Neuroscience/Cellular Neurobiology/Neurotransmitters

Neurotransmitters, as noted previously, are molecules that act as messages in the nervous system. These molecules range in complexity from the two carbon transmitter glycine to large proteins. There are three major classes of neurotransmitters:

Neurotransmitter Criteria
There are three criteria for a chemical to be classified as a neurotransmitter: It must be synthesized and stored in presynaptic terminals, released from terminals upon stimulation, and it must have specific receptors on the postsynaptic cells. Synthesis and storage of the chemical can be demonstrated with immunocytochemistry and in situ hybridization. Release of the chemical upon stimulation can be shown with a chemical assay. The presence of the receptors can be demonstrated with neuropharmacological methods or autoradiography.

Discovery of first neurotransmitter
Otto Loewi's frog heart experiment first demonstrated the existence of a neurotransmitter. Two frog hearts were placed in separate but connected chambers, bathed in solution. Loewi stimulated one heart, and the other was stimulated as well. The stimulation of the second is the same as the stimulation of the first, but it is delayed because the molecule must travel through the solution connecting the two chambers. In this case the chemical is acetylcholine.

Types of neurotransmitters
There are many neurotransmitters, but the basic transmitters are the amino acid neurotransmitters: glutamate, GABA (gamma-amino butyric acid) and glycine. In addition, there is acetylcholine, serotonin and the catecholamines: dopamine, norepinephrine and epinephrine. Others include histamine, opiates, gases (NO, CO), lipids, endocannabinoids and neuropeptides.

Synthesis, transportation and packaging
Neurotransmitters are synthesized, transported and packaged in slightly different ways depending upon whether they are small molecule neurotransmitters or neuropeptides. Small molecule neurotransmitters are synthesized by cytosolic proteins which are slowly transported to the terminal. In the terminal, synthesis of the neurotransmitter occurs. With the large neuropeptides, synthesis of precursor proteins occurs in the soma, and then the neuropeptides are packaged. The vesicles undergo fast anterograde transport and while in transport, the large precursor proteins are cleaved to form the neuropeptides. So while small molecule neurotransmitters are synthesized in the terminals, neuropeptides are synthesized partly in the soma and partly during transport.

Release
Axon terminals can release both a large neuropeptide neurotransmitter and a small molecule neurotransmitter. The synaptic vesicles (small) that contain the small molecule neurotransmitter will sit on the membrane and wait for release while the synaptic granules (large) containing the neuropeptides will remaing off the membrane farther back. The distance difference creates different conditions for exocytosis: low frequency firing causes small [Ca2+] inside the axon terminal, sufficient only for the release of the small molecule neurotransmitter vesicles. High frequency firing will cause a high [Ca2+] inside the cell, which will cause the exocytosis of the large neuropeptide granules.

Glutamate
Glutamate is an excitatory amino acid ntr. Glutamate is synthesized from glutamine by the enzyme glutaminase. After release, it is taken up by glutamate transporters on the membranes of astrocytes and neurons. It is converted back to glutamine by glutamine synthetase. Transporters will then transfer the glutamine from the astrocytes to the neuron's axon terminal, where repackaging occurs. The postsynaptic receptors for glutamate include three types of ionotropic receptors, AMPA, kainate, and NMDA, and eight metabotropic receptors, mGluR1 through mGluR8.

GABA
Gamma-amino butyric acid, or GABA, is an inhibitory amino acid. Its synthesis occurs from glutamate via glutamic acid decarboxylase. GABA has an ionotropic receptor, GABAA, that directly gates Cl- channels, and it has a metabotropic receptor, GABAB, that gates K+ and Ca2+ channels indirectly. Reuptake of GABA occurs by astrocytes and neurons, and transporters are also responsible for its recycling and breakdown.

