Neurotransmitters

The forensic investigation of an accident or death is not always aided by the presence of physically obvious signs, such as a stab wound or gunshot wound. Injury or death inflicted by toxic agents may have less subtle physical effects. Toxins can interfere with the normal physiological functions of the body. Then, their presence is forensically evident by a physiological change in the norm. One example is agents that disrupt the action of neurotransmitters.

Neurotransmitters are chemicals released in minute amounts from the terminals of nerve cells in response to the arrival of an action potential. There are now more than 300 known neurotransmitters and they act either locally in point-to-point signal transmission (e.g., the motor nerve of a neuromuscular junction) or at a distal site (e.g., the hypothalamic releasing hormones acting on the anterior pituitary). Locally acting neurotransmitters relay the electrical signal traveling along a neuron as chemical information across the neuronal junction, or synapse, that separates one neuron from another neuron or a muscle. Neurons communicate with peripheral tissues, such as muscles, glands etc., or with each other, largely by this chemical means rather than by direct electrical transmission.

Neurotransmitters are stored in the bulbous end of the nerve cell's axon. When an electrical impulse traveling along an axon reaches the junction, the neurotransmitter is released and diffuses across the synaptic gap, a distance of as little as 25 nanometers (nm) or as great as 100 micrometers (mm). The interaction of the neurotransmitter with the postsynaptic receptor of the target cell generates either an excitatory postsynaptic potential (EPSP) or an inhibitory postsynaptic potential (IPSP). Transmitters that lead to EPSPs appear to open large, non-specific membrane channels, permitting the simultaneous movement of Na⁺, K⁺ and Cl^-. IPSPs are caused by Cl^- flux only.

Neurotransmitters include such diverse molecules as acetylcholine, noradrenalin, serotonin, dopamine, γ-aminobutyric acid, glutamate, glycine and numerous other small monoamines and amino acids. There are also small peptides, which appear to act as chemical messengers in the nervous system. They include substance P, vasopressin, oxytocin, endorphins, angiotensin, and many others. A rather unusual but interesting neurotransmitter is the gas nitric oxide. This diverse range of chemical neurotransmitters may suggest that chemical coding could play as important a part in communication between neurons as do the strict point-to-point connections of neural circuitry.

Acetylcholine is one of the neurotransmitters functioning in the peripheral nervous system. It is released by all motor nerves to control skeletal muscles and also by autonomic nerves controlling the activity of smooth muscle and glandular functions in many parts of the body. Norepinephrine is released by sympathetic nerves controlling smooth muscle, cardiac muscle, and glandular tissues. In these tissues acetylcholine and norepinephrine often exert diametrically opposed actions.

The neurotransmitters used by the majority of fast, point-to-point neural circuits in the central nervous system (CNS) are amino acids. Of these, the inhibitory substance γ-aminobutyric acid (GABA) is well characterized and it is present in all regions of the brain and spinal cord. GABA rapidly inhibits virtually all CNS neurons when applied locally by increasing cell permeability to chloride ions, thus stabilizing resting membrane potential near the chloride equilibrium level. Although GABAergic (GABA-producing) neurons also exist in the spinal cord, another inhibitory amino acid, glycine, predominates in this region of the CNS. Glycine is present in small inhibitory interneurons in the spinal cord gray matter and mediates the inhibition of most spinal neurons. The amino acids L-glutamate and L-asparagine depolarize neurons by activating membrane sodium channels and are ubiquitously distributed, appearing as the most common excitatory transmitters for interneurons in the CNS.

In contrast to the point-to-point signaling in which amino acids are involved, the monoamines are mainly associated with the more diffuse neural pathways in the CNS. The monoamines are present in small groups of neurons, primarily located in the brain stem, with elongated and highly branched axons. These diffuse ascending and descending monoaminergic innervations impinge on very large terminal fields and there is evidence that the monoamines may be released from many points along the varicose terminal networks of monoaminergic neurons. Most monoamines released in this way occur at nonsynaptic sites and a very large number of target cells may be affected by the diffuse release of these substances, which are therefore thought to perform modulatory functions of various types.

One of the most remarkable developments was the realization that most peptide hormones of the endocrine and neuroendocrine systems also exist in neurons. These are by far the largest group of potential chemical messengers. For example, the opioid peptides (endorphins) have attracted enormous interest because of their morphine-like properties. They are consequently of considerable interest in the understanding of pain. Endorphins represent a family of chemical messengers found in all regions of the CNS including the pituitary (e.g., beta-endorphin and dynorphin) and the peripheral enteric nervous system. Their presence in regions such as the basal ganglia and the eye's retina, where it is unlikely that they have any connection with pain pathways, suggests that they may also have other diverse functions. There is still much to be learned about the possible functions of neuropeptides in the CNS. In all cases so far examined the peptides seem to be capable of being released by a specialized secretory mechanism from stimulated CNS neurons. They can exert powerful effects on the CNS. For example, the direct administration of small amounts of peptide to the brain can elicit a variety of behavioral responses, including locomotor activity (substance P), analgesia (endorphins), drinking behavior (angiotensisn II), female sexual behavior (LHRH), and improved retention of learned tasks (vasopressin).

An interesting and novel neurotransmitter identified in the 1980s is nitric oxide (NO). This is a highly reactive naturally occurring gas generated in the body from arginine and has the alternative name "epithelium-derived-relaxing factor." Synthesis of NO in blood vessel epithelia occurs in response to the distortion of blood vessels by blood flow. The gas then rapidly diffuses into the surrounding muscle layers, causing them to relax. It, therefore, has vasodilatory (dilation of blood vessels) properties and as a neurotransmitter occurs in a number of nerve networks. For example, it is known to be active in the dilation of arteries supporting the penis and in the relaxation of muscles of the corpora cavernosa (the two chambers filled with spongy tissue which run the length of the penis). NO released from stomach nerves causes the stomach to relax in order to accommodate food. Intestinal nerves also induce the relaxation of the intestinal muscle by releasing NO. In addition, nervous activity in the cerebellum is increased by NO and it appears that NO is an important neurotransmitter associated with memory. Despite its usefulness, nitric oxide can have a toxic effect on body cells and has been implicated in Huntington's disease and Alzheimer's disease.