Synaptic and behavioural actions of antidepressant drugs

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TINS -bebruarv 1981

Synaptic and behavioural actions of antidepressant drugs Further thoughts on the implications for theories of depression P. E. Harrison-Read In their recent TINS article, Willner and Montgomery 2~(see also ref. 8) stressed the value of behavioural studies for interpreting changes at noradrenergic (NA) synapses which occur during treatment with tricyclic antidepressant drugs (TADs). By reflecting the integrated functioning of neural systems, behavioural studies can reveal the net effect on NA transmission of various pre- and postsynaptic changes which potentially could alter transmission in opposite directions. A similar case can be made for the value of electrophysiological studies in which the activity of cells receiving NA input is recorded~l.t~2L Studying the integrated function of NA systems during long-term drug administration may also help in distinguishing primary effects of drugs on synaptic functions from adaptive or compensatory changes occurring secondarily. ~ ENe~,cr/North-Ht~lland Buomcdical Presx 19N]

and may be particularly relevant to antidepressant effects which typically have a slow onset. Effects of TAD on NA systems

The behavioural data described by Willnet and Montgomery 27 suggest that NA transmission in rat brain is initially increased by the antidepressant drug desmethylimipramine (DMI), but subsequently the 'efficacy' of NA synapses appears to return to its status quo ante, resulting in no net behavioural change, provided drug administration is continued. However other studies which also reflect integrated functioning in NA systems suggest that a different balance of synaptic effects can occur after long-term TAD administration. For example, NA transmission in atrial muscle is only slightly enhanced by short-term administration of

DMI, but after 3 weeks, NA release and nerve transmission are markedly increased 4. The firing rate of hippocampal pyramidal cells which receive an inhibitory NA input is reduced by acute administration of DMI, but increased by pretreatment for 3 weeks, suggesting early enhancement followed by reduction of NA transmission11.12. No doubt in each of these studies a different balance was achieved between opposing synaptic changes such as reduced neuronal reuptake and prcsynaptie a-receptor subsensitivity 13 tending to increase synaptic levels of NA on the one hand, and postsynaptic fl-receptor subsensitivity =4 tending to reduce NA transmission on the other. However, in trying to draw conclusions about the therapeutic actions of TADs from these studies, we are no nearer to deciding whether the drugs are likely to increase, decrease, or stabilize NA transmission in depressed patients?* The functional significance of synaptic changes produced by TADs will probably be determined by any pre-existing abnormalities in NA synaptic functions. If evidence for these in depression is mainly drawn from studies of TAD actions in 'normal' systems such as those mentioned above, there is a danger of arguing in circles. However, independent evidence (see below) suggests that a deficiency in

33

TINS-February 1981 brain NA may exist at least in those patients who respond well to treatment with imipramine-like antidepressant drugs. If reduced synaptic levels of NA constitute a primary pathogenic mechanism in these cases of depression, secondary increases in the sensitivity of both pre- and post synaptic receptors may occur, the latter effect tending to restore NA transmission, whereas the former would be maladaptive, tending to decrease NA synthesis and release even further. The delayed onset of the therapeutic effects of TADs may therefore result from the need to desensitize supersensitive presynaptic a-receptors before neuronal reuptake blockade can achieve a sustained rise in the synaptic levels of NA and restore NA transmission to normal. The concomitant reduction in postsynaptic receptor sensitivity would, if anything, represent an unfavourable aspect of prolonged drug treatment since it removes a partially effective compensatory mechanism. The need for chronic administration of TADs in the therapy of depression may therefore reflect not the emergence of a fundamentally new action at NA synapses, but the removal of an interfering maladaptire change which pre-empts the benefit of the drugs' acute effect on the NA reuptake pump. This view tends to rehabilitate studies of the acute effects of TADs on model NA systems because they may still provide a valid approach to understanding the drugs' therapeutic actions. However this is not to deny the possibility that other synaptic changes occur which are unique to the long-term use of the drugs, and which may be essential for their antidepressant effect. For example, forebrain neurons receiving an inhibitory 5-HT input show a selective increase in sensitivity to 5-HT after long-term but not short-term drug administration, an effect which is specific to drugs which have known antidepressant efficacy, despite other differences in their spectrum of pharmacological actionsn. Antidepressants and information transfer The actions of TADs at NA synapses mentioned above are all likely to alter the 'gain' or 'efficacy' of synaptic transmission. In systems which exert control through the integrated activity of tonically firing NA neurons, this should have fairly predictable consequences on the firing rate of postsynaptic output cells, provided that the net effect on synaptic efficacy is known. However this may be an over-simplistic view of NA systems likely to be involved in human depressive disorders. Information transfer

