disease. Journal of Alzheimer’s Disease57(4), 969-974.

Shamon, S. D., & Perez, M. I. (2009). Blood pressure lowering efficacy of reserpine for primary hypertension. Cochrane Database of Systematic Reviews, (4).

Singer, C., Papapetropoulos, S., Uzcategui, G., & Vela, L. (2006). The use of amantadine HCL in clinical practice: a study of old and new indications. Journal of Applied Research in Clinical and Experimental Therapeutics6(3), 240.

Snyder, S. H. (2009). Neurotransmitters, receptors, and second messengers galore in 40 years. Journal of Neuroscience29(41), 12717-12721.

Zbili, M., Rama, S., & Debanne, D. (2016). Dynamic control of neurotransmitter release by presynaptic potential. Frontiers in cellular neuroscience10, 278.