Chemical Messengers

When an action potential reaches the axon terminus, the change in potential causes voltage-gated calcium ion channels to open and calcium ions enter the synaptic knob. Synaptic vesicles of neurotransmitters move towards the membrane and release neurotransmitter by exocytosis. The neurotransmitter diffuses into the cleft and binds to post-synaptic vesicles, leading to a response. Neurotransmitter is removed from the synaptic cleft to prevent over-excitation.

Non-peptide neurotransmitters may be monoamines, amino acids or something else entirely. Common monoamine neurotransmitters include dopamine, noradrenaline, adrenaline, serotonin and histamine. Noradrenaline and adrenaline are produced from dopamine. Amino acid neurotransmitters include glutamate, glycine and GABA. GABA, or gamma aminobutyric acid, is formed by glutamate decarboxylation. Other non-peptide neurotransmitters include acetylcholine, ATP and nitric oxide. ATP isn’t released in a calcium dependent manner and it activates purinergic receptors.

To be classically identified as a neurotransmitter, a substance must be synthesised within the neuron and stored in the nerve terminal. It must be released by nerve stimulation in a calcium-ion dependent manner and have specific mechanisms of inactivation. An exogenously applied substance can mimic the endogenous response to the neurotransmitter and an antagonist must inhibit both the neurotransmitter and the exogenously applied substance.

Dopamine is synthesised within the neuron from tyrosine (primarily dietary). Tyrosine is converted into L-DOPA in a hydroxylation reaction catalysed by tyrosine hydroxylase. L-DOPA is decarboxylated by Dopa decarboxylase, forming dopamine.

After dopamine has bound to its post-synaptic receptors, it is transported back into the pre-synaptic cell and either recycled or broken down in the mitochondria by monoamine oxidase.

Nigrostriatal projection is the projection of dopamine from the substantia nigra to the striatum.

Ventral tegmental area dopaminergic neurons project either the mesolimbic or the mesocortical pathway. In the mesolimbic pathway, axons ascend in the brainstem and the forebrain to supply limbic structures (amygdala, septal and hippocampal) and the nucleus accumbens. In the mesocortical pathway, axons ascend and innervate frontal and cingulate cortices. The hypothalamic arcuate nucleus projects to median eminence and releases dopamine directly into hypophyseal portal circulation. Dopamine goes to anterior lobe of the pituitary to inhibit release of prolactin.

Noradrenaline is released from the brain stem and distributed throughout the cortex, limbic system, cerebellum and brain stem. Its functions include feelings of reward, mood, sleep/wakefulness, state of arousal/alertness and blood pressure regulation.

Dopamine is released from the substantia nigra to the basal ganglia for motor control, from the ventral tegmental area to the limbic system and cortical forebrain for reward, mood and motivation, and from the hypothalamus to the pituitary for prolactin secretion..

Serotonin (aka 5-HT) is released from the brain stem and distributed to the cortex, limbic system, thalamus, hypothalamus and cerebellum for sleep, wakefulness, temperature regulation and mood.

Acetylcholine is released from basal forebrain and interneurons in basal ganglia and its physiological functions include arousal, learning and motor control.

Glutamate is widespread in the brain and mainly found in interneurons. Its physiological functions include memory, epilepsy and relay of sensory information. May also be involved in depression.

GABA is widespread in the brain and mainly found in interneurons. Its physiological functions include anxiety and epilepsy.

Glycine is mainly found in spinal cord interneurons and it modulates NMDA receptors. Glycine has inhibitory functions and may be involved in epilepsy.

In 1975, neuropeptides known as enkephalins were discovered. Over 30 have been discovered since, with 5 being over 30 amino acids long. Neuropeptides have many functions, for example substance P is involved in pain.

Like classical neurotransmitters, neuropeptides are also stored in vesicles in specific regions, their release is dependent on calcium ions and they cause release of 2nd messengers or change in ion channels. However, they differ from classical neurotransmitters in that they’re synthesised in the cell body as part of a large precursor protein and are transported to the terminal where they’re processed to an active peptide. Neuropeptides are released at lower concentrations and are longer action, removed more slowly from the synaptic cleft and their inactivation mechanisms are currently unclear.

Slow neurotransmission takes seconds to minutes and is indirect, occurring via G proteins and cytoplasmic second messengers. Examples include the binding of serotonin to type 1 and 2 serotonin receptors. Binding to 5-HT1R causes decrease in cAMP whereas binding 5-HT2R causes increased IP3/DAG.

Binding of dopamine to D1R causes increased cAMP and binding D2R causes decreased cAMP.

Fast neurotransmission takes place in 10s of milliseconds and is direct via receptor-operated ion channels. Entry of sodium and potassium ions into the postsynaptic neuron create an excitatory post-synaptic potential and entry of chloride ions creates an inhibitory-post synaptic potential. Temporal summation involving excitatory post-synaptic potentials may be needed for an action potential to occur.