3.3.4 Basic pharmacology of neurotransmitters

3.3.4 Basic pharmacology of neurotransmitters

Basic Pharmacology of Neurotransmitters

Pharmacology is the study of drugs and their effects on biological systems, including neurotransmitters. The basic pharmacology of neurotransmitters involves understanding how drugs interact with neurotransmitter systems to produce therapeutic or adverse effects.

Neurotransmission occurs via calcium-induced exocytosis of vesicles containing the neurotransmitter in the pre-synaptic neuron.

Noradrenaline:

Noradrenaline is a sympathomimetic amine derived from tyrosine. Structural noradrenaline and adrenaline are the same. The difference is that noradrenaline lacks a methyl group on the nitrogen atom. This difference alone makes noradrenaline a primary agonist at alpha-1 and beta-1 receptors. There is almost no alpha-2 or beta-2 activity (Smith, 2019).

Activation of alpha-1 receptors leads to its primary physiological and clinical use as a peripheral vasoconstrictor. Dose-dependent increases in increased systemic vascular resistance.

Noradrenaline is metabolized by the enzymes catechol-O-methyltransferase (COMT) and MAO in the liver and other tissues:

The major metabolites are vanillylmandelic acid (VMA) and normetadrenaline.

A common drug class that can influence synthesis or degradation are monoamine oxidase inhibitors.

Serotonin:

Serotonin is a monoamine whose production occurs in two steps:

Once synthesized, serotonin is stored within the central nervous system (CNS) in the presynaptic neurons. The raphe nuclei are the major nuclei for serotonin, possessing both ascending serotonergic fibres that project to the forebrain and descending fibres extending to the medulla and the spinal cord (Bakshi, 2022).

Serotonin is important for mood-regulating, cognition functions, reward, memory, learning, and other different physiological processes like vasoconstriction and vomiting (Robinson, 1987).

A common drug class that can influence synthesis or degradation are monoamine oxidase inhibitors.

Dopamine:

Dopamine is a peripheral vasostimulant commonly utilised for the management of low blood pressure, cardiac arrest and low heart rate. Dopamine is considered important for the management of chronic congestive heart rate, and renal failure. In low doses, dopamine can also have an important role in managing hypotension, and cardiac low output (Beaulieu, J.M. and Gainetdinov, R.R., 2011).

Dopamine is synthesised following the same enzymatic sequence as noradrenaline. Dopamine is the precursor in the synthesis of noradrenaline.

Notable dopamine circuits:

  • Tuberoinfundibular pathway – responsible for regulating prolactin from the anterior pituitary gland (Grattan, 2015).
  • Nigrostriatal pathway involved in motor deficits seen in Parkinson’s disease – dopaminergic neurons originating in the substantia nigra.
  • Lesser roles in water/salt homeostasis, immune response and cell-cycle regulation (Dobolyi, 2014).

Acetylcholine:

Acetylcholine works by attaching to the cholinergic receptors (muscarinic and nicotinic). Acetylcholine operates in a variety of ways via cholinergic receptors. There are both nicotinic acetylcholine receptors which are ligand-gated ion channels and muscarinic acetylcholine receptors which are G-protein coupled receptors (Kokaz, 2020).

Acetylcholine (ACh) has a role in a variety of disease processes, the most prevalent of which is Alzheimer’s disease (AD), Lambert-Eaton myasthenic syndrome (LEMS), and myasthenia gravis (MG).

A common drug class that can influence synthesis or degradation are anticholinesterases.

GABA receptors:

Gamma-aminobutyric acid (GABA) is an amino acid that functions as an inhibitory neurotransmitter within the CNS. GABA reduces neuronal excitability by inhibiting nerve transmission. GABAergic neurons are found in the basal ganglia, brainstem, hippocampus, hypothalamus, and the thalamus (Allen, 2022).

GABA synthesis:

GABA contains 5 protein subunits, these all are connected with each other in a circular shape. These sites don’t open until a ligand binds with them. GABA is an inhibitory effect that helps to “calm the neuron’s excitability”. In order to slow the process of the CNS, GABA blocks the signals. In this way, it can control hyperactivity that is associated with fear, anxiety, and stress (Löscher, 2002)

However, during embryonic development, GABA acts as an excitatory neurotransmitter and plays a role in promoting neuronal progenitor cell size and proliferation in ventricular areas (Wang, 2009) (Wu, 2015).

A common drug that can influence synthesis or degradation is Vigabatrin.

Excitatory amino acids

Glutamate is known as the most abundant principal excitatory amino acid neurotransmitter of the central nervous system. It acts upon both ionotropic and metabotropic receptors.

It is concentrated in synaptic vesicles of neuronal terminals, from which it is released by exocytosis, anion channels, and transporter reversal. It cannot pass the blood-brain barrier and is constantly cleared from the extracellular fluid by astrocytes to prevent excessive receptor activation (Stallard, 2018).

Glutamate has vast-ranging clinical relevance:

  • Depression
  • Substance misuse disorder
  • Schizophrenia
  • Neurodegenerative disorders

References:

(1) Allen, M.J., Sabir, S. and Sharma, S. (2022). GABA receptor. [online] PubMed. Available at: https://www.ncbi.nlm.nih.gov/books/NBK526124/.

(2) Bakshi, A. and Tadi, P. (2022). Biochemistry, Serotonin. [online] PubMed. Available at: https://www.ncbi.nlm.nih.gov/books/NBK560856/#:~:text=%5B2%5D%5B4%5D%20Although [Accessed 5 Jan. 2023].

(3) Beaulieu, J.M. and Gainetdinov, R.R., 2011. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacological reviews, 63(1), pp.182-217.

(4) Dobolyi A, Grattan DR, Stolzenberg DS. Preoptic inputs and mechanisms that regulate maternal responsiveness. J Neuroendocrinol. 2014 Oct;26(10):627-40. 

(5) Grattan DR. 60 Years of Neuroendocrinology: The hypothalamo-prolactin axis. J Endocrinol. 2015 Aug;226(2):T101-22.

(6) Kokaz, S.F., Deb, P.K., Abed, S.N., Al-Aboudi, A., Das, N., Younes, F.A., Salou, R.A., Bataineh, Y.A., Venugopala, K.N. and Mailavaram, R.P. (2020). Pharmacology of Acetylcholine and Cholinergic Receptors. Frontiers in Pharmacology of Neurotransmitters, [online] pp.69–105. doi:10.1007/978-981-15-3556-7_3.

(7) Löscher, W., 2002. Basic pharmacology of valproate. CNS drugs, 16(10), pp.669-694.

(8) Robinson, M.B. and Coyle, J.T., 1987. Glutamate and related acidic excitatory neurotransmitters: from basic science to clinical application. The FASEB journal, 1(6), pp.446-455.

(9) Smith, M.D. and Maani, C.V. (2019). Norepinephrine. [online] Nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK537259/.

(10) Stallard, C.N. and Abdolreza Saadabadi (2018). Biochemisty, Glutamate. [online] Nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK537267/.

(11) Wang DD, Kriegstein AR. Defining the role of GABA in cortical development. J Physiol. 2009 May 01;587(Pt 9):1873-9.

(12) Wu C, Sun D. GABA receptors in brain development, function, and injury. Metab Brain Dis. 2015 Apr;30(2):367-79.