in these systems may be critically dependent on which NA inputs are active, when, and for how long. Inhibition of NA reuptake is likely to distort temporal inputoutput relationships at NA synapses because the transmitter remains longer in the synaptic cleft after release. Changes in the population of NA cells activated by a given input, and the duration of their response, may result from reduced selfinhibition due to subsensitive presynaptic t~-receptors. Alterations in the 'gain' of NA synapses may alter the population of neurons firing in the presence of an inhibitory NA input, as well as causing changes in their firing rate. These considerations make the study of integrated systems even more important if the full consequences of synaptic changes induced by TADs are to be appreciated. They also imply that it may be unwise to extrapolate from the drugs' actions on simple NA systems to the relative complexity of those likely to be involved in the therapeutic effects in man. Antidepressants and lithium as 'stabilizers' of monoaminergic transmission Numerous authors t~,27 have speculated that antidepressant drugs may alter the 'stability' of NA transmission, e.g. by producing changes with opposite consequences for synaptic efficacy which therefore tend to cancel out but reduce the capacity for subsequent maladaptive increases or decreases in transmission. This is an attractive idea because it promises to explain not only the drugs' normalizing actions in depressive disorders against a wide range of symptoms, but also their relative lack of effect in normal people. Similarly stabilization of 5-HT transmission by lithium has been proposed to contribute to its prophylactic action in manicdepression 6.~e. When given in high doses to rats, lithium increases tryptophan uptake into serotonergic neurons, and then subsequently causes a reduction in tryptophan hydroxylase activity. The net effect on 5-HT synthesis after prolonged administration is therefore small, but the capacity of 5-HT neurons for further increases or decreases in 5-HT synthesis may be 'used up', and perhaps accounts for the ability of lithium to prevent excessive mood swings ~e. Our behavioural experiments in rats using a non-toxic dose of lithium (2 mmol/kg/day) suggest that chronic pretreatment may increase serotonergic transmission but prevents excessive 5-HT release and the functional consequences of excessive 5-HT receptor activiation¢~. Thus an increase in rats' exploratory reac-

tivity to stimulus change occurs after five or six days of lithium pretreatment, and can be abolished by the 5-HT precursor L-tryptophan, and mimicked by methysergide, a 5-HT antagonist. This suggests that the increased synthesis and intraneuronal turnover of 5-HT which is found after short-term lithium pretreatment may be accompanied by reduced rather than increased synaptic availability of 5-HT, possibly because lithium interferes with 5-HT storage and stimulus-release coupling. When lithium is given for two weeks or longer, rats' response to stimulus change returns to normal or is reduced, but vigorous sniffing and fore-paw treading is seen instead. This change in behaviour may be partly due to an increase in dopaminergic activitys, and partly to the development of 5-HT receptor supersensitivity as a reaction to the prolonged reduction in 5-HT release, since the behavioural 'serotonin syndrome' produced by the 5-HT agonist 5-methoxy N,N-dimethyltryptamine is enhanced. However excessive activation of 5-HT systems seems to be limited by a simultaneous increase in susceptibility to desensitization after 5-HT receptor stimulationL These findings clearly illustrate the value of behavioural studies for evaluating the functional significance of neurochemical changes produced by lithium, and in this sense parallel those described by Willner and Montgomery27 for TADs. However, theories proposing a 'stabilizing' action of lithium or TADs on monoaminergic transmission need to be tested more directly by showing that NA or 5-HT systems are incapable of responding with extremes of activity after drug pretreatment. The results of another series of experiments~,1° suggest that TADs with a predominant effect on NA reuptake may have an indirect stabilizing action on 5-HT functions by reducing the behavioural expression of drug-induced or naturally occurring differences in serotonergic activity. After short-term pretreatment with imipramine, or acute administration of protriptyline, rats' rearing and walking scores in a Y-maze showed less withingroup scatter, and no longer reflected the consistent individual differences characteristic of controls. However mean scores were not significantly altered by the drugs, and nor was there any change in individual differences in another measure of exploratory activity (sniffing), indicating that the drugs did not generally disrupt behaviour. Individual differences in exploratory activity have been found to

