Drugs, Biochemistry, and Conscious Experience: Toward a Theory of Psychopharmacology

DRUGS, BIOCHEMISTRY, AND CONSCIOUS EXPERIENCE: TOWARD A THEORY OF PSYCHOPHARMACOLOGY PAUL WILLNER* Levels ofExplanation ofPsychotropic Drug Effects A few micrograms of lysergic acid diethylamide (LSD) can produce a major psychological experience, usually described as an "altered state of consciousness," which can sometimes be the most powerful experience a person has ever had. "Explanations" ofthese phenomena usually involve a discussion of the neurotransmitter 5-hydroxy-tryptamine (5-HT) [1, 2]. Clearly, however, a description of biochemical phenomena in no sense explains the LSD experience, since no account is offered of how the biochemical changes give rise to altered states of consciousness. A similar problem arises in relation to biochemical "theories" of mental disorder, such as the dopamine (DA) hypothesis of schizophrenia or the catecholamine hypothesis of depression. Paranoid delusions are not explained by demonstrating that DA systems are hyperactive; neither are ideas of suicide explained by a malfunction of noradrenergic (NA) systems . However successful these reductionist hypotheses may be in generating testable hypotheses, leading, for example, to the development of effective pharmacological agents, a hypothesis of brain function which omits any reference to the structure or operating principles ofthe brain is unlikely to be of more than heuristic value. An alternative approach attempts to bridge this conceptual gap by seeking explanations of psychotropic drug effects in four independent explanatory domains: biochemical, physiological, cognitive, and subjective (using die word "cognitive" in the information-processing sense in which it is now used in cognitive psychology, rather than as a synonym for "conscious"). In terms of a computer analogy, these four domains ?Psychology Department, City of London Polytechnic, Old Castle Street, London El 7NT, England.© 1984 by The University of Chicago. AU rights reserved. 003 1-5982/85/2801-0404$01 .00 Perspectives in Biology and Medicine, 28, 1 · Autumn 1984 \ 49 include two levels of "hardware" and two of "software," corresponding very roughly to components, wiring, programming, and editing. Each explanatory domain has its own language and logic, and each must be understood in its own terms. A recent theory of the action of anti-anxiety drugs [3] will serve as an illustration. In this account, which is embedded within the context of a comprehensive neuropsychological theory of anxiety, anxiolytic drugs act at the GABA-benzodiazepine receptor complex, or at other sites (level 1), to disrupt the flow of impulses in neural circuits in the hippocampus and subiculum (level 2). The information carried in these circuits is used to make a comparison between actual and expected events: a mismatch activates a "behavioural inhibition system," which suppresses ongoing motor activity and increases arousal and attention to the environment (level 3); these effects are experienced as anxiety (level 4). Irrespective of its empirical merits [4], the hypothesis has a sound conceptual basis. The analysis spans all four levels ofexplanation, rather than the usual two: physiological (level 2) and cognitive (level 3) levels are interposed between biochemistry (level 1) and subjective experience (level 4). In addition to describing an empirical relationship between receptor interactions and an anti-anxiety effect, die account also specifies the neural pathways implicated, their role in normal cognitive functioning , and the relationship between changes in cognitive function and changes in experience. In describing the psychological effect of a drug or an endogenous biochemical change, it is important to consider not only the intervening levels of explanation but also the nature of the transitions between adjacent levels. The generation of changes in neural firing (level 2) from the biochemical effect of a drug (level 1) depends on the integration of that biochemical effect into a context of other ongoing biochemical processes , which include adaptive regulation resulting from the primary drug effect. The effect of tricyclic antidepressant drugs at noradrenergic synapses is a well-worked example: it is now established that, in addition to potentiating neurotransmission by blocking neurotransmitter reuptake, after chronic treatment, tricyclics also decrease neurotransmission by reducing the sensitivity of postsynaptic beta-receptors [5]. It is rather less frequendy recognized, however, that the important issue is the net outcome of these and other effects on the traffic of nerve impulses in postsynaptic structures [6, 7]. Similar considerations apply to die transition from physiology (level 2) to cognitive processes (level 3). A good...