5-HT: on the psychiatrist's couch

TiPS - September 1992 [Vol. 131

337

5-HT: on the psychiatrist’s couch That 5-HT is involved to a greater or lesser degree in virtually all psychiatric disorders has become a standard introductory phrase to many research and review articles. A recent symposium* went beyond the cliche to determine the extent to which this dictum is true. Since psychiatric disorders are, by definition, a uniquely human problem, the meeting progressed from ‘Humans to Molecules’ so that the clinical domain was first under the spotlight. Stuart Montgomery (St Mary’s Hospital, London) confirmed that the specific 5-HT rei.ptake inhibitors (SRIs) are unequivocally effective as antidepressants, equal to or possibly better than the tricyclic compounds in major depression, and clearly superior in severe depression where tricyclics have poor efficacy. In addition, the SRIs provide effective prophylaxis when given chronically, and evidence is accumulating that they are also active on anxiety associated with depression and in obsessivecompulsive disorders. ‘Anxiety is a generic term’ pointed out Herman Westenberg (Academic Hospital, Utrecht). Separate types of anxiety disorder should be dealt with separately. Panic and obsessive-compulsive disorders, for example, respond well to SRIs, which appear to have an additional action independent of their effect on the associated depression. By contrast, 5-HTiA agonists such as buspirone have efficacy in generalized anxiety disorders but not in panic disorders. This suggests that 5-HT may be implicated in several neurobiological mechanisms that control different types of anxiety neurochemically states. Thus selective drugs may have a narrower range of therapeutic action. Herman Van Praag (Albert Einstein College of Medicine, New York) presented data suggesting that a defective control *The Role of Serotonin in Psychiafric Disorders, Cadres,24-26 june 1992.

of aggression and anxiety related to reduced 5-I-H activity may be a core feature in depression and that lowered mood was secondary to this. Bill Deakin (University of Manchester) also felt that the fundamental action of 5-I-H was not mood control but rather to reduce or prevent the impact of aversive events. The dorsal raphe system appears to be involved in coping with current events (fight or flight behaviour) whereas the median raphe system may be active in preparation for future events (avoidance behaviour). Data presented by Markku Linnoila (NIAAA, Bethesda) from studies in rodents, non-human primates, healthy volunteers and patients with various mental disorders and alcohol dependency, and in impulsive and non-impulsive criminals, suggest that there may be a familial trait associated with low levels of 5-hydroxyindole acetic acid in CSF, depression, alcoholism and impaired control of behavioural impulses. Phil Cowen (MRC, Oxford) discussed new kinds of measurements of 5-HT function, for example ‘challenge’ studies measuring various neuroendocrine parameters (hypothalamic 5-HT system), changes in slowwave sleep (related to 5-HTz receptor function) and temperature changes (related to 5-HTrA or 5-HTlc receptor function) in response to drugs, to determine the sensitivity of different 5-HT receptors or pathways. Are the changes seen in 5-HT function the cause or the result of Dennis psychiatric disorder? Murphy (NIMH, Bethesda) cited the example of desensitization of 5-HTiA receptors by chronic elSince hydrocortisone. evated hydrocortisone levels are frequently increased in many psychiatric disorders including devariation in 5-HTu+, pression, receptors could be secondary to this change. Since, however, 5-HT is also involved in the regulation of hydrocortisone release, the answer is far from simple. Murphy

went on to highlight the effects of m-Cl?‘, a preferential 5-HTlc agonist, to produce anxiety in panic patients, worsen the symptoms of obsessive-compulsive disorder and lower mood in depressed patients, suggesting that 5-I-lTic receptor function may be implicated as a causal factor in these psychiatric disorders. Is food an antidepressant? Dick Wurtman (MIT, Cambridge, USA) showed that carbohydrates increase 5-I-H production and release, while satiety is regulated by 5-I-H-containing neurons. This, he suggested, could lead to the use of carbohydrate-rich foods as dietary ‘antidepressants’, such that overeating, obesity and carbohydrate craving may be considered to be symptoms related to 5-HT dysfunction. Presentations by Bryan Leonard (University College, Galway) and Jean De Vry (Troponwerke, Cologne) showed that the value of sophisticated animal models, such as the bulbectomized rat model for depression, is their use in elucidating the pathophysiology of the modelIed disorder. Simpler models, which are useful for screening new potential drugs, are often efficient for detecting drugs acting upon a specific mechanism. They are thus suitable for optimizing a drug lead but are often of little help in finding new innovative drugs. The road from humans to molecules passes, inevitably, via animal models. Chris Broekkamp (Organon, Oss) presented animal data that suggested that the effects of SRIs could be best mimicked with 5-I-ITic agonists, implying that 5-HTlc receptor function may play a central role in the therapy and possibly the pathogenesis of depression. Before we can hope to determine the role of 5-HT in psychiatric disorders we need to understand the functional neuroanatomy of this transmitter. Mark Molliver (Johns Hopkins University, Baltimore) described two classes of 5-HT neurons originating from the raphe: those with beaded axons arising from the median raphe and those with fine axons arising from the dorsal raphe. The beaded axons arising

in the median raphC have a more specific localization and appear to innervate

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TiPS - Sepfe~~er 1992 EV01.231

