Neurotransmitters

Neurotransmitters

Synaptic transmission relies on local synthesis, and release of neurotransmitter molecules at the synapse, binding of the neurotransmitter to its cognate post-synaptic receptor(s) and inactivation/removal of the neurotransmitter from the synaptic space to terminate the activation. Neurotransmitter inactivation is achieved by several mechanisms, including diffusion away from the synaptic space, enzymatic degradation (e.g. acetylcholinesterase which breaks acetylcholine) and reabsorption into the pre-synaptic terminal (e.g. reuptake of the monoamines by the selective reuptake transporters for dopamine, serotonin and noradrenaline).

Neurotransmitters act via ionotropic receptors and/or metabotropic receptors. Ionotropic receptors are ion channels to which the neurotransmitter binds directly, to modulate channel opening. Metabotropic receptors are ion channel associated G protein-coupled receptors which bind the neurotransmitter molecule facilitating indirect modulation of ion channel activity.

Neurotransmitters can be either excitatory or inhibitory in action.

Inhibitory neurotransmitters include serotonin, GABA and dopamine. Depending on context dopamine can be both excitatory and inhibitory. Serotonin is discussed in its own separate section below.

GABA (gamma-aminobutyric acid) acts via GABAB receptors (a pair of subunits which form a dimeric G protein-coupled receptor) which couple to ion channels, and ionotropic GABAA receptors (ligand-gated ion channels). GABA action contributes to motor control, vision and many other cortical functions, such as anxiety regulation. Epilepsy and Huntington’s disease tremor are two conditions treated by drugs which increase central GABA levels.

Dopamine acts via a family of G protein-coupled receptors. Activation of dopamine receptors is involved in controlling movement and posture. Loss of dopamine in specific areas of the brain causes the muscle rigidity typical of Parkinson’s disease. Dopamine analogues are used to re-establish physiological levels of dopamine to treat Parkinsonism. Dopamine also plays a central role in positive reinforcement and dependency, drive and motivation and is required for focus. Stimulants such as ADHD medications and caffeine mediate dopamine release at the synapse, thereby improving focus and attention span. It should be noted that prolonged stimulation can lead to dopamine depletion. Dopamine is also a chemical precursor required for the synthesis of epinephrine and norepinephrine.

 

Excitatory neurotransmitters include acetylcholine, glutamate, and the catecholamines dopamine, epinephrine and norepinephrine.

Acetylcholine is a very widely distributed excitatory neurotransmitter that triggers muscle contraction and stimulates the excretion of certain hormones. In the central nervous system, it is involved in wakefulness, attentiveness, anger, aggression, sexuality, and thirst. It acts via a family of muscarinic acetylcholine receptors (mAch receptors).

Glutamate binds to an orthosteric binding site on G protein-coupled receptors  of the metabotropic glutamate receptor family (mGlu receptors) which transmit the signal to ionotropic glutamate receptors. It is a major excitatory neurotransmitter associated with memory and learning.

Epinephrine (adrenaline) acts via alpha- and beta-adrenoceptors (G protein-coupled receptors) to regulate heart rate and blood pressure. Epinephrine levels can be reduced in response to long-term stress or insomnia, and can be elevated in ADHD.

As a neurotransmitter norepinephrine (noradrenaline) is required for attentiveness, emotions, sleeping, dreaming, and learning. Low levels of norepinephrine are associated with low energy, decreased ability to stay focussed and sleep cycle problems. Elevated norepinephrine can cause anxiety and low mood. Norepinephrine also acts in the circulatory system to cause vasoconstriction and increased heart rate.

Stress, poor diet, neurotoxins, genetic predisposition, drugs (prescription and recreational), alcohol and caffeine can all reduce neurotransmitters to suboptimal levels.

Other neurotransmitters: aspartate (an excitatory amino acid), glycine (an inhibitory amino acid), histamine, adenosine and adenosine triphosphate (ATP) are all thought to have some neurotransmitter function. Peptides such as substance P, beta endorphin, enkephalin, somatostatin, vasopressin, prolactin, angiotensin II, oxytocin, gastrin, cholecystokinin, thyrotropin, neuropeptide Y, insulin, glucagon, calcitonin, neurotensin and bradykinin may also exhibit some neurotransmitter-like activities, or more likely act as neuromodulators affecting the the synthesis, breakdown, or reabsorption (reuptake) of neurotransmitters. The gasotransmitter NO, acts as a signalling molecule at synapses, passing between cells by passive diffusion.