Current concepts on the mechanisms of action of antidepressant drugs

Pllarlnac. Tiler. Vol. 13. pp. 219 247 ,~ Pergamon Pre~s Lid 1981. Printed in Great Britain

0163 7258.,'81/07010219505.00j0

CURRENT CONCEPTS ON THE MECHANISMS OF ACTION OF ANTIDEPRESSANT DRUGS MICHAEL

F. SUGRUE

Centre de Recherche Merrell International, 16, rue d'Ankara, 67084 Strasbourg-Cedex, France

1. INTRODUCTION Depression is a major illness. While its precise prevalence is unknown, some 400,000 patients are treated annually in the U.S.A. and suicide is rated as the tenth greatest cause of death in that country (Hollister, 1978a). Approximately two decades ago, the clinical efficacy of both the tricyclic antidepressants and the monoamine oxidase (MAO) inhibitors was discovered by chance. In spite of intensive efforts, not only the molecular mechanism(s) by which antidepressants work but also the genesis of the disease remain to be elucidated. Knowledge that depression can be induced by monoamine depleting drugs such as reserpine and that antidepressants affect monoamine functioning has resulted in attention being focused on the roles of norepinephrine (NE) and serotonin (5-HT) in depression. The catecholaminergic (Schildkraut, 1965) and serotoninergic (Coppen, 1967) hypotheses of affective disorders related the illness to a deficiency of the monoamines at their respective central synapses. Both hypotheses may currently be considered to represent an oversimplification. However, their contribution to psychotherapeutic research has been extremely profound. To-day, NE and 5-HT are still believed to play a critical role in depression (Van Praag, 1977; Murphy et al., 1978a,b; Schildkraut, 1978; Garver and Davis, 1979). The possible role of dopamine (DA) in depression has been long overlooked but this is changing (Randrup et al., 1975). This review will be essentially confined to these monoamines. In the 60s and early 70s attempts to uncover the mechanisms of action of antidepressants focused on presynaptic changes elicited by acutely administered drugs. However, a characteristic feature of antidepressant therapy is the lag phase of one to three weeks before the appearance of a beneficial effect. As a result, attention has increasingly focused on adaptive changes following long-term antidepressant administration. The main thrust of this review will be concentrated on the effects of chronically administered antidepressants on central monoamine functioning. Pertinent acute pharmacological studies together with a brief overview of the role of monoamines in depression are incorporated to present an integrated picture. 2. ROLE OF MONOAMINES IN DEPRESSION Much effort has been directed to causally relate some facet of monoaminergic functioning to affective disorders. The area is one of considerable controversy. A comprehensive coverage of the literature is beyond the scope of this review and a brief overview will be presented. 2 . 1 . E N Z Y M E S I N V O L V E D IN M O N O A M I N E

SYNTHESIS AND DEGRADATION

Since inbibitors of the enzyme MAO are effective antidepressants, numerous studies have attempted to establish a relationship between affective disorders and the activity of the enzyme in platelets and plasma. This area has been reviewed recently in depth and the conclusion was that not only does no correlation exist between MAO characteristics and the psychiatric state of depressives but also that results in the literature are not ~,T 132 A

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comparable because the methodological approaches are too incompatible (Coper et al., 1979). The enzyme catechol-O-methyltransferase is responsible for the O-methylation of catecholamines (Guldberg and Marsden, 1975). Its activity in erythrocytes has been studied in relation to depressive illness. Results are contradictory (Gershon, 1978; Shulman et al., 1978; Davidson et al., 1979). Dopamine-fi-hydroxylase not only catalyzes the conversion of DA to NE but the enzyme is also released with catecholamines from sympathetic nerves and the adrenal medulla. Hence, determinations of serum dopamine-fi-hydroxylase activity have been used as an index of the functioning of the sympathetic nervous system (Weinshilboum, 1979). The activity of the enzyme in the serum of patients with affective disorders has been the subject of several investigations but no clear-cut picture has emerged (Weinshilbourn, 1979). Dopamine-fi-hydroxylase activity in the cerebrospinal fluid (CSF) of patients suffering from a variety of psychiatric disorders has been studied with no overall differences in activity being observed (Lerner et al., 1978). 2.2. NOREPINEPHRINE

The functional status of monoaminergic neurotransmitter systems in the central nervous system (CNS) of man has been extensively investigated by measurements of their metabolites in urine and CSF. 3-Methoxy-4-hydroxyphenylethyleneglycol (MHPG) is the major metabolite of NE in human brain and, while controversy exists concerning what proportion of urinary M H P G arises from the central metabolism of NE, it is generally accepted that the proportion is significant (Maas et al., 1979; De Met and Halaris, 1979). Urinary M H P G levels have been used for the prognosis of therapy with tricyclic antidepressants. Several studies have shown that patients with low urinary M H P G levels respond favourably to secondary tricyclics, e.g. desipramine, which preferentially inhibit NE uptake whereas patients with normal or high urinary M H P G values respond better to tertiary tricyclics, e.g. amitriptyline, which preferentially block 5-HT uptake (Maas et al., 1972; Schildkraut, 1973; Beckmann and Goodwin, 1975; Sacchetti et al., 1979). Using urinary 24 hr M H P G output as the selection criteria for tricyclic antidepressant drug therapy is claimed to give significantly better results than have previously been obtained using traditional selection methods (Cobbin et al., 1979), As a consequence of these and other ancillary observations, it has been proposed that patients with low urinary M H P G levels have a disorder involving NE metabolism. Conversely, patients with high or normal urinary M H P G values do not appear to have a NE-related disorder and it is possible that alterations in 5-HT functioning are involved in their illness (Maas, 1977; Sweeney and Maas, 1978). It has been demonstrated in several studies that in bipolar depressives urinary M H P G levels are lower during depressions and higher during manic or hypomanic episodes than during periods of remission (cf. Schildkraut, 1978). On the basis of urinary catechol metabolites, Schildkraut et al. (1978a,b) have reported the discrimination of three biochemically discrete subgroups of depressive disorders. If the urinary excretion of M H P G would provide a biochemical basis for differentiating subtypes of depressive disorders, this would be a major advancement in clarifying the role of NE in affective disorders. An alternative strategy for investigating NE functioning in depression has focused on postsynaptic NE receptor sensitivity. A limitation of this approach is the extrapolation of peripheral findings to the CNS. This avenue of research was first used by Prange et al. (1967) who reported a reduced pressor response to NE in depressives. In contrast, others have observed an enhanced pressor response to both the indirectly acting sympathomimetic tyramine and the postsynaptic ~-adrenoceptor agonist phenylephrine (Ghose et al., 1975; Coppen and Ghose, 1978; Friedman, 1978). These findings are suggestive of the presence of supersensitive peripheral postsynaptic ~-adrenoceptors. Whereas the pressor response of depressives to phenylephrine is unaltered by electroconvulsive shock therapy (ECT) the response is diminished by chronic lithium, thus suggesting an induced de-

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creased sensitivity of peripheral postsynaptic c~-adrenoceptors (Ghose, 1980). Others have used as a model the ability of NE to inhibit the synthesis of adenosine 3',5'-monophosphate (c-AMP) in platelets. No difference was observed between depressives and controls (Murphy et al., 1974; Wang et al., 1974). Possible evidence for peripheral/~-adrenoceptor subsensitivity is the finding that the isoproterenol-induced increase in c-AMP synthesis in leukocytes from depressives is less than that of controls (Pandy et al., 1979a). Another approach is based on a neuroendocrinological strategy. Growth hormone release is regulated in part by central NE systems, as indicated by a diminished growth hormone release following postsynaptic c~-adrenoceptor blockade (Weiner and Ganong, 1978). Growth hormone release elicited by insulin-induced hypoglycaemia is less in depressives than in controls (Mueller et al., 1969). The growth hormone response to amphetamine is also deficient in many depressives (Langer et al., 1976). A parallel diminished growth hormone response to insulin-induced hypoglycaemia and decreased urinary MHPG levels has been observed in a small group of depressives (Garver et al., 1975). These observations have been viewed as reflecting a central deficiency in NE functioning (Van Praag, 1978). 2.3. SEROTONIN