338 particutar. He also showed that the dorsal raphe neurons were particularly vulnerable to the neun&n& effects of certain amphetamine derivatives. Ron Leslie (oxford University/ Beecham Centre, SmithKline Oxford) described the measnrement of Fos expression during activation of 5-HTrn or 5-IiT receptors with direct or indirect agonists. The pattern of Fos expression following stimulation of each type of receptor was different and correspondedto the distribution of 5HTrA and 5-HTs receptors respectively. This technique effectively provides a semiquantitative image of neuronal iillWtiOiL 30 !hderpab

and Arvid Car&son (University of Giiteborg) each addressed the influence of 5-HT on other neurotransmitter systems and of other systems on 5-I-H’. Soderpahn described IHT~oradrenaline, %-IT-acetylcholine, 5-HTGABA and 5-H% dopamine (nigrostriatal and mesohmbic) interactions. 5-HT interacts principahy with dopamine as part of the ‘brain reward system’. where its role in obsessiv+compulsive disorder and craving may find a molecular substrate. Experimental reduction of 5-HT input also induces aggression and irritability, which is probably linked to dopamine function. The role of 5-I-H in conBitt behaviour is, however, probably related to the interaction with GABA neurons possibly via control of the release of an endogenous ligand acting at the GABA/ benzodiazepine receptor complex. 5-HT also interacts with, and is affected by, neuropeptides. Sven Ogren (Karolinska Institute, Stockholm), for example, showed that galanin, which is co-stored with S-HT in raphe cell bodies, interacts wi& 5-I-H and vice versa. The affinity of the 5-HT14\ receptor, in particular, appears to be regulated through an intramembrane feedback loop involving by ~~-~~~ galanin receptors. Galanin may also change the 5-HT2/5-I-Tfm equilibrium. The theme of functional adaptation was addressed by Chantal Moret (Pierre Fabre, Cast@. Taking SRIs as an example, she explained that they have no acute effect on in uivo or in viiro 5-HT levels. This, she proposed, was

due to several feedback mechanisms that maintain the status quo. Only after desensitization of these feedback systems by chronic administration of the SRI, does an increase in 5-HT neurotransmission become apparent, thus offering a possible explanation of the delay in therapeutic action of antidepressant drugs. Posters by Michel Weiss and Pierre Blier (McGill University, Montreal) showed that milnacian antidepressant that P-p blocks uptake of both noradrenaline and 5-HT, initially decreases firing of both locus coeruleus noradrenergic neurons and raphe 5-l-H neurons. After 14 days a~s~tion, the firing of locus coeruleus noradrenergic neurons was still reduced whereas the firing of raphe 5-HT neurons had returned to normal, although the responsiveness of raphk 5-HTrA receptors to iontophoretic~y applied 8-OH-DPAT was not modified. terminal Although 5-I-H autoreceptors were unchanged, as measured by the ability of 5-CT to inhibit the release of 5-HT from hippocampal slices, the release of 5-HT in the hippocampus was increased after 14 days administration of the antidepressant. This effect appears to be related to the desensitization of lu2-adrenoceptors present on terminals of 5-I-H neurons. These studies illustrate how drugs with varying primary activities on upake of 5-HT or noradrenaline can have a common effect on 5-HT transmission after chronic administration. In a related poster, Francesco Artigas (University of Barcelona) showed that SRIs increase extra-

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cellular 5-i-H concentrations in the raphd but not in the cortex. This is compatible with the existence of regulatory autoreceptors in the cortex that are absent from the raphe. This underlines the importance of autoreceptors in control of 5-HT release, and also that dendritic release of 5-HT in the raphe may be important in drug action. Michel Hamon (INSERM, Paris) presented evidence for the somatodendritic localization of the 5-HT1, receptor in the raphe and its role in conning neuronal firing. The long road from humans to molecules finally arrived at the level of 5-I-H receptor subtypes and the question of their functional significance. Daniel Hoyer (Sandoz, Basel) reviewed the two receptor superfamilies, a G protein-linked receptor family with seven membrane-spanning regions (5-HTr, 5-HTs and 5-IIT& the other a ligand-gated ion channel receptor type (5-IITs), formed of several subunits. It was left to Mike Briley (Pierre Fabre, Castres) to complete the circle by proposing a strategy, illustrated with examples from the symposium, by which pharmacologists and chemists from the pharmaceutical industry could hope to find new drugs for the 5-I-H’ system and thus proceed from molecules to humans. MIKE BRILEY DAVID

Cenfre de Recherche Pierre Fake, Casfres, France, and University Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford, UK. l

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Lecture

We are delighted to announce that Professor Peter H. Seeburg ZMBH, University of Heidelberg will be giving this year’s TiNS/TiPS Lecture The Lecture entitled

‘Molecular biology of GABA,+and glutamate receptors’ l!Rh Annual Meeting S-17

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will be given at the

of tire European Neurosdence Association September1992, Munich