ACh
Actylcholine, or ACh, is another small molecule ntr. The precursors are Acetyl CoA and choline (an amino acid), and it is synthesized by acetyl transferase. After release, it is broken down in the synapse by acetyl cholinesterase into acetate and choline. A choline transporter brings choline back into the terminal, where resynthesis of acetylcholine occurs. ACh has the nicotinic receptor, which is ionotropic, and the muscarinic receptor, which is metabotropic. In the central nervous system, ACh is generated by three areas: the PMT complex, which projects to the basal forebrain; the basal nucleus of Meynart, has cortical projections, and the medial septum, which also projects to the cortex. In Alzheimers patients, the ACh system begins to fail to produce enough ACh. In the autonomic nervous system, there are two divisions, sympathetic and parasympathetic. The sympathetic system uses acetylcholine in just the preganglionic neurons, but not the postganglionic neurons. The parasympatheticdivision uses ACh in both the preganglionic and the postganglionic neurons. The word parasympathetic has more a's in it that sympathetic, so it must use more ACh (this is how to remember the sympathetic system uses ACh in only one division.)

Catecholamines
The catecholamines are a group of transmitters that share the catechol chemical group, and they are all synthesized from the same chemical pathway. Dopamine, norepinephrine and epinephrine are the ntrs. The precursor is tyrosine, which is an amino acid, and the chemical DOPA is synthesized from tyrosine by tyrosine hydroxylase. Dopamine is then synthesized from DOPA by DOPA decarboxylase. Norepinephrine is synthesized from dopamine by dopamine beta hydroxylase, and epinephrine from norepinephrine by PNMT. The catecholamines are associated with mood, stress, fluid and energy homeostasis, and autonomic function. There are two metabotropic epinephrinergic receptors, two norepinephrinergic receptors and four dopaminergic receptors.

Dopamine System
The dopamine system is roughly divided into the three sources. The ventral tegmental area projects to the frontal lobe of the cortex, and it is associated with Schizophrenia and reward systems. The substantia nigra projects to the striatum, and its failure to produce enough dopamine is correlate with Parkinson's disease; this system affects fine motor control. The basal hypothalamus projects to the neuroendocrine cells, which regulate posterior pituitary functions, including prolactin secretion.

Norepinephrine System
The central norepinephrine system has two main sources, the pons and the medulla. Within the pons, norepinephrine is produced in the locus coerulus and the dorsal NA bundle. Within the medualla, the solitary tract nucleus, ventrolateral medulla, and the ventral NA bundle are responsible for the production of norepinephrine. These five areas diffuse projections throughout the brain, and the system affects arousal and mood. In the autonomic nervous system, norepinephrine is used in the postganglionic neurons of the sympathetic division (beta receptors).

Serotonin
Serotonin (5-HT) is another ntr synthesized from an amino acid, and it is synthesized in two steps: 5-hydroxytryptophan is synthesized by tryptophan-5 hydroxylase from tryptophan, and then 5-Hydroxytryptamine (5-HT, or serotonin) is synthesized from 5-hydroxytryptophan by aromatic L-amino decarboxylase. Serotonin receptors are numbered, 5-HT1 through 5-HT7; 5-HT4 is thought not to be used in the brain, and 5-HT3 is an ionotropic receptor (the other six are metabotropic.) Serotonin is produced in the Raphe nuclei, and projections to the spine affect pain while projections to the rest of the brain affect arousal, mood, and the sleep/wake cycle.

Hypothalamic Neuropeptides
The hypothalamus is arranged around the third ventricle in three layers, periventricular, medial and lateral layers. Under the hypothalamus is an outcropping called the pituitary gland. The pituitary gland has two divisions: the posterior pituitary and the anterior pituitary. The posterior part of the pituitary gland contains magnocellular neuroendocrine cells that release oxytocin, which mediates the milk ejection reflex, vasopression (or ADH), which regulates blood volume and osmolality. The anterior part of the pituitary gland contains parvocellular neuroendocrine cells which release neuropeptides that cause the secretion of hormones.