In some, but not all, studies decreased levels of 5-HT and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) have been detected in post-mortem samples from brains of suicides (Murphy et al., 1978a,b). CSF levels of 5-HIAA are considered to reflect changes in brain 5-HT metabolism. Most studies report lower levels of 5-HIAA in CSF samples from depressives. No studies have reported higher levels (Murphy et al., 1978a,b). Asberg et al. (1976) have observed a bimodal distribution of 5-HIAA in CSF samples from depressives, one group having normal values and the other low concentrations. Their preliminary data suggested that patients in the latter group were more likely to commit suicide. Regarding drug therapy, individuals who respond to chlorimipramine have been found to possess lower levels of 5-HIAA in their CSF than non-responders to the drug. Conversely, individuals who subsequently responded to the secondary tricyclic nortriptyline had higher CSF 5-HIAA levels (Van Praag, 1977). The observation that the increase in CSF levels of 5-HIAA after tryptophan loading in depressives with low 5-HIAA values does not differ from controls suggests that the enzymatic machinery involved in 5-HT synthesis is not impaired in the brain of depressives (Ashcroft et al., 1973). Brain 5-HT synthesis is highly dependent upon plasma tryptophan levels and reports of a lowered content of free tryptophan in the plasma of depressives affords a plausible explanation for the apparent diminution in 5-HT synthesis in the brain of depressives. However, others have failed to confirm this observation (cf. Green and Costain, 1979). Moreover, if tryptophan deficiency is a causative factor in depression, then tryptophan administration should be an extremely effective antidepressant. However, the status of the amino acid as an antidepressant remains equivocal. A decreased accumulation of 5-HT has been observed in platelets from depressives. This is due to a change in the maximum capacity of transport (Vmax) and not to an alteration in the affinity of the carrier for substrate (K,,) (Tuomisto and Tukiainen, 1976; Coppen et al., 1978b). The decreased Vmaxof platelets from depressives is normalized by treatment with imipramine (Tuomisto et al., 1979) or mianserin (Coppen et al., 1978a). However, the significance of these observations is clouded by the fact that patients on imipramine or amoxepine therapy show no differences in clinical recovery yet the Vmax of 5-HT accumulation into platelets from the amoxepine-treated group is still decreased (Tuomisto et al., 1979). The decreased accumulation of 5-HT in platelets from bipolar depressives is corrected by chronic lithium administration (Born et al., 1980; Coppen et al., 1980). Perhaps the most compelling reason for a role of 5-HT in depressive disorders is the observation that the concomitant administration of the tryptophan hydroxylase inhibitor

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p-chlorophenylalanine (PCPA) to depressives on tranylcypromine (Shopsin et al., 1976) or imipramine (Shopsin et al., 1975) therapy results in a return of depressive symptoms. Cessation of PCPA administration results in symptom remission. In contrast, the tyrosine hydroxylase inhibitor ~-methyl-p-tyrosine (~-MT) exhibits no antagonistic effect on the tranylcypromine- or imipramine-related improvements (Shopsin et al., 1975, 1976). 2.4. CONCLUSION

On the basis of clinical phenomenology, it has been long recognized that depression does not represent a homogeneous entity (Schildkraut, 1965). Biochemical data point in the same direction. The concept that there may be NE- and 5-HT-mediated depressions is a significant advancement not only in attempting to elucidate the possible biochemical aberrations underlying the disease but also in the choice of antidepressant therapy. However, a currently insoluble question is whether the biochemical parameter being used is a cause or a product of the disease. An intimate relationship exists between pre- and postsynaptic events. The assumption that a decreased level of neurotransmitter metabolites represents a state of monoamine deficiency is an over-simplification. An inverse relationship exists between sustained changes in monoamine turnover and postsynaptic receptor sensitivity (cf. Schwartz et al., 1978). Hence, an apparent reduction in monoamine turnover could well be associated with postsynaptic receptor subsensitivity. Attempts to assess monoamine postsynaptic functioning in depressives are a worthwhile research strategy.

3. ACUTE EFFECTS OF ANTIDEPRESSANTS ON NEUROTRANSMITTER AND IMIPRAMINE-BINDING SITES In addition to their well documented effect on monoamine uptake (cf. Maxwell and White, 1978), antidepressants directly interact with a number of central receptors. These include adrenergic, serotoninergic, histaminergic and cholinergic receptors. Moreover, the possible presence of high affinity binding sites for antidepressants has been the subject of several investigations. In this section, these interactions will be reviewed. 3.1. ADRENERGIC Adrenoceptors can be subdivided into ~- and fl-adrenoceptors. The interaction of antidepressants with both groups of central adrenoceptors has been investigated by the use of radioactive ligand binding assays, fl-Adrenoceptors can be further subdivided into fll and f12. 3H-Dihydroalp renolol (3H-DHA) and 12Sl-iodohydroxybenzylpindolol are the radioligands most frequently used in fl-adrenoceptor binding studies. Both radioligands bind to both ill- and fl2-adrenoceptors. Techniques are available to distinguish ill- and fl2-adrenoceptor binding (Minneman and Molinoff, 1980). Using 3H-DHA as the radioligand, it has been demonstrated that the affinity of classical tricyclics and atypical antidepressants for central fl-adrenoceptors is very weak (Peroutka and Snyder, 1980; Tang and Seeman, 1980). :~-Adrenoceptors have been subdivided into :q and ~2 (Langer, 1974; Berthelsen and Pettinger, 1977). c~- and 0~2-Adrenoceptors are frequently regarded as being synonymous with post- and presynaptic e-adrenoceptors respectively although this is not always the case. Presynaptic ~-adrenoceptors play an important role in regulating NE release (Langer, 1977; Starke et al., 1977; Westfall, 1977). In the light of the comments of Starke and Langer (1979) on terminology for presynaptic adrenoceptors, the term :~2-adrenoceptor will be used in this review. A number of antidepressants have been studied for blockade of central ~-adrenoceptors. Tang and Seeman (1980) have investigated the effect of several atypical antidepressants on calf frontal cortex ~H-WB-4101 binding, mianserin being the most

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potent. Regarding tricyclics, in general, tertiary tricyclics are more potent than secondary analogues in competing for 3H-WB-4101 binding to rat cortical ~-adrenoceptors. Among the tertiary tricyclics, doxepin and amitriptyline are the most potent having Ki values (apparent inhibition constant) of approximately 23 nm (U'Prichard et al., 1978; Maggi et al., 1980; Peroutka and Snyder, 1980). Tertiary tricyclics are considered to be particularly effective in patients with psychomotor agitation and they also elicit a higher incidence of sedative and hypotensive side effects. Conceivably such actions could stem from blockade of ~l-adrenoceptors (U'Prichard et al., 1978). Tricyclic and atypical antidepressants have been investigated for blockade of central ~2-adrenoceptors, 3H-clonidine being the radioactive ligand (Maggi et al., 1980; Tang and Seeman, 1980). With the exception of mianserin, all drugs show weak activity. The lack of selectivity of mianserin for at- or ~2-adrenoceptors has been demonstrated in peripheral (Borowski et al., 1977; Doxey et al., 1978; Cavero et al., 1980) and in behavioral investigations (Clineschmidt et al., 1979; Delini-Stula et al., 1979).

