Elsevier

Journal of Affective Disorders

Volume 61, Issue 3, 2 December 2000, Pages 161-176
Journal of Affective Disorders

Anxiolytic action on the behavioural inhibition system implies multiple types of arousal contribute to anxiety

https://doi.org/10.1016/S0165-0327(00)00344-XGet rights and content

Abstract

According to “The Neuropsychology of Anxiety” [Gray, J.A., 1982, The Neuropsychology of Anxiety: An Enquiry into the Functions of the Septo-hippocampal System, Oxford University Press, Oxford; Gray, J.A., McNaughton, N., 2000, The Neuropsychology of Anxiety: An Enquiry into the Functions of the Septo-hippocampal System, 2nd ed., Oxford University Press, Oxford], anxiolytic drugs of all types act on a behavioural inhibition system, the most important neural component of which is the septo-hippocampal system. Anxiolytics affect septo-hippocampal function by impairing the subcortical control of hippocampal ‘theta’ activity — the principle response of the septo-hippocampal system to arousal. Our recent experiments show that there are multiple systems controlling theta activity and that anxiolytics act on several, but not all, of these systems. This pattern of results implies that there are many different types of arousal, only some of which appear to contribute to the generation of anxiety in normal subjects and to the etiology of pathological anxiety.

Introduction

Gray (1982) published a “Neuropsychology of Anxiety” which had as its key suppositions that:

  • 1.

    the neural and behavioural actions of anxiolytic drugs in other animals can provide us with keys to the nature of anxiety in people;

  • 2.

    the behavioural actions of the anxiolytics drugs are best described as impairment of the ‘Behavioural Inhibition System’ (BIS) depicted in Fig. 1;

  • 3.

    the most important common neural actions of the anxiolytic drugs are to impair the control of ‘theta activity’ in the septo-hippocampal system (SHS);

  • 4.

    changes in septo-hippocampal function, and especially theta activity, can underlie both normal and pathological changes in anxiety.

An updated “Neuropsychology of Anxiety” (Gray and McNaughton, 2000) retains all of the above suppositions and summarizes the extensive confirmatory evidence for them which has accrued since 1982. It also describes modifications of the specific mechanisms of the theory needed to bring it into line with the details of these recent data. In this paper we will summarise the 1982 theory and briefly describe the aspects of its updating which are directly relevant to the role of theta activity (omitting many other aspects). We then consider in more detail the implications for anxiety of what we now know about the mechanisms of control of theta activity and of the actions of anxiolytics on that control.

Section snippets

The Neuropsychology of Anxiety (1982)

The foundations of the theory (both in 1982 and in its updated form) are the data showing that:

  • 1.

    anxiolytic drugs produce behavioural effects in animals that are qualitatively (although not always quantitatively) the same as lesions of the SHS;

  • 2.

    anxiolytic drugs impair the control of theta activity (rhythmical burst firing of cells in the SHS at 5–12 Hz in the free moving rat), the occurrence of which depends on a pacemaker input from the medial septal area.

The theory then attributes the

The Neuropsychology of Anxiety (second edition)

The 1982 theory attempted to encompass all the information available at that time on the neural and behavioural actions of the anxiolytic drugs, the nature of theta activity and the neural and behavioural functions of the SHS. The explosion of data since its publication prompted us to produce a second edition of “The Neuropsychology of Anxiety” to assess the predictive validity of the 1982 theory and to update its formulation. Some of the updating is cosmetic — altering only the way the theory

Anxiolytic action on the control of theta activity

In Gray (1982), as in O’Keefe and Nadel (1978) and in Miller (1991), theta activity was held to be essential for hippocampal function. In all three cases, too, the precise frequency of theta was held to be important, reflecting some form or other of indexing function. However, the reformulation of the comparator shown in Fig. 2 suggests a less absolute, but nonetheless fundamental, role for theta activity in the SHS.

In Fig. 2, the comparator is held to receive inputs from the various goal

The subcortical control of theta activity …

We have already indicated that the locus coeruleus provides a noradrenergic input to the hippocampal formation that alters the threshold at which input from the medial septum can entrain theta activity. Thus, under some circumstances, reductions in this noradrenergic input could prevent the occurrence of theta in the middle of the frequency range when otherwise it would have occurred. This effect is best viewed as a ‘gating’ of theta since loss of noradrenaline does not affect the frequency or

… and its implications for the role of arousal in anxiety

There has always been a clear link between arousal and the occurrence of theta activity. Green and Arduini (1954) stated that arousal led to theta activity and Brucke et al. (1959) went so far as to describe theta as ‘der “Hippocampus-arousal-Reaktion”’. More recently, Sainsbury (1985) has linked the occurrence of theta in a non-moving animal to the presence of arousal — and has obtained particularly high frequencies of theta in response to the arousal produced by predatory threat. However, the

Conclusions

While this overview of our theory and of the subcortical control of theta activity has been both brief and selective (see Gray, 1982; Gray and McNaughton, 2000, for more extended treatment), we believe it gives good reason to see amnesia and generalized anxiety disorder as opposite poles of a continuum defined by the reactivity of the SHS. While it may seem peculiar that both extremes of output from the SHS should result in psychopathology, it should be noted that the complex circuitry

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