Introduction

Glutamate is the principal excitatory neurotransmitter in the central nervous system, playing an essential role in virtually every brain system and their associated behavioral functions. Modulation of glutamate-mediated neurotransmission is a major way in which the function of the nervous system is modified in response to experience (see Chapter 4). Drug addiction and the related behavioral and pharmacological states of sensitization, tolerance, and physical dependence appear to develop and be maintained in ways that may be functionally equivalent to other neural plasticity phenomena for which changes in the strength of glutamate-mediated synaptic transmission plays a principal role (cf. ref. 1). As such, understanding the physiological roles of glutamatergic neurotransmission and its modulation by drugs of abuse is important in identifying the neurobiological substrates of addiction and relevant molecular targets for therapeutic intervention. Agents that target glutamate receptors are the main pharmacological tools available for investigating the functions of glutamatergic synapses and their roles in behavior. The present chapter is therefore devoted to glutamate-receptor pharmacology and provides the background necessary to appreciate the use of drugs that target glutamate receptors in the specific applications discussed in later Chapters. Here, we focus on the specificity of action of these agents, their particular advantages and disadvantages as tools for neurobiological inquiry, and their efficacies and side-effect profiles, including information from studies of human subjects where available. In addition, we briefly consider agents that modify glutamate neurotransmission through effects on glutamate release, by inhibition of NAALADase, and through effects on the downstream effector nitric oxide.

In addition to their potential therapeutic roles in a range of neurological and psychiatric disorders such as epilepsy, stroke, anxiety, depression, chronic pain, and cognitive impairments, drugs affecting glutamatergic neurotransmission are also potentially important therapeutic modalities in drug-dependence disorders. Basic information on glutamate pharmacology is necessary to guide drug discovery efforts. Moreover, there is an increasing body of information on the effects of drugs that modify glutamate neurotransmission in human subjects in health and disease. An appreciation of these clinical studies is crucial for the appropriate selection of drugs for clinical trials in drug dependence.

As noted in other chapters, compounds that modulate glutamatergic transmission can interact with several types of glutamate receptors, including the ionotropic N-methyl-d-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and kainate receptors as well as a diversity of metabotropic receptors, each with unique functional roles and distributions in the central nervous system. Thus, the potential range of biological effects of glutamate modulators is theoretically quite diverse and the biological evidence is in concordance with this prediction.

From: Contemporary Clinical Neuroscience: Glutamate and Addiction Edited by: Barbara H. Herman et al. © Humana Press Inc., Totowa, NJ

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