3.2. SEROTONINERGIC

A number of antidepressants behave like classical 5-HT receptor antagonists in a variety of neuropharmacological test systems e.g. spinal reflexes and the so-called 5-HT behavioral syndrome. Antidepressants blocking central 5-HT receptors on acute administration include amitriptyline (Fuxe et al., 1977; Maj et al., 1979a), mianserin (Van Riezen, 1972; Maj et al., 1978) and trazodone (Maj et al., 1979d). Fuxe and his associates have investigated a large number of antidepressants for their abilities to block both 5-HTP and d-lysergic acid diethylamide (d-LSD)-induced behavior in mice and to displace 3H-5-HT and 3H-d-LSD from membrane binding sites in rat neocortex. A correlation exists between blockade of behavior and affinity for 3H-d-LSD binding sites, resulting in the speculation that blockade of central 5-HT receptors could contribute to the mechanism of action of antidepressants (Ogren et al., 1979). However, a possible argument against this hypothesis is the wide range of drug potencies required for displacement of 3H-d-LSD from central binding sites and the essentially equipotent clinical effects of antidepressants (Peroutka and Snyder, 1980; Tang and Seeman, 1980). Electrophysiological (see Section 7) and radioligand binding studies suggest the heterogeneity of postsynaptic 5-HT receptors in the CNS. Central 5-HT receptors can be labelled with 3H-5-HT, 3H-d-LSD and 3H-spiroperidol. Whereas 3H-spiroperidol labels almost exclusively DA receptors in the corpus striatum, in the cerebral cortex 3H-spiroperidol binding is essentially associated with 5-HT receptors. Differential drug potencies in competing for 3H-5-HT and 3H-spiroperidol binding sites suggest that the two radioligands label two distinct populations of receptors. The aH-5-HT and 3H-spiroperidol binding sites have been termed 5-HT1 and 5-HT2 receptors respectively (Peroutka and Snyder, 1979). The ability of various drugs to block the so-called 5-HT behavioral syndrome parallels closely their affinity for 5-HTz rather than for 5-HT1 receptors (Snyder and Goodman, 1980). A series of classical and atypical antidepressants have been investigated for their affinities to rat cortical 5-HT1 and 5-HT2 receptors. Antidepressants are more potent at 5-HT2 than at 5-HTx receptors. However, a wide range of drug potencies exist and there is no correlation with any known antidepressant action. In addition, the neuroleptics chlorpromazine and haloperidol are comparable to the most active antidepressants, i.e. amitriptyline and nortriptyline, at 5-HT2 binding sites (Peroutka and Snyder, 1980).

3.3. HISTAMINERGIC

Classical tricyclic and atypical antidepressants such as mianserin and iprindole are potent inhibitors of the histamine (H)-induced stimulation of c-AMP production in brain homogenates, an action mediated via H2-receptors (Green and Maayani, 1977; Kanof

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and Greengard, 1978). The possibility that such an action contributes to the antidepressant action of the drugs has been proposed by Kanof and Greengard (1978). However. several points argue against this. For example, neuroleptic phenothiazines arc comparable in potency to the antidepressants (Kanof and Greengard, 1978). In addition, no relationship exists between clinical dosage and blockade of the cyclase and, ~hereas tricyclics are more potent than cimetidine at blocking the histamine-sensitive cyclase. they neither resemble typical H2-antagonists on isolated organs nor do they possess anti-ulcer properties (Schwartz, 1979). Tricyclic antidepressants are extremely potent inhibitors of H~-receptors in both mouse neuroblastoma cells (Richelson, 1978)and guinea-pig ileum (Figge et al., 1979). In fact, doxepin and amitriptyline are more potent than classical antihistaminics. A similar finding has been made when studying the ability of tricyclics to block 3H-mepyraminc binding to rat brain Hi-receptors (Tran et al., 1978; Diffiey et al., 1980). The drug concentrations required for H~ blockade are much less than those required for t-t, antagonism. The relevance of histamine receptor antagonism both in terms of mechanism of action and drug-induced side effects, e.g. sedation, is not clear (Snyder, 1980). 3.4. CHOLINERGIC

By using radioactively labelled receptor ligands, the ability of both tricyclics and MAO inhibitors to interact with rat brain muscarinic cholinergic receptors has been investigated (Fjalland et al., 1977; Snyder and Yamamura, 1977). MAO inhibitors, in contrast to tricyclics, have little activity. Of the tricyclics studied, amitriptyline is the most potent and this could well account for its atropine-like side effects (Hollister, 1978b). Tricyclics differ considerably in their affinity for central muscarinic receptors. For example, nortriptyline, imipramine and desipramine are appreciably less active than amitriptyline. This observation, together with the weak action of MAO inhibitors, suggests that blockade of central muscarinic receptors is not involved in the antidepressant action of the drugs. 3.5. IMIPRAMINE BINDING SITES

The discovery of high affinity binding sites for opiates (Pert and Snyder, 1973) and benzodiazepines (Squires and Braestrup, 1977) and their possible endogenous ligands (Hughes, 1975; Tallman et al., 1980) has stimulated the quest for specific high aMnitv binding sites for antidepressants. Initial attempts failed to reveal such a site (Rehavi and Sokolovsky, 1978; Biegon and Samuel, 1979). However, the existence of a specific, saturable, high affinity binding site for 3H-imipramine has been demonstrated in both rat (Raisman et al., 1979) and human brain (Rehavi et al., 1980). High affinity binding sites for 3H-imipramine are also present in human platelets (Briley et al., 1979; Paul et al.. 1980) and of extreme interest is the observation that 3H-imipramine binding sites arc decreased in platelets obtained from untreated depressives (Briley et al., 1980). Tricyclic antidepressants such as desipramine, protriptyline, chlorimipramine and amitriptyline are potent inhibitors of 3H-imipramine binding to rat cortical membranes whereas atypical antidepressants, e.g. mianserin and iprindole, are much weaker (Raisman et al.. I980). The affinity of antidepressants to the 3H-imipramine binding sites does not correlate with drug potencies at neurotransmitter binding sites. Rat cortical 3H-imipraminc binding is decreased by long-term administration of desipramine (Raisman et al.. 1980j. The over-all significance of the 3H-imipramine binding site awaits clarification. 3.6. CONCLUSION Both classical tricyclic and atypical antidepressants display considerable affinity for a number of central neurotransmitter binding sites. However, in no instance does alfinity correlate with clinical efficacy. It is unlikely that acute blockade of central neurotransmitter binding sites relates to antidepressant activity, but it may contribute to drug-

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induced side effects. The discovery of a high affinity 3H-imipramine binding site is of obvious interest, but to view it as an antidepressant receptor is premature. 4. PRESYNAPTIC ADAPTIVE CHANGES FOLLOWING CHRONIC ANTIDEPRESSANT ADMINISTRATION A characteristic feature of all antidepressants is the lag phase in onset of clinical effectiveness and it is currently fashionable to relate efficacy to adaptive changes in central monoaminergic functioning following long-term drug administration. Druginduced adaptive changes can occur both pre- and postsynaptically. In this section, presynaptic adaptive changes in central monoaminergic systems following chronic antidepressant administration will be reviewed. The subject matter has been covered in depth elsewhere (Sugrue, 1981b). 4.1. CHANGES IN MONOAMINE TURNOVER

