Pharmac. Ther. Vol.55, pp. 149-181,1992 0163-7258/92$15.00 Printed in Great Britain. All rightsreserved © 1993 Pergamon PressLtd Associate Editor: D. J. K. BALFOUR THE NEUROANATOMICAL BASIS OF ANXIETY JUDITH A. PRATT Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, G1 IXW, U.K. Abstract--This review details the neural systems that are important in anxiety-related behaviours. In particular, the role of the amygdaloid complex, Papez circuit, septohippocam- pal formation and raphe nuclei are described and discussed. Evidence is gathered from a variety of experimental approaches. These include behavioural assessment of anxiety in animals after intracerebral injection of pharmacological agents and following lesions of discrete brain nuclei and selective neurotransmitter pathways. Further evidence is provided by functional brain mapping studies applied to animals and humans. It is proposed that the neural systems recruited in different experimental conditions of anxiety may differ, supporting the notion that clinical anxiety exists in several forms. This has implications for the identification of new anxiolytic treatments. In particular, the findings suggest that approaches aimed at identifying new anxiolytic agents must take into account both the distribution of receptors for the drug and the neuronal systems activated by the experimental protocol. CONTENTS 1. Introduction 150 1.1. Anxiety: Forms and components 150 1.2. The use of animal behavioural models to assess anxiety 151 2. Neural Pathways Involved in Anxiety-related Behaviours: Evidence from Electrical Stimulation and Lesion Studies 152 2.1. Historical perspective 152 2.2. Components of the Papez circuit 153 2.3. Amygdala 154 2.3.1. Introduction 154 2.3.2. Amygdala and learned behaviours 155 2.3.3. The amygdala as part of the circuitry involved in conditioned fear 155 2.3.4. The amygdala, fear potentiated startle and other models of anxiety 156 2.4. Periaqueductal gray 158 2.5. Septohippocampal system 159 2.6. Raphe nuclei 160 2.7. Locus coeruleus 162 2.7.1. Electrical stimulation and lesion studies 162 2.7.2. Responses of noradrenergic neurons to stressful stimuli 163 2.7.3. Noradrenergic function in patients with anxiety disorders 163 3. Pharmacological Manipulation of 5-HT Systems and Anxiety 164 3.1. 5-HT antagonists and reduction of 5-HT function 164 3.2. Enhancement of 5-HT function 164 3.3. 5-HT receptor subtype-specific ligands 164 3.4. Interaction between benzodiazepines and 5-HT systems 165 4. Neuroanatomical Sites of Action of Anxiolytic and Anxiogenic Drugs in Modifying Anxiety-related Behaviours: Focal Injection Studies 167 4.1. Benzodiazepine-receptor ligands 167 4.1.1. Neuroanatomical locations of receptors 167 Abbreviations--CBF, cerebral blood flow; DHT, dihydroxytryptamine; FG 7142, N-methyl-fl-carboline-3- carboxamide; GABA, 7-aminobutyric acid; 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino)tetralin; 5-HT, 5-hydroxytryptamine; 5-MeODMT, 5-methoxy,N,N-dimethyltryptamine; PAG, periaqueductal grey; PCPA, parachlorophenylalanine; PET, positron emission tomography. 149