This chapter reviews the normal physiology of neurotransmission, the molecular action and biochemistry of several major neurotransmitters and their receptors, and the toxicologic mechanisms by which numerous xenobiotics act at the molecular level. Acetylcholine, norepinephrine, epinephrine, dopamine, serotonin, γ-aminobutyric acid (GABA), γ-hydroxybutyrate (GHB), glycine, glutamate, and adenosine are the neurotransmitters and neuromodulators of toxicologic interest that are discussed in this chapter.
When examining molecular actions of xenobiotics on neurotransmitter systems, it quickly becomes apparent that substances rarely possess single pharmacologic actions. As examples, doxepin, in part, antagonizes voltage-gated sodium channels, histaminic H1 and H2 receptors, α-adrenoceptors, muscarinic acetylcholine receptors, dopamine D2 receptors, and GABAA receptors; prevents potassium efflux; and inhibits norepinephrine, serotonin, and adenosine uptake. And carbamazepine blocks voltage-gated sodium channels; inhibits uptake of norepinephrine, adenosine, and serotonin; antagonizes adenosine and muscarinic receptors; and activates GABAB and mitochondrial benzodiazepine receptors. For obvious reasons, then, this chapter cannot include every action of every xenobiotics on the nervous system. Nor is it meant to be a complete discussion of toxic syndromes produced by various xenobiotics, as these are discussed in specific chapters. Rather, it provides a general and basic understanding of the mechanisms of action of various xenobiotics affecting neurotransmitter function and receptors, especially in the central nervous system. With this focus, the clinical effects produced are more easily understood and predicted, and specific treatments can be rationally undertaken. Given the complexity of the nervous system and the numerous actions of a given xenobiotic, it is not always clear which neurotransmitter system is producing an observed effect. Therefore, specific xenobiotics may be found in several sections. An attempt is made to note a xenobiotics main mechanism of action, although other actions are noted when possible.
Membrane Potentials, Ion Channels, and Nerve Conduction
Membrane-bound sodium–potassium adenosine triphosphatase (ATPase) moves three sodium ions (Na+) from inside the cell to the interstitial space while pumping two potassium ions (K+) into the cell. Because the cell membrane is not freely permeable to large, negatively charged intracellular molecules, such as proteins, an equilibrium results in which the inside of the neuron is negative with respect to the outside. This typical neuronal resting membrane potential is –65 mV.
Sodium, calcium (Ca2+), K+, and chloride (Cl–) ions move into and out of neurons through ion channels. Ions always move passively down electrochemical gradients through ion channels, which are long polypeptides comprising several subunits that span the plasma membrane several times. Many different ion channels are structurally comparable, sharing similar amino acid sequences.15 Channels for a specific ion can also vary in structure, depending on the specific subunits that have combined to form the channel. Because of structural similarity of different channels, it is not surprising that many xenobiotic are able to bind to more than one type of ion channel.