4.1.1. Tricyclic Antidepressants

The chronic administration of secondary tricyclics such as desipramine or protriptyline is frequently associated with a diminution in rat brain NE content (Schildkraut et al., 1971 ; Roffier-Tarlov et al., 1973; Rosloff and Davis, 1974; Pugsley and Lippmann, 1979; McMillen et al., 1980). Basal levels of monoamines give little information on the over-all functional dynamics of the system. Such knowledge may be obtained from turnover studies (Costa and Neff, 1968). Acutely administered secondary tricyclics, e.g. desipramine and nortriptyline, elicit a reduction in rat brain NE turnover (Nielsen, 1975; Nielsen and Braestrup, 1977a; Roffman et al., 1977; Bareggi et al., 1978; Tang et al., 1978). This effect of the drug generally correlates with its ability to block NE uptake (Carlsson and Lindqvist, 1978). Whereas acute desipramine decreases rat brain NE turnover, the converse generally occurs following multiple dosing of the antidepressant. This has been demonstrated using a variety of experimental approaches, e.g. enhancement of the decline in brain NE content following ~-MT administration (Neff and Costa, 1967; Rosloff and Davis, 1974; Sugrue, 1980a); increased levels of MHPG and its sulphate conjugate (Roffman et al., 1977; Tang et al., 1978; Sugrue, 1980a); and increased disappearance of aH-NE after pool labeling by intracisternal 3H-NE (Schildkraut et al., 1976; Pugsley and Lippmann, 1979). Long-term imipramine and protriptyline also increase rat brain NE turnover, as demonstrated by the use of the intracisternal model (Schildkraut et al., 1971). Although imipramine is a tertiary tricyclic, it is rapidly demethylated in the rat with the result that chronic imipramine administration is associated with high levels of desipramine in rat brain (Nagy, 1977). In contrast to imipramine, the tertiary tricyclic amitriptyline on chronic administration fails to alter rat brain NE turnover (Roffman et al., 1977; Tang et al., 1978). Not in all instances is chronic desipramine or imipramine associated with increased turnover of NE in rat brain. For example, the incorporation of 3H-tyrosine into aH-NE is decreased by long-term desipramine (Nielsen and Braestrup, 1977b; Rosloff and Davis, 1978). The chronic administration of imipramine retards the decline in NE levels in several brain regions following dopamine-fl-hydroxylase inhibition (Mogilnicka and Klimek, 1979a). Other presynaptic changes in rat brain NE systems following chronic desipramine administration include decreased tyrosine hydroxylase activity (Segal et al., 1974) and a rate of locus coeruleus firing which, though less than that seen in controls, is greater than that seen after the acute administration of the antidepressant (McMillen et al., 1980). In contrast to these adaptive responses, long-term desipraminedoes not lose its ability to block rat brain NE uptake (Schildkraut et al., 1976; Nielsen and Randrup, 1977b; Bergstrom and Kellar, 1979a; Pugsley and Lippmann, 1979).

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There are several reports in the literature claiming that DA uptake is blocked by tricyclic antidepressants (Halaris et al., 1975; Friedman et al., 1977: Randrup and Braestrup, 1977). However, it must be borne in mind that drug concentrations and/or doses required for activity are much greater than those needed for inhibition of NE and 5-HT uptake. The more generally accepted view is that tricyclics at realistic doses have little or no effect on DA uptake (cf. Carlsson, 1970; Carlsson and Lindqvist, 1978; Maxwell and White, 1978). Rat brain DA uptake in vitro is unaffected by long-term desipramine (Pugsley and Lippmann, 1979). In contrast to tricyclics, some new atypical antidepressants can block DA uptake. Examples are nomifensine (Brodgen et al., 1979) and bupropion (Soroko et al., 1977). Acutely administered chlorimipramine or amitriptyline, but not desipramine or protriptyline, elevates rat striatal levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) (Persson, 1979; Keller et ai., 1980). The increased DA turnover, as reflected by the increased levels of DOPAC and HVA, is attributed to, an albeit weak, blockade of DA receptors (Keller et al., 1980). Acutely administered chlorimipramine or amitriptyline blocks apomorphine-induced stereotypies in rats and the block is increased by the chronic administration of either antidepressant (Delini-Stula and Vassout, 1979). The tetracyclic antidepressant maprotiline (Pinder et al., 1977; Baumann and Maitre, 1979) also blocks central DA receptors on acute administration but tolerance develops after chronic treatment (Delini-Stula and Vassout, 1979). Rat brain DA turnover is unaltered by chronic desipramine (Neff and Costa, 1967; Nielsen and Braestrup, 1977b; Rosloff and Davis, 1978; Sugrue, 1980a). Protriptyline (Neff and Costa, 1967) and chlorimipramine (Sugrue, 1980a) are also devoid of effect. Slight reductions in central DA turnover have been observed after long-term imipramine (Friedman et al., 1974) or amitriptyline (Nielsen and Braestrup, 1977b). These observations are not in harmony with the behavioral data cited above. This raises the possibility that the behavioral observations may be related to some factor other than DA receptor blockade. It is of interest to note that the affinity of tricyclic antidepressants for central DA receptors is weak (Peroutka and Snyder, 1980). Of extreme interest is the finding that subsensitive DA presynaptic receptors may be induced by the chronic administration of imipramine, amitriptyline or mianserin, as demonstrated by an antagonism of the ability of low doses of apomorphine to decrease rat spontaneous motor activity and caudate DOPAC levels (Serra et al., 1979). Electrophysiological confirmation is the observation that chronic imipramine or amitriptyline decreases the ability of a presynaptic dose of apomorphine to attenuate neuronal discharge of single DA neurones in the zona compacta of the substantia nigra (Chiodo and Antelman, 1980). Acutely administered tertiary tricyclics such as chlorimipramine decrease rat brain 5-HT turnover (Corrodi and Fuxe, 1969; Meek and Werdinius, 1970; Modigh, 1973; Goodlet and Sugrue, 1974; Carlsson and Lindqvist, 1978). Investigations of the effect of long-term antidepressant administration has yielded inconsistent findings. Multiple dosing of chlorimipramine has been reported to induce an adaptive change in rat brain 5-HT turnover, as reflected by a loss of its ability to decrease turnover of the monoamine (Marco and Meek, 1979). Conversely, chronic, like acute, chlorimipramine has been observed to reduce rat brain 5-HT turnover (Van Wijk et al., 1977). The observation that long-term imipramine augments rat neocortex 5-HT turnover (Sherman, 1979) contrasts with the finding that the drug, on chronic administration, loses its ability to decrease turnover (Svensson, 1978). 4.1.2. Atypical and Putative Antidepressants. The atypical antidepressants most extensively investigated are mianserin and iprindole. Mianserin is a clinically effective antidepressant (Brodgen et al., 1978) and differs structurally from the tricyclics, being a tetracyclic. The acute neurochemical profile of mianserin is dissimilar to that of a tricyclic antidepressant such as desipramine. Mianserin