TINS - February 1981

34 correlate with measures of brain 5-HT metabolism, and imipramine pretreatment reduced the effects on exploratory activity of both the 5-HT precursor 5-hydroxytryptophan, and the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA). The tertiary amine TAD chlorimipramine, which has a much greater effect in blocking the neuronal reuptake of 5-HT than the other tricyclics, did not abolish normal individual differences, but on the contrary tended to exaggerate them. It therefore seems likely that the effects of imipramine and protriptyline depended on an alteration in NA synaptic function.

From rat belmviour to a 'permissive' monoamine hypothesis of depression It is tempting to speculate that the normalizing effects of imipramine and protriptyline on rat behaviour may be related to their therapeutic actions in man. If so, this suggests that depression may occur because of impaired ability of an NA system to limit the functional consequences of serotonergic activity. This implies an imbalance between NA and 5-HT systems in depression, but not a simple interaction amounting to mutual antagonism or cooperation. Rather it is proposed that in the absence of adequate 'NA control', even moderate increases or decreases in 5-HT activity have a disproportionate influence on brain functions and behaviour. Unlike other so-called 'permissive' monoamine hypotheses of depression (e.g?9,2~), this allows the possibility that 5-HT a c t i v i t y p e r se may be within the normal range in depression, even though it is primarily responsible for the affective disorders which occur. Reducing 5-HT activity artificially with PCPA does not produce depression in normal people ~, but it can reverse the therapeutic action of imipramine in deprcssed patients ~a. Reduced or otherwise abnormal 5-HT activity may therefore be insufficient on its own to produce depression, but presumably it can do so if there is also a deficiency in 'NA control'. If the abnormality in '5-HT state' is sufficiently severe, it may even constitute the overriding defect in depression. These proposals are in line with the findings that some depressed patients show biochemical indices of abnormal NA function (e.g. reduced urinary excretion of the glycol metabolite of NA, MHPG, which may largely derive from the brain), whereas other patients who may be clinically indistinguishable, appear to have abnormal 5-HT activity instead, as suggested by abnormally low levels of the

5-HT metabolite 5-HIAA in the cercbrospinal flt.id (CSF) 28. It is however necessary to assume that the latter group also have a defect in 'NA control" which is not detectable with the available methods for measuring NA synaptic functions in human brain. This, of course, still begs the question of what exactly the defect in "NA control" constitutes at the synaptic level. Urinary and CSF levels of MHPG do not correlate closely with mood state in depression 26, nor does the catecholamine synthesis inhibitor c~-methy[-p-tyrosine produce depression in normals '7, or reverse the antidepressant effect of drugs~a, so a simple deficie ncy of NA at synapses in depression seems rather unlikely. However responsc to treatment with imipramine or desipramine is most favourable in patients who, prior to treatment, show abnormal urinary excretion of MHPG ts, suggesting that these TADs may act primarily by altering NA activity, and thereby restore 'NA control' over 5HT-dependent brain functions, The severity of the defect in 'NA control' is likely to vary both within and across individuals, so measures reflecting brain 5-HT activity may not closely correlate with depressive symptoms, and need not necessarily revert to normal on recovery, which indeed does not seem to happen in most cases 2,s. However in patients with very low CSF levels of 5-HIAA, the defect in "5-HT state" is presumably severe and may represent the predominant pathogenic defect, so an inverse correlation between "5-HT state' and depression is more likely and has in fact been foundL Re-examination of previous data (e.g. 2) also reveals that in the patients with the lowest CSF 5-HIAA levels, recovery from depression produced a rise in 5-HIAA, even though the mean level of the group as a whole did not alter significantly. Patients with a predominant defect in '5-HT state' would not be expected to show a good response to TADs primarily affecting NA mechanisms, but they should respond to treatments which additionally affect 5-HT synaptic functions directly. This prediction is bourne out by the admittedly preliminary data so far available~.2o,26. FinaLly, there has been a recent reawakening of interest in the role of dopamine in the affective disorders, and in mania in particular TM. Although in general TADs do not appear to have marked effects on dopaminergic systems, this is not the case with lithium which is of particular importance because of its unique and selective actions in manic-depression. It there-

fore seems likely that future 'permissive" hypotheses will have to include dopaminc as well as NA and 5-HT, and that animal behavioural studies will play an important part in their development.

