Chapter 13: Neurotransmitters and Neuromodulators

INTRODUCTION

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 neurotransmitters and neuromodulators of toxicologic interest discussed herein.

When examining molecular actions of xenobiotics on neurotransmitter systems, it quickly becomes apparent that xenobiotics rarely possess single pharmacologic actions. As examples, doxepin, in part, antagonizes voltage-gated sodium channels, voltage-gated potassium channels, histaminic H₁ and H₂ receptors, α-adrenergic receptors, muscarinic acetylcholine receptors, dopamine D₂ receptors, and GABA_A receptors; and inhibits norepinephrine, serotonin, and adenosine reuptake. Similarly, carbamazepine blocks voltage-gated sodium channels; inhibits the reuptake of norepinephrine, adenosine, and serotonin; antagonizes adenosine and muscarinic receptors; activates GABA_B receptors; and binds to benzodiazepine-binding sites on mitochondria. For obvious reasons, then, this chapter cannot include every action of every xenobiotic on the nervous system. Nor is it meant to be a complete discussion of toxidromes produced by various xenobiotics, as these are discussed in specific chapters. Rather, this chapter provides a general and basic understanding of 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 are found in several sections. An attempt is made to note the major mechanism of action of a xenobiotic, although other actions are noted when possible.

NEURON PHYSIOLOGY AND NEUROTRANSMISSION

Membrane Potentials, Ion Channels, and Nerve Conduction

Membrane-bound sodium, potassium adenosine triphosphatase (ATPase) moves 3 sodium ions (Na⁺) from inside the cell to the interstitial space while pumping 2 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. When moving through ion channels, which are long polypeptides comprising several subunits that span the plasma membrane multiple times, ions always move passively down electrochemical gradients. Many different ion channels are structurally comparable, sharing similar amino acid sequences.²⁹ Channels for a specific ion 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 xenobiotics are ...