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blocks NE uptake in vitro, its potency being comparable to that of imipramine (Raiteri et al., 1976; Baumann and Maitre, 1977; Goodlet et al., 1977). However, mianserin has little (Baumann and Maitre, 1977) or no effect on central NE uptake in vivo (Leonard, 1974; Goodlet et al., 1977). A lack of effect of the drug on peripheral NE uptake has been observed in clinical studies (Ghose et al., 1976). Raiteri et al. (1979) have hypothesized that the weak binding of mianserin to the NE uptake carrier explains the essential lack of effect of the drug on NE uptake in vivo. In addition to its lack of effect on NE uptake in vivo, mianserin, unlike secondary tricyclics, increases rat brain NE turnover (Leonard, 1974; Leonard and Kafoe, 1976; Fludder and Leonard, 1979a; Sugrue, 1980b). Chronic, like acute, mianserin increases rat brain NE turnover, as assessed by precursor incorporation (Kafoe et al., 1976) and elevated levels of NE metabolites, e.g. normetanephrine (NME) (Fludder and Leonard, 1979b), M H P G (Tang et al., 1979) and MHPG-SO4 (Sugrue, 1980a,b). Long-term mianserin fails to alter rat brain DA turnover (Kafoe et al., 1976; Sugrue, 1980a). Mianserin is a very weak inhibitor of 5-HT uptake in vitro (Raiteri et al., 1976; Goodlet et al., 1977) and lacks activity in vivo (Goodlet et al., 1977). The drug is an antagonist of 5-HT1 and 5-HT2 receptors (Clements-Jewery and Robson, 1980; see also Section 3.2). However, acute (Kafoe et al., 1976) and chronic mianserin (Kafoe et al., 1976; Sugrue, 1980a) do not change rat brain 5-HT turnover. Although there are a number of studies showing the clinical effectiveness of iprindole, the status of the drug as an antidepressant has been recently questioned (Zis and Goodwin, 1979). Iprindole is neither a MAO inhibitor nor a blocker of uptake (Gluckman and Baum, 1969; Lahti and Maickel, 1971; Freeman and Sulser, 1972; Rosloff and Davis, 1974). Chronic iprindole has essentially no effect on rat brain NE turnover, as assessed by synthesis inhibition (Rosloff and Davis, 1974), precursor conversion (Rosloff and Davis, 1978) and metabolite formation (Sugrue, 1981a). Although long-term iprindole is devoid of effect on mouse brain 5-HT turnover (Sanghvi and Gershon, 1975) an increased turnover of the monoamine has been observed in rat neocortex (Sherman, 1979). Possibly the greatest interest in putative antidepressants currently centres on specific inhibitors of 5-HT uptake. The quest for such compounds has been triggered by the potential involvement of 5-HT in the disease (Section 2.3). A number of such compounds now exist (Van Dijk et al., 1978). However, data on clinical efficacy is sparse. Zimelidine is one such compound (Ross et al., 1976) and its antidepressant activity has been demonstrated in several trials (Benkert et al., 1977; Coppen et al., 1979; Georgotas et al., 1980). Acute (Carlsson and Lindqvist, 1978) and chronic zimelidine (Fuxe et al., 1979) reduce rat brain 5-HT turnover. Moreover, multiple dosing of zimelidine to humans results in decreased levels of CSF 5-HIAA, an observation indicating a diminished turnover (Siwers et al., 1977). Rat brain 5-HT turnover is also decreased by chronic Org 6582 (Sugrue, 1980a), another specific inhibitor of 5-HT uptake (Sugrue et al., 1976; Mireyless et al., 1978). Fluoxetine is also a specific inhibitor of 5-HT uptake (Fuller et al., 1975a; Wong et al., 1975) which on chronic, like acute, administration has been demonstrated to reduce mouse brain 5-HT turnover (Hwang and Van Woert, 1980). The ability of acutely and chronically administered fluoxetine to inhibit mouse brain 5-HT uptake does not differ (Hwang and Van Woert, 1980). The lack of adaptive change in central 5-HT turnover following the prolonged blockade of uptake of the monoamine contrasts with the situation in NE systems after long-term blockade of NE uptake by desipramine (Section 4.1.1.). In spite of the fact that blockade of 5-HT uptake is maintained, it is feasible that, as a consequence of the prolonged reduction in synthesis, the chronic administration of a specific 5-HT uptake inhibitor is not associated with an enhancement of 5-HT functioning. This possibility has been explored in two studies. In one, a comparison was made of the effect of acutely and chronically administered fluoxetine on the haloperidol-induced increase in rat striatal DOPAC and HVA levels. Acute fluoxetine potentiates the effect of haloperidol (Waldmeier and Delini-Stula, 1979). This effect is attributed to the existence

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of an excitatory 5-HT input into striatal cholinergic interneurones (Waldmeier, 1979). In contrast to the acute situation, chronic fluoxetine fails to potentiate the response to haloperidol (Sugrue, 1980c). In the other study, chronic fluoxetine was observed to be much less potent than a single dose in enhancing the '5-HT syndrome' elicited in mice by tranylcypromine plus tryptophan (Hwang et al., 1980). The lack of effect of chronic fluoxetine is not due to postsynaptic changes, as indicated by the failure of chronic tluoxetine to alter central 3H-5-HT binding (Section 5.2.2). Hence, the results of both studies reveal that adaptive changes occur in central 5-HT systems following the prolonged blockade of uptake of the monoamine. The adaptive response results in the loss of the ability of the uptake blocker to enhance central 5-HT functioning. 4.1.3. M A O

lnhihitors

The use of MAO inhibitors in the treatment of depression is limited. The discovery that MAO exists in two functionally different forms, type A which preferentially oxidizes NE and 5-HT, and type B which, in man, oxidizes DA (Neff and Yang, 1974; Murphy, 1978) has renewed interest in the possibility of obtaining selective inhibitors devoid of the undesirable side effects of classical MAO inhibitors. Possible presynaptic adaptive changes resulting from the chronic administration of MAO inhibitors have not been extensively investigated. Once daily phenelzine or tranylcypromine for six weeks results in peak increases in rat brain NE, DA and 5-HT content occurring between one and seven days treatment followed by a gradual decline to control levels. Chronic phenelzine has no effect on tyrosine hydroxylase activity but results in elevated tryptophan hydroxylase activity. Chronic tranylcypromine does not alter tyrosine hydroxylase or tryptophan hydroxylase activity but increases aromatic amino acid decarboxylase activity, the elevation occurring after 2-3 weeks treatment (Robinson et al., 1979). Chronic clorgyline increases rat brain 5-HT levels for the first two weeks of treatment. Levels return to control level at the end of the third week of drug administration. Brain NE levels increased for the duration of the three week study. Long-term clorgyline has no effect on the activity of tryptophan hydroxylase or tyrosine hydroxylase in brain (Campbell et al., 1979). 4.1.4. L i t h i u m In contrast to the tricyclic antidepressants and MAO inhibitors, lithium is essentially used in the treatment of bipolar depression. Short-term lithium increases rat brain NE turnover (Corrodi et al., 1967; Schildkraut et al., 1969; Greenspan et al., 1970; Poitou and Bohuon 1975). In contrast, turnover is unaltered after long-term administration (Corrodi et al., 1969; Bliss and Ailion, 1970; Ho et al., 1970; Poitou and Bohuon, 1975; Schildkraut et al., 1976). The effect of chronic lithium on 3H-NE uptake into rat brain slices is biphasic. Initially uptake is increased, followed by a gradual return to control (Cameron and Smith, 1980). Indirect clinical evidence has led to the suggestion that chronic lithium increases peripheral NE uptake (Ghose, 1980). In some studies, chronic lithium has been observed to have no effect on rat brain DA turnover, (Bliss and Ailion, 1970; Ho et al., 1970; Schubert, 1973), whereas a reduction in turnover has been found in others (Corrodi et al., 1969; Poitou and Bohuon, 1975). Furthermore, others report an increase in striatal turnover, as reflected by elevated levels of 3-methoxytyramine (Maggi and Enna, 1980) and DOPAC and HVA (Hesketh et al., 1978). Regional studies indicate an increased turnover of the monoamine in striatal and mesolimbic areas but not in the cortex or hypothalamus (Fadda et al., 1980). In general terms, 5-HT turnover in rat brain would appear t o b e unaltered lollowing long-term lithium administration (Bliss and Ailion, 1970; Ho et al., 1970). In contrast, short-term treatment increases turnover (Sheard and Aghajanian, 1970; Perez-Cruet et al., 1971; Schubert, 1973). The increased turnover occurs independently of neuronal impulse flow (Schubert, 1973). This observation is in harmony with the postulated lith-

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ium-induced increased intraneuronal deamination of 5-HT (Sheard and Aghajanian, 1970; Perez-Cruet et al., 1971) which may result from an impairment in 5-HT storage mechanisms (Collard and Roberts, 1977). The effect of lithium on 5-HT synthesis has been studied in detail (Mandell and Knapp, 1977). Short-term lithium (one to five days) increases tryptophan transport into striatal synaptosomes and consequently increases 5-HT synthesis. The elevated 5-HT synthesis in turn leads to a decrease in tryptophan hydroxylase activity. After long-term lithium (ten to twenty one days), the augmented tryptophan transport is still maintained, enzyme activity is decreased and the net result is a return of 5-HT synthesis to control values. Neurophysiological studies also suggest an increased uptake of tryptophan after chronic lithium (Sangdee and Franz, 1980). 4.2. EFFECT ON ~2-ADRENOCEPTORS