Reading List 1 ~sberg. M., Thoren, P. and Traskman, I_. (1976) Science 191. 478-480 2 Ashcroft,G. W., Blackburn, I. M.. Eccteston, D., Glen, A. I. M., Hartley. W. et al. (1972) Psychol. Med. 3. 319-325 3 Coppen,A., Prange, A. J. Jr, Whybrow.P. C. and Noguera, R. (1972) Arch. Gen. Psychiat. 26. 474-478 4 Crews,F. T. and Smith,C. B. (1978) Science 2(12, 322-324 5 de Montigny, C. and Aghajanian, G. K. (1978) Science 202, 1303-1306 6 Harrison-Read, P.E.(1978)inLithiuminmedical practice (Johnson,F. N. and Johnson.S., eds), pp,

298-303, MTP Press, Lancaster 7 Harrison-Read, P, E. in Neuroendocrine regula. tion and altered behaviour (Hrdina, P. D. and Singhal, R. L., eds), Croom Helm, London (in press) 8 Harrison-Read, P. E. (1980)IRCS Med. Sei. 8. 313 9 Harrimn-Read, P. E. and Steinberg, H. (1980) Psychopharmacol. 69, 85-91 10 Harrison-Read, P. E. and Steinberg, H. (1980) Br. J. Pharmacol. 70, 277-285 11 Huang,Y. H. (1979) Life Sci. 25,709-716 12 Huang,Y. H. (1979) Life Sci. 25, 73%746 13 Langer,S. Z, (1980) Trends NeuroSci. 3, 110-112 14 Maas,J. W. (1979) Trends NeuroSci. 2, 306-308 15 Maas.J. W., Fawcen,J. A. and Dekirmenjian, H. (1972) Arch. Get. P~ychiat. 26, 252-262 16 Mandell, A. J. and Knapp, S. (1976) Pharmakopsychiat. 9, 116-126 17 Mendels. J. and Frazer, A. (1974) Arch, Gen. Psychiat. 30,447-451 18 Post.R. M.. Jimerson,D. C., Bunney.W. E. Jr and Goodwin, F. K. (t980) Psychopharmacol. 67, 297-305 l 9 Prange,A. J, Jr, Wilson,1.C., Lynn,C. W., Alltop, L. B. and Strikeleather, R. A. (1974)Arch. Gen. P~ychiat. 30, 56~62 20 Ridges, A. P. (1976) Postgrad. Med. J. 52 (Suppl. 3), 9-16 2l Sangdee. C. and Franz, D. N. (1979) Psychopharmacol. 62, 9-16 22 Shaw,D. M., Riley, G., Michalakeas, A. C,, Tidmarsh,S. F., Blazek, R. and Johnson,A. L. (1977) Lancet i, 1259-1260 23 Shopsin, B., Gershon, S., Gotdstein. M., Friedman. E. and Wilk, S, (1975) Psychopharmacol. (_)gmrn. 1,239-249 24 Sulser,F. (1979) Trends PharmacoL Sci. 1,92-94 25 Svensson. T. H. and Usdin, T. (1978 ) Science 202, 1089-109 I 26 Wehr, T. and Goodwin, F. K. (1977) in Handbook of studies on depression (Burrows,G. D., ed.), pp. 283-301, ExcerptaMediea, Amsterdam 27 Wilner. P. and Montgomery, T. (1980) Trends NeuroSci. 3.21)1 P. E. Harrison-Read is" at the Department of Pharmacology, The Medical College o f St. Bartholomew's Hospital, Charterhouse Square, London ECI M 6BQ, U.K.