Elsevier

Biological Psychiatry

Volume 52, Issue 10, 15 November 2002, Pages 1008-1030
Biological Psychiatry

Review article
Molecular targets in the treatment of anxiety

https://doi.org/10.1016/S0006-3223(02)01672-4Get rights and content

Abstract

Although the cathecholamine systems have long been the focus of drug therapy in anxiety and depression, the development of novel drugs specifically aimed at new targets within these traditional neurotransmitter systems and at targets outside of these systems is now propelling the field of drug development in anxiety. A greater understanding of regional brain networks implicated in stress, anxiety, and anxious behaviors has provided localized targets for anxiolytics. Within the serotonin and norepinephrine systems, increased understanding of postsynaptic receptor regulation with chronic treatment and cross-system effects of drug therapy have been critical in furthering our understanding of effective pharmacological interventions. Receptors within the glutamate, γ-aminobutyric acid, and neuropeptide systems provide a rich diversity of drug targets, both in localization and function. While acknowledging significant clinical and biological differences between the various anxiety disorders, an important aspect of modern neurobiological research is to look for similarities among these disorders, given that they are highly comorbid with each other and often respond to the same spectrum of treatments. Here we review current views on both traditional and new molecular targets in the treatment of anxiety, realizing that the ultimate challenge in effective anxiolytic drug development may be achieving specificity in brain regions important in generating and sustaining anxiety.

Introduction

Since the introduction of lithium in 1948, the field of neuropsychiatry has successfully employed psychotropic medications in the treatment of a wide range of psychiatric disorders with limited knowledge of the mechanism of action of these drugs. A focused effort to study the neurobiological basis of psychiatric disorders has led to greater understanding of important neurophysiological and neurochemical abnormalities related to these disorders, and thus related mechanisms of action for effective drugs have been proposed. Therefore, although we now understand that tricyclic antidepressants inhibit the reuptake of norepinephrine and serotonin (5-HT), and that the selective serotonin reuptake inhibitors (SSRIs) inhibit reuptake of 5-HT by blockade of the presynaptic transporter, our understanding of alloreceptor and heteroreceptor changes with chronic antidepressant use is still developing.

Encouragingly, new drugs have recently been developed to specifically target systems and receptors previously established through neurobiological studies to be functioning aberrantly. For instance, drugs developed to affect targets outside the classic catecholamine pathways, such as the neuropeptides corticotrophin-releasing factor (CRF) and substance P, are the result of the translation of findings from basic and clinical research into novel pharmacologic targets for the treatment of depressive and anxiety disorders.

Although we acknowledge the well-established clinical differences between the various anxiety disorders, they share many clinical and biological similarities, are highly comorbid, and tend to respond to the same treatments. Therefore, in this article we discuss commonalities in the neurobiological basis of anxiety as they pertain to potential molecular targets and new pharmacological mechanisms of action for the treatment of anxiety disorders. We focus on current drugs being used in the treatment of anxiety disorders and on molecular targets for new agents under investigation and currently in development.

Section snippets

Brain circuitry and anxiety

Anxiety, although not identical to fear, is closely linked to fear responding. Fear learning, such as that involving fear-conditioning or fear-potentiated startle, recruits a neuroanatomical network centered around the amygdala, the key structure in coordinating fear responding Davis 1992, Anderson et al 1993. In addition to its role in detecting, coordinating, and maintaining fearful emotions, the amygdala is also important in vigilance, detecting threat, and determining the meaning and

Basic research/preclinical studies

Abnormalities in serotonergic function in anxiety may be the result of varied processes, including deficient or excessive innervations to key structures, and/or cellular mechanisms resulting in aberrant neurotransmission. At the cellular level, abnormalities may include abnormal regulation of 5-HT release and/or reuptake (a role of the presynaptic receptors) or abnormal responsiveness to 5-HT signal (a role of the postsynaptic receptors). The presence of 5-HT heteroreceptors on neurons of other

Basic research/preclinical studies

The noradrenergic system, with cell bodies originating within the locus coeruleus (LC) and other medullary and pontine nuclei, has extensive connections with fear circuitry structures and, along with the CRF system, is a principal stress–response system of the body. The LC projects to the prefrontal and entorhinal cortices, the amygdala, the bed nucleus of the stria terminalis (BNST), the hippocampus, the periaqueductal gray, the thalamus, the hypothalamus, and the nucleus of the solitary tract

Basic research/preclinical studies

Corticotropin-releasing factor peptides play a critical role in the human stress response, and therefore there has been increasing interest in investigating the potential pharmacological modulation of this system to reduce the maladaptive responding to stressful stimuli, which is characteristic of the anxiety disorders. The CRF peptide family consists of the polypeptides CRF, urocortin, stresscopin, and stresscopin-related peptide.

Corticotropin-releasing factor–containing neurons are widely

Basic research/preclinical studies

Gamma-aminobutyric acid is the predominant inhibitory neurotransmitter in the central nervous system. It is formed by the decarboxylation of glutamate, the major excitatory amino acid in the central nervous system, utilizing the enzyme l-glutamic acid decarboxylase (GAD) (see Olson 2002 for review). The source for much of the GABA neurotransmitter pool is derived from glial storage pools of glutamine, which also provide the source for glutamate.

Gamma-aminobutyric acid receptors consist of

Basic research/preclinical studies

A full review of the complex neuropharmacology of L-glutamic acid (glutamate) is beyond the scope of this article (see Coyle et al 2002). As the major excitatory amino acid in the central nervous system, this single neurotransmitter is integral to the functioning of up to 40% of all brain synapses (Coyle et al 2002). Glutamate is primarily derived from intermediary glucose metabolism and can be formed directly from glial cell–synthesized glutamine stores. Several glutamate transporters serve to

Substance P

The peptide tachykins are widely distributed throughout the brain, spinal cord, and peripheral nervous system. Although interest in this peptide group has primarily focused on its role in pain and inflammation, researchers have long noted that peptide tachykinins are positioned to modulate neuronal activity in brain areas implicated in the pathophysiology of mood and anxiety disorders. Limbic areas in which substance P has been identified include the amygdala, hypothalamus, LC, hippocampus, and

Conclusions

The scope of this article, although not complete, describes the varied systems that have been implicated in the pathogenesis and maintenance of anxiety, and suggests a tremendous range of potential targets for the development of new anxiolytic compounds. Clearly, the relationship between preclinical neurochemical models of stress and fear and the clinical anxiety disorders requires further investigation and clarification. And although we have focused here on common mechanisms and

Acknowledgements

Aspects of this work were presented at the conference, “Learning and Unlearning Fears: Preparedness, Neural Pathways and Patients,” held March 21, 2002 in Austin, TX. The conference was supported by an unrestricted educational grant to the Anxiety Disorders Association of America (ADAA) from Wyeth Pharmaceuticals, and jointly sponsored by the ADAA, the ADAA Scientific Advisory Board, and the National Institute of Mental Health.

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