The effects on acutely and chronically administered antidepressants on ~2-adrenoceptors are currently a topic of considerable interest. Two reasons account for this. One is the ability of mianserin to block central ~2-adrenoceptors in vitro (Baumann and Maitre, 1977). The second is the induction of subsensitive ~2-adrenoceptors in rat heart following chronic desipramine (Crews and Smith, 1978). The experimental paradigm usually used for investigating ~2-adrenoceptor functioning in vivo is to study the effect of drug administration on the ability of clonidine to lower NE turnover. Clonidine achieves this effect by activating ~-adrenoceptors. Depending on the dosage, clonidine can preferentially activate ~2-adrenoceptors. Neurochemical (And6n et al., 1976) and behavioral studies (Delini-Stula et al., 1979; Drew et al., 1979) indicate that doses of clonidine of 0.1 mg/kg or less may be considered selective for ;¢2-adrenoceptors. Acutely administered mianserin attenuates the clonidine-induced decrease in rat brain NE turnover (Fludder and Leonard, 1979a; Tang et al., 1979; Sugrue, 1980b). Studies investigating the effect of multiple dosing of the antidepressant on the response to clonidine have yielded contradictory results. Long-term mianserin attenuates the reduction in rat amygdaloid NME levels elicited by concurrently administered clonidine (2.5 mg/kg) (Fludder and Leonard, 1979b). Similarly, chronic mianserin blocks the ability of clonidine (0.35 mg/kg) to lower rat brain M H P G levels (Tang et al., 1979). It is to be noted that the dose of clonidine used in both experiments may be in excess of that required for selectively activating ~2-adrenoceptors. In contrast to these observations, twice daily mianserin for 14 days is devoid of effect on the ability of clonidine (25/~g/kg) to lower rat brain MHPG-SO4 content (Sugrue, 1981a). When the acute experiment is mimicked in rats which have received chronic mianserin (10 mg/kg once daily for 15 days) the ability of the antidepressant to attenuate the response to clonidine is absent. Moreover, this would appear to be an adaptive response as indicated by the development of the phenomenon between 5-9 days of mianserin administration (Sugrue, 1980b). Assuming that doses of clonidine of 0.1 mg/kg and less are selective for :~2-adrenoceptors, it would appear that the inability of long-term mianserin to block c~2-adrenoceptors is an adaptive response of the receptors to prolonged exposure to the drug. This finding would suggest that the antidepressant action of mianserin is not due to blockade of ~2-adrenoceptors. In spite of the apparent inability to block :~2-adrenoceptors, chronic mianserin elevates rat brain MHPG-SO4 levels (Sugrue, 1980a). This could be due to blockade of z~l-adrenoceptors by the antidepressant (Section 3.1.). Blockade of 71-adrenoceptors could well account for the observed ability of chronic mianserin to attenuate the change in rat brain NE utilization elicited by doses of clonidine in excess of 0.1 mg/kg (Fludder and Leonard, 1979b; Tang et al., 1979). The observation that long-term desipramine induces subsensitive 72-adrenoceptors in rat heart (Crews and Smith, 1978) has stimulated studies to determine if an analogous change occurs in the CNS. Desipramine in vitro is essentially devoid of effect on both central (Baumann and Maitre, 1977; Maggi et al., 1980; Tang and Seeman, 1980) and peripheral (Harper and Hughes, 1979) :¢2-adrenoceptors.

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The clonidine-induced decrease in rat brain M H P G levels is apparently not blocked by acute desipramine (Tang et al., 1978). However, a complicating factor is the fact that desipramine itself lowers metabolite levels (Tang et al., 1978). Inhibition of NE uptake by desipramine activates a negative feedback mechanism which, in turn, elicits a reduction in NE neuronal impulse flow (Nyb~ick et al., 1975; Bareggi et ell., 1978: Scuvde-Moreau and Dresse, 1979). Decreased neuronal impulse flow accounts for the reduction in M H P G levels. Long-term twice daily administration of desipramine attenuates the reduction in rat brain MHPG-SO+ levels elicited by clonidine (25/~g/kg) (McMillen et ell., 1980: Sugrue, 1981a). The ability of chronic desipramine to block the response to clonidine could be due to either the induction of subsensitive :~2-adrenoceptors or to a receptor blocking effect of the antidepressant. The in vitro data cited above suggests that this is not the case. Moreover, if receptor blockade was the explanation, antagonism of the MHPG-SO4 lowering action of clonidine would be anticipated when brain levels of desipramine are high. Following the daily administration of imipramine (10 mg/kg) rat-brain steady-state levels of desipramine are achieved before day 4 (Nagy, 1977). The observation that twice daily desipramine (10 mg/kg) for five days is devoid of effect on the clonidine-induced fall in MHPG-SO,~ levels (Sugrue, 1981a) argues against a receptor blocking effect and favours the concept of receptor subsensitivity. The development of :z%-adrenoceptor subsensitivity is an adaptive response as indicated by the finding that it becomes apparent between 5-9 days of twice daily desipramine administration (Sugrue, 1981a). The ability of chronic desipramine to attenuate the response to clonidine is dependent upon a number of factors. These include the frequency and duration of desipramine administration and the dose of clonidine. The importance of duration has been discussed. In contrast to results obtained with twice daily treatment, the response to clonidine (25/~g/kg) is unaltered by the once daily administration of desipramine (10mg/kg) for 14 days. When the dose of clonidine is raised to 0.1 mg/kg, twice daily desipramine for 14 days is ineffective at blocking the MHPG-SO,~ reduction elicited by the :~-agonist (Sugrue, 1981a). Perhaps the larger dose of clonidine surmounts the inhibitory effect of chronic desipramine. Electrophysiological experiments confirm the presence of subsensitive :~2-adrenoceptors in rat brain following chronic desipramine. The injection of desipramine at a dose which, in the acute situation, markedly decreases rat locus coeruleus firing is essentially devoid of effect in chronically treated rats (McMillen et al., 1980). Moreover, the ability of a low i.v. dose or iontophoretic clonidine to depress rat locus coeruleus firing is attenuated by chronic imipramine (Svensson and Usdin, 1978). In view of the finding that chronic desipramine is associated with the development of subsensitive c~2-adrenoceptors in rat brain, experiments have been undertaken to determine if this property of desipramine is shared by other putative and established antidepressants possessing markedly different acute pharmacological profiles. The drugs investigated were nisoxetine, a specific inhibitor of NE uptake (Fuller et al., 1975b) with purported antidepressant activity (Fuller et al., 1979); iprindole (Section 4.1.2)" salbutamol, a fl2-adrenoceptor stimulant which is claimed to be as effective as chlorimipramine in the treatment of depression (Lecrubier et al., 1980) and trazodone, a clinically effective antidepressant possessing a multiplicity of pharmacological actions (cf. Maj eta/., 1979d). Nisoxetine (10 and 20 mg/kg), iprindole (10 mg/kg), salbutamol (5 mg/kg) and trazodone (10 mg/kg) were injected twice daily for 14 days. Clonidine (25 llg/kg) was administered 12 hr after cessation of drug administration. In no instance was there an attenuation of the clonidine-induced diminution in rat brain MHPG-SO+ levels (Sugrue+ unpublished observations). Hence, under identical experimental conditions, none of the drugs possess the ability of desipramine to induce central :~2-adrenoceptor subsensitivity. 4.3. CONCLUSION Long-term antidepressant administration is associated with a number of important presynaptic adaptive changes in rat brain monoaminergic systems.

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Chronic treatment with secondary tricyclics such as desipramine appears to be associated with an increased availability of NE in the synaptic cleft. The development of subsensitive ~-adrenoceptors is an undoubted contributor. Synaptic NE concentrations are also elevated by chronic mianserin. However, whereas acute mianserin blocks rat brain :~2-adrenoceptors, this effect is lost following the chronic administration of the antidepressant. Increase in synaptic NE levels is not a property common to all antidepressants, as indicated by the failure of chronic iprindole to alter NE turnover, MHPG-SO4 levels or ~2-adrenoceptor sensitivity in rat brain. Of six established and putative antidepressants possessing markedly dissimilar acute pharmacological profiles only desipramine alters rat brain ~2-adrenoceptor sensitivity. It would be of interest to know if the latter is modified by ECT or chronically administered MAO inhibitors. Although chronic antidepressants have little or no effect on rat brain DA turnover, the findings that both tricyclic antidepressants and mianserin induce subsensitive presynaptic DA receptors is an exciting observation warranting further exploration. Investigations of the effect of chronic tricyclics on central 5-HT turnover have yielded contradictory results. Perhaps this is the culmination of a number of various factors, e.g. dosage, frequency and duration of administration and, possibly, the experimental model utilized. Central 5-HT turnover is diminished following the chronic administration of specific inhibitors of 5-HT uptake. This could conceptually result in a decreased availability of 5-HT in the synaptic cleft. In accord with this concept are the observations that, in contrast to acute, chronically administered specific inhibitors of 5-HT uptake fail to enhance 5-HT functioning. The relevance of these observations to postsynaptic events will be discussed in subsequent sections.

5. EFFECTS OF CHRONIC ANTIDEPRESSANTS ON NEUROTRANSMITTER BINDING SITES 5.1. ADRENERGIC 5.1.1. Tricyclic antidepressants

Chronic, but not acute, tricyclic antidepressant administration is associated with a reduction in rat brain fl-adrenoceptor binding. This phenomenon was first reported by Banerjee et al. (1977) who showed that the observed effect is due to a decreased number of binding sites and not to a change in apparent affinity. The ability of desipramine to diminish rat brain fl-adrenoceptor binding has been demonstrated in a number of studies (Banerjee et al., 1977; Sarai et al., 1978; Wolfe et al., 1978; Bergstrom and Kellar, 1979a; Dibner and Molinoff, 1979; Greenberg and Weiss, 1979; Maggi et al., 1980; Peroutka and Snyder, 1980; Sellinger-Barnette et al., 1980). The phenomenon extends to other tricyclics e.g. imipramine (Rosenblatt et al., 1979; Maggi et al., 1980; Peroutka and Snyder, 1980), amitriptyline (Peroutka and Snyder, 1980; Sellinger-Barnette et al., 1980), nortriptyline and chlorimipramine (Sellinger-Barnette et al., 1980). The ability of multiple dosing of desipramine to reduce central fl-adrenoceptor binding appears to be dependent upon the presence of intact NE nerve terminals since the phenomenon is absent in rats depleted of brain NE by the prior administration of 6-hydroxydopamine (Wolfe et al., 1978; Schweitzer et al., 1979). It is of interest to note that chronic desipramine has no effect on heart fl-adrenoceptor binding (Wolfe et al., 1978). Regional differences exist in the onset of the desipramine-induced decrease as indicated by the finding that cortical binding is decreased after one week whereas four weeks treatment is necessary for a diminution in fl-adrenoceptor binding in the hippocampus (Bergstrom and Kellar, 1979a). ill- and flE-Adrenoceptors are present in rat brain and the desipramine-induced decrease in confined to the former (Minneman et al., 1979). The ability of chronic desipramine to decrease rat cortical fl-adrenoceptor binding is accelerated by the concomitant administration of either yohimbine (Wiech and Ursillo,

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1980) or phenoxybenzamine (Paul and Crews, 1980). It is also of interest to note that ral cortical fl-adrenoceptor binding is redutced by ECT (Bergstrom and Kellar, 1979b, Gillespie et al., 1979; Pandey et al., 1979b). The mechanism by which chronic tricyclics decrease fl-adrenoceptor binding awaits clarification. Incubating rat cortical slices with isoproterenol or NE restllts in a reduction in fl-adrenoceptor binding sites. Re-incubation or exposure to guanine nucleotides restores fi-binding. In contrast, neither of these procedures affects the decrease elicited by chronic desipramine. Moreover, incubation of cortical slices from chronic desipraminetreated rats with isoproterenol leads to a further decrease in the density of binding sites. Hence, it would appear that the reductions elicited by chronic desipramine and isoproterenol are mediated ~ia distinct mechanisms (Dibner and Molinoff, 1979). In other experiments, incubation of rat cortical slices with either isoproterenol or tricyclic antidepressants, albeit at high concentrations (0.1 mM) decreases fl-adrenoceptor binding. The effects are not additive thus suggesting that a similar mechanism is involved. Pargyline. unlike the tricyclics, is devoid of effect (U'Prichard and Enna, 1979}. This observation is not in harmony with in vivo data (see below). In contrast to their ability to decrease /7-adrenoceptor binding, chronically administered tricyclics such as desipramine (Bergstrom and Kellar, 1979a; Peroulka and Snyder, 19801, imipramine (Rosenblatt et al., 1979; Peroutka and Snyder, 1980) and amitriptyline (Peroutka and Snyder, 1980) fail to alter rat brain al-adrenoceptor binding. Perhaps ~-adrenoceptors are more resistant to modification than fl-adrenoceptors although this is difficult to reconcile with electrophysiological observations (Section 7). Chronically administered tricyclics such as desipramine, imipramine and amitriptyline are devoid of effect on rat striatal DA binding (Rosenblatt et al., 1979; Peroutka and Snyder, 1980). 5. 1.2. A typical Antidepressants

Rat central fl-adrenoceptor binding is decreased by multiple dosing of iprindole (Banerjee et al., 1977; Wolfe et al., 1978; Peroutka and Snyder, 1980; Sellinger-Barnette et al., 1980). Pretreatment with 6-hydroxydopamine attenuates the iprindole-induced diminution (Wolfe et al., 1978). The significance of this observation is far from clear since chronic iprindole appears to be totally devoid of effect on presynaptic NE systems (Section 4.3.). Chronic mianserin has been observed in one study (Clements-Jewery, 1978) but not in others (Mishra et al., 1980; Sellinger-Barnette et al., 1980) to decrease rat cortical fl-adrenoceptor binding. If the concept that decreased binding is due to a prolonged increased availability of NE in the synaptic cleft (Wolfe et al., 1978), a mianserin-induced reduction in fi-adrenoceptor binding would be clearly anticipated in view of the increased turnover of NE in rat brain following long-term mianserin (Section 4.1.2.). The inability of chronic nisoxetine to decrease rat cortical fl-adrenoceptor binding (Mishra et al., 1979: Maggi et at., 1980) will be discussed in greater depth in Section 6. 5.1.3. M A O lnhibitors Chronically administered pargyline decreases rat cortical fl-adrenoceptor binding (Wolfe et al., 1978; Peroutka and Snyder, 1980). In contrast, ~l-adrenoceptor binding is unaltered (Peroutka and Snyder, 1980). Rat cortical fl-adrenoceptor binding is also reduced by long-term nialamide or tranylcypromine (Sellinger-Barnette et al., 1980). 5.1.4. Lithium The chronic administration of lithium evokes a small statistically significant (Rosenblatt et al., 1979: Treiser and Kellar, 1979) or a nonsignificant (Maggi and Enna, 1980) reduction in rat central fl-adrenoceptor binding. A slight increase in :~l-adrenoceptor

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binding has been observed in whole brain (Rosenblatt et al., 1979), but not cerebral cortex (Treiser and Kellar, 1979) after chronic lithium. In spite of its slight effect per se, chronic lithium prevents the 6-hydroxydopamineinduced increase in the density of rat-brain ~1- and fl-adrenoceptors (Rosenblatt et al., 1979) and the reserpine-induced increase in cortical/3-adrenoceptor binding (Treiser and Kellar, 1979). In contrast, the ability of long-term imipramine to reduce rat-brain h'-adrenoceptor binding is unaltered by chronic lithium (Rosenblatt et at., 1979). Chronic lithium has no effect on rat striatal 3H-spiroperidol binding (Pert et al., 1978; Rosenblatt et al., 1979). However, in rats treated concurrently with lithium and haloperidol, the ability of the latter to develop both increased sensitivity to apomorphine and increased striatal binding of 3H-spiroperidol is attenuated (Pert et al., 1978). The ability of chronic lithium to prevent the development of DA receptor supersensitivity has also been observed by others using alternative pharmacological approaches (Gallager et al., 1978; Friedman et al., 1979; Allikmets et at., 1979). Perhaps an increased release of DA by chronic lithium explains the phenomenon (Section 4.1.4.).

5.2. SEROTONINERGIC

5.2.1. Tricyclic antidepressants The density of rat brain 5-HT~ receptor binding sites is not resistant to change as indicated by an increased binding following the chronic administration of the 5-HT receptor antagonist methergoline (Samanin et al., 1980) and the reduction following chronic LSD (Trulson an~t Jacobs, 1979) or the purported 5-HT releaser fenfluramine (Samanin et al., 1980). Studies on the effect of 10rig-term tricyclic antidepressant administration on rat brain 5-HT1 binding are equivodal. For example, chronic desipramine has been observed in some studies (Segawa et al., 1979; Maggi et al., 1980) but not in others (Bergstrom and Kellar, 1979a; Peroutka and Snyder, 1980) to decrease central 5-HT1 binding. A lack of effect of chronic chlorimipramine has also been observed (Wirz-Justice et al., 1978; Bergstrom and Kellar, 1979a; Savage et at., 1980). Of extreme interest is the observation that rat cortical 5-HT2 binding is decreased by multiple dosing of amitriptyline, desipramine or imipramine (Peroutka and Snyder, 1980).

5.2.2. Atypical antidepressants Long-term administration of iprindole (Peroutka and Snyder, 1980) and mianserin (Sugrue, unpublished observation) has no effect on rat brain 5-HT1 binding. Also ineffective is the putative antidepressant fluoxetine (Savage et al., 1979, 1980; Maggi et al., 1980; Peroutka and Snyder, 1980). Perhaps the lack of effect of fluoxetine may be a consequence of the inability of the drug on chronic administration to enhance central 5-HT functioning (Section 4.1.2.). Interestingly, chronic iprindole, but not fluoxetine, diminishes rat cortical 5-HT2 binding (Peroutka and Snyder, 1980). It is worth recalling that chronic iprindole increases rat neocortical 5HT turnover (Sherman, 1979).

5.2.3. M A O lnhibitors Rat cortical 5-HT 1 binding is decreased by the chronic administration of type A MAO inhibitors, e.g. chlorgyline and nialamide, whereas deprenyl, a type B inhibitor, is ineffective (Savage et al., 1979, 1980). The 21 day administration of pargyline is associated with a reduction in rat cortical 5-HT1 and 5-HT2 binding sites (Peroutka and Snyder, 1980).

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5.2.4. Lithium Long-term administration of lithium is associated with a reduction in 5-HT~ binding sites in hippocampus but not in cerebral cortex (Maggi and Enna, 1980; Treiser and Kellar, 1980). The ability of reserpine to induce supersensitive 5-HT receptors in mice is blocked by chronic lithium administration (Friedman et aL, 1979). However, long-term lithium fails to prevent the development of supersensitivity in rat hippocampal pyramidal cells by multiple dosing with chlorimipramine (Gallager and Bunney, 1979). 5.3. CONCLUSION Rat brain neurotransmitter binding sites are modified by chronic antidepressant administration. Classical tricyclic and atypical antidepressants, together with MAO inhibitors, decrease the density of fi-adrenoceptor and 5-HT 2 binding sites. Although NE hyperinnervation is associated with decreased fl-adrenoceptor binding (Harden et al., 1979), the concept that the reduction in fl-adrenoceptor binding is the result of a prolonged increase in NE levels is the synaptic cleft is an over-simplication. The precise mechanism by with chronic antidepressants decrease the density of fl-adrenoceptor binding remains to be ehicidated. Of the other forms of antidepressant treatment, chronic lithium, in contrast to ECT, would appear to have little effect on fl-adrenoceptor binding. In contrast to the fl-adrenoceptor, the ~l-adrenoceptor is resistant to change following chronic antidepressant treatment. Results of studies investigating the effect of long-term tricyclic antidepressants on rat brain 5-HT1 receptor binding sites have yielded inconsistent findings. The observation that rat cortical 5-HT 2 binding is decreased by a wide spectrum of antidepressants, including MAO inhibitors, is intriguing. It is of interest to know if the property extends to ECT, lithium and specific inhibitors of NE uptake, e.g. maprotiline and nisoxetine. The presynaptic contribution to the phenomenon remains to be determined.

6. EFFECTS OF C H R O N I C ANTIDEPRESSANT ADMINISTRATION ON RAT BRAIN ADENYLATE CYCLASE ACTIVITY 6.1. TRICYCLIC ANTIDEPRESSANTS

Sulser and his associates have pioneered the use of the NE-stimulated adenylate cyclase system in rat limbic forebrain as a model for monitoring central postsynaptic NE functioning. There are two receptors coupled to the system. One has the characteristics of a fll-adrenoceptor whereas the other cannot be classified as either :~ and fl (MoNey and Sulser, 1979). Depletion of brain catecholamines either by reserpine or by 6-hydroxydopamine is associated with an increased responsiveness of the NE-stimulated adenylate cyclase in rat limbic forebrain slices. The increased response to NE is not due to a change in the affinity of NE for the receptor moiety since the concentration of NE necessary for half-maximal stimulation is the same in control and treated preparations (Vetulani et al., 1976b). The increased sensitivity of cortical NE-stimulated adenylate cyclase activity is associated with an increased density of fl-adrenoceptors (Sporn et al., 1977). In contrast to the situation following NE depletion, the once daily administration of desipramine to rats for three to six weeks was observed by Sulser and his colleagues to elicit a diminution in the sensitivit3 of the limbic NE-coupled adenylate cyclase system. The decreased response is not due to a change in affinity since the concentration of NE causing half-maximal stimulation is unaltered. Acute desipramine has no effect on the system and no correlation exists between the reduced response and the concentration of desipramine in brain tissue (Vetulani and Sulser, 1975: Vetulani et al., 1976a). The

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induction of subsensitivity by chronic desipramine is unlikely to be due to a direct effect since no change has been observed in the activity of NE-stimulated adenylate cyclase in rat diaphragm, a tissue lacking sympathetic innervation (Frazer et al., 1978). The ability of chronic desipramine to induce a subsensitive adenylate cyclase system has been confirmed by others (Frazer and Mendels, 1977; Schmidt and Thornberry, 1977; Frazer et al., 1978; Wolfe et al., 1978). This property is shared by other chronically administered tricyclics, e.g. imipramine (Frazer et al., 1974; Schultz, 1976), amitriptyline and chlorimipramine (Mishra and Sulser, 1978). Multiple dosing of desipramine attenuates the increase in rat cortical c-AMP content following electrical stimulation of the locus coeruleus, ~- and fl-adrenoceptors being involved in the response. The response is unaltered and slightly attenuated by chronic chlorimipramine and imipramine respectively (Korf et al., 1979). An alternative strategy has involved the use of the rat pineal gland. This tissue contains a high density of fl-adrenoceptors and a highly sensitive adenylate cyclase system. The gland is innervated by postganglionic NE fibres and light inhibits the activity of the sympathetic innervation to the pineal. Hence moving a rat from light to dark enhances NE neuronal impulse flow (Axelrod, 1974). The acute administration of desipramine to rats 1 hr before being placed in the dark for 1 min results in an augmented increase in pineal c-AMP content. In contrast, c-AMP content is not enhanced by multiple dosing of desipramine (Heydorn et al., 1980), a procedure which also decreases the density of fl-adrenoceptors in the gland (Moyer et al., 1979).

6.2. ATYPICAL ANTIDEPRESSANTS

The ability of tricyclic antidepressants to induce a subsensitive response of the NEstimulated adenylate cyclase system is shared by a number of atypical antidepressants e.g. iprindole (Vetulani and Sulser, 1975; Vetulani et al., 1976a), nisoxetine (Mishra et al