The neuropsychology and neuropharmacology of the dorsal ascending noradrenergic bundle—a review

Abstract

• (1) The present paper is concerned with the behavioural and pharmacological data relating to the dorsal ascending noradrenergic bundle (DB), and thus supplements Amaral and Sinnamon's 1977 review of the neurobiology of the locus coeruleus (LC). For completeness, discussion of the neuroanatomy and neurophysiology of the DB has also been included.

• (2) Neuroanatomy: The DB contains efferents from the LC which have been reported to project, largely ipsilaterally, to the neocortex (frontal, sensorimotor, cingulate, pyriform), rhinecephalon (hippocampus, septum, amygdala, olfactory bulb) and various subcortical areas (thalamus, hypothalamus, colliculi, geniculate bodies and probably the habenula). It appears that not all LC cells project to all these areas. Cells in some parts of LC may project specifically to particular areas.

• (3) Neurophysiology: In such areas as have been investigated, activation of the DB results in inhibition of the spontaneous activity of single cells by the release of noradrenaline. In the cortex, the released NA may act on some neurones by a process of extra-synaptic diffusion, but this is less likely to be the case in the hippocampus. Despite the inhibition of spontaneous activity, activation of the DB can produce increased rather than decreased responses to subsequent activation of other inputs to the same cells. Thus the main effect of DB input does not appear to be a reduction in the general excitability of target cells, but may be, e.g., a reduction in noise level.

  The DB appears to provide some type of frequency-specific modulatory influence with respect to hippocampal theta rhythm, but this does not involve obvious changes in the spontaneous occurrence or frequency of the rhythm, and its exact nature remains to be clarified.

• (4) Physiological functions: The possible involvement of the DB in a number of physiological processes (sensory transmission, visual plasticity, sleep, sexual behaviour, homeostasis) was considered, but cannot be resolved at the present time because few experiments in these areas have employed neurotoxic lesions of the DB alone. There is, however, good evidence for interaction between the DB and the pituitary-adrenal axis. In many cases combination of DB lesion and adrenalectomy impaired avoidance responses which the individual lesions did not affect to any great extent.

• (5) Pharmacology: Dopaminergic, cholinergic, opiate, intoxicating, convulsant, minor tranquilizing and antidepressant drugs were considered. As might be expected, the DB is not clearly involved with the entire behavioural profile of any of these groups, nor, surprisingly, does it have a uniform influence with respect to similar responses induced by different classes of drug. Thus, the nature of the interaction of DB lesions with drug-induced changes depends on the class of drug for catalepsy, taste aversion, locomotor stimulation and self administration. However, DB lesions potentiate seizures whatever the inducing agent.

  The clearest involvement of the dorsal bundle is with the behavioural effects of the minor tranquillizers; many of these effects are reproduced by DB lesions, the main exceptions being paradigms involving noxious stimuli.

• (6) Behavioral functions: Self stimulation and the acquisition of a number of learned responses survive neurotoxic lesion of the DB. Changes are obtained in extinction of almost all simple appetitively- and aversively-reinforced responses, in some reactions to novelty (spontaneous alternation, response to stimulus change, rearing, distraction of licking by a tone), and in some reactions to complex tasks (successive brightness discrimination, spatial alternation, fixed ratio, variable interval, partial reinforcement extinction effect with small numbers of trials) but not others (acquisition of fixed interval, variable ratio or differential reinforcement of low rates schedules, extinction of Sidman avoidance, partial reinforcement extinction effect with large numbers of trials). While forebrain noradrenaline systems may be involved in fear and avoidance responding, the present evidence suggests that the DB is not critically involved. However, it may be concerned in some aspects of aggressive responses, and this may be related to both its effects on novelty and its interaction with hormonal systems.

  The exceptions to each of the above generalizations, and the broad range of behaviours which are affected by lesions of the DB indicate that its behavioural functions cannot be described by some single simple generalization but must be considered within a detailed theoretical framework.

• (7) Theories of DB function: It has been suggested that the DB is critically involved in reward processes and fear processes. As has been noted above, there appears to be clear contradictory data in both cases.

  One of us (Mason) has proposed that the DB controls the capacity of animals to ignore irrelevant stimuli. This suggestion accounts for a wide range of the behavioural data, but is not intended to account for any of the pharmacological data. Assessment of the completeness of this theory depends on clear definition of the idea of “irrelevance” and on more extensive experimental analysis of many of the behavioural paradigms mentioned above.

  Gray has proposed that the minor tranquillizers owe a large part of their behavioural profile to actions on the septo-hippocampal system. He has recently included in this theoretical scheme, on electrophysiological grounds, the suggestion that the DB input to the hippocampus is involved in processes consequent on frustration, and, more generally, that it is part of a behavioural inhibition system. This accounts for much of the data on DB lesions, except where noxious stimuli are involved, and also accounts for the relation between the effects of DB lesions and minor tranquillizers on behaviour. Further definition would be required to extend this proposal to DB afferents to structures other than the hippocampus, and, again, more extensive analysis of behavioural paradigms is required before the completeness of the theory can be fully assessed.

• (8) Conclusions: As yet no theory has been proposed to cover the entire neuropsychology and neuropharmacology of the dorsal bundle. The neuroanatomy and neurophysiology suggest that the operation of the DB itself may be remarkably simple, if not homogeneous, but that its interaction with behaviour will be complicated by the nature of tis target neurones. In this respect, comparison of DB lesions with those of the hippocampus, for example, may give us considerable insight into the functions of the latter. However, such insight is likely to depend more on an extension of our understanding of the psychological variables involved in the various paradigms that have been investigated, than on an extension of the behavioural profile of DB lesions. The way would appear to be open for a successful integration of most of the behavioural and pharmacological data on this small but pervasive pathway.