Overview of Toxicants that Affect Neurotransmitters

General

• Transmission of nervous impulses across the synapse is chemically mediated through neurotransmitters.
• Neurotransmitter is released from the presynaptic nerve terminal of a stimulated neuron, crosses the synaptic cleft, and combines with a specific receptor on the postsynaptic membrane. Binding to the postsynaptic receptor causes a conformational change in the postsynaptic membrane and, depending on the nature of the neurotransmitter and receptor, causes either depolarization (excitation) or hyperpolarization (inhibition) in the postsynaptic neuron.
• Criteria used to define neurotransmitters:

1. Substance must be synthesized and stored within the neuron from which it is released.
2. Substance is released from neuron on arrival of a nerve impulse.
3. A synthetic neurotransmitter applied exogenously must mimic the actions of the true neurotransmitter on the postsynaptic membrane.
4. A mechanism for the rapid termination of the action of a released neurotransmitter must exist.

• Classes of neurotransmitters:

1. Acetylcholine (ACh)
2. Catecholamines: dopamine (DA), norepinephrine (NE), epinephrine (E)
3. Amino acids and amino acid derivatives: Serotonin (5-hydroxytryptamine = 5-HT), gamma-aminobutyric acid (GABA), histamine, glycine, aspartic acid, glutamic acid
4. Peptides: enkephalins, thyroid-releasing hormone, substance P, bombesin, endorphins

Sites at which toxins can act to modify neurotransmission

1) axonal transport, 2) axonal membrane, 3) precursor availability, 4) neurotransmitter synthesis, 5) storage, 6) intra-cellular organelles, 7) neurotransmitter release, 8) receptor sites, 9) postsynaptic mechanisms, 10) neurotransmitter-inactivating mechanisms [1].

Acetylcholine

Synthesized from choline and acetyl CoA by choline acetyltransferase.

• Broken down by acetylcholinesterase to choline and acetate

Action of acetylcholine and acetylcholinesterase

• Functions as neurotransmitter at following sites:

1. All preganglionic nerve terminals (both parasympathetic and sympathetic) of the autonomic nervous system.
2. All postganglionic parasympathetic nerve terminals.
3. The neuromuscular junction (voluntary nerve to skeletal muscle).
4. The adrenal medulla.
5. The central nervous system.
6. Postganglionic sympathetic nerve terminals at sweat glands.

• Two main types of cholinergic receptors:

1. Muscarinic receptors - mimic the effect of parasympathetic nerve stimulation (slow heart, miosis, exocrine gland stimulation, smooth muscle stimulation in the GI and bronchioles, micturition).
2. Nicotinic receptors - located at the neuromuscular junction of voluntary nerves and skeletal muscle, at all ganglia in the autonomic nervous system, at the adrenal medulla, and in the CNS.

Location of cholinergic synapses in the nervous system - N = postsynaptic nicotinic receptors, M = postsynaptic muscarinic receptors, Ad = adrenaline release from adrenal medulla, NA = noradrenaline release from sympathetic nerve ending.

Catecholamines

• Synthesized from tyrosine
• Broken down by monoamine oxidase (MAO) and catecholamine o-methyltransferase (COMT)

Norepinephrine

• Neurotransmitter in postganglionic sympathetic nerves (stress, fright, fight, or flight reaction) and within the central nervous system. Norepinephrine is also released in association with epinephrine from the adrenal medulla.
• Two main types of receptors:

1. α-adrenergic receptors:

1. α1 adrenoreceptor--postsynaptic receptor on smooth muscles and glands.
2. α2 adrenoreceptor--presynaptic receptor located on postganglionic neurons, mediating feedback inhibition of norepinephrine release. Postsynaptic a2 receptors also appear to be present at extrasynaptic sites in the blood vessels and in the CNS.

2. β-adrenergic receptors:

1. β1 adrenoreceptors - in heart.
2. β2 adrenoreceptors--other tissues outside CNS.

• Functions of α-adrenoreceptors:

1. α1 receptors - mydriasis - contraction of radial muscle of iris.
2. α receptor - asoconstriction.
3. α1 receptors - GI nonsphincteric smooth muscle relaxation; a receptors - sphincter muscle contraction.
4. α receptor--constriction of the trigone and sphincter in bladder.
5. α receptor--contract smooth muscle of pilomotor muscles, nictitating membrane, splenic capsule and salivary glands.

• Functions of β-adrenoreceptors:

1. β1 receptors in heart--stimulation results in increase in both the force and rate of contraction.
2. β2 receptors--vasodilation in skeletal muscles and liver.
3. β2 receptors--relaxation of bronchial smooth muscle--bronchodilation.
4. β2 receptors--relaxation of nonsphincteric smooth muscle of GI tract.
5. β2 receptors--mediate relaxation of uterus in pregnancy--relaxation of detrusor muscle of bladder.
6. β1 receptors--increased renin release from juxtaglomerular cells.
7. β2 receptors--enhance glycogenolysis in liver, β1 receptors increase lipolysis in adipose tissue, and decrease release of insulin from pancreas
8. Increase cAMP synthesis

1. cAMP alters membrane permeability to ions and changes intracellular ion binding.
2. cAMP is broken down by phosphodiesterases.
3. Substances inhibiting phosphodiesterases (methylxanthines) prolong the life of cAMP and tend to potentiate and prolong the effects of β -adrenoceptor stimulation.

See Ware [2], for a more comprehensive review of β blockers.

Dopamine

• Neurotransmitter in the CNS.
• Functions: integrates incoming sensory stimuli; initiates and controls fine movement (nigro-neostriatal pathway); controls emotional behavior (midbrain mesolimbic-forebrain system); controls hypothalamic-pituitary endocrine system (tubero-infundibular system).

Amino Acid Derivatives

Serotonin (5-HT) -

• Located peripherally in enterochromaffin granules of the gut and in blood platelets; it has a neurotransmitter role only in the CNS.
• Has the structure of an indole alkyl amine and is synthesized from the amino acid L-tryptophan.
• Distribution of 5-HT in the CNS forms a diffuse network, and exact functional roles are not firmly established.
• May be important in the control of mood and behavior, motor activity and its control, feeding and control of hunger, thermoregulation, sleep, certain hallucinatory states, and possibly some neuroendocrine control mechanisms in the hypothalamus.

Histamine

• Occurs in several tissues of the body - stored in a bound form in mast cells, platelets, and basophils and released in response to stimuli such as allergic reactions and injury. In the CNS, gastric mucosa, lungs, and skin, histamine is stored in a different complex, and at these sites, it can be released in response to signals of hormonal or neuronal origin.
• Formed by the decarboxylation of L-histidine.
• Two types of histamine receptors peripherally:

1. H1 receptors - bronchoconstriction, increased capillary permeability, wheal and flare reaction.
2. H2 receptors- gastric acid secretion.

• Uneven distribution of histamine receptors within CNS--suggested that histamine may have a role in arousal, in mechanisms related to nausea and vomiting, and in the control of blood pressure and water metabolism.

Amino Acid Neurotransmitters

• Certain amino acids found within the mammalian CNS appear to fulfill the criteria for neurotransmitters. Amino acids found in peripheral nervous system don't fulfill all the criteria.
• Two main classes:

1. Excitatory - acidic amino acids-glutamic acid, aspartic acid.
2. Inhibitory - neutral amino acids-q-aminobutyric acid (GABA), glycine, taurine.

• Excitatory amino acid neurotransmitters cause increased sodium conductance of the postsynaptic membrane and increase neuronal firing rate (like acetylcholine).
• Inhibitory (or depressant) amino acid neurotransmitters cause increased chloride conductance of postsynaptic membranes and decreased firing rate.

Gamma-Aminobutyric Acid

• Inhibitory neurotransmitter in brain, spinal cord, and retina.
• Formed by the decarboxylation of L-glutamic acid.
• Widespread distribution within CNS, with high concentrations in the hypothalamus, hippocampus, and basal ganglia of the brain in the substantia gelatinosa of the dorsal horn of the spinal cord. Most GABA is associated with short inhibitory interneurons, although some long-axon pathways within the brain are known.
• Presynaptic inhibition--reduces excitatory transmission in primary afferent fibers by action of GABA.
• If GABA function is impaired, may result in convulsive, tetanic, and spastic disorders.

Glycine

• An important inhibitory neurotransmitter in small inhibitory interneurons in the brainstem and spinal cord.
• Effects of glycine are postsynaptic.
• Neurotransmitter for Renshaw cells in ventral horn of spinal cord--Renshaw cells receive excitatory input from recurrent collaterals of spinal motor neurons--axons from the Renshaw cells synapse on the motor neuron.
• Probably involved in regulation of spinal and brainstem reflexes.

Adenosine

• Inhibitory neurotransmitter in the brain.
• Inhibition by methylxanthines, especially caffeine, results in increased alertness.

L-Glutamic Acid

• Excitatory neurotransmitter.
• In spinal cord concentrated at primary afferent fibers in dorsal roots--may relay sensory information and regulate motor activity and spinal reflexes.
• In brain--high concentrations in cortex, hippocampus, neostriatum, and cerebellum.
• Role not determined yet.
• Some excitatory amino acids found in certain toxic plants over-stimulate glycine receptors. Persistent overstimulation can lead to neuronal damage.

L-Aspartic Acid

• Excitatory neurotransmitter.
• Highest concentration in midbrain and dorsal and ventral grey matter of spinal cord.
• Role unknown.

Taurine

• Inhibitory neurotransmitter or neuromodulator.
• May act as a membrane stabilizer.
• Functional role unknown.

Peptides

• Relatively newly recognized--still unsure if true neurotransmitters or neuromodulators.

Endorphins and Enkephalins

• Mimic effects of morphine in biological system.

Substance P

• Concentrated in dorsal horn of spinal cord and substantia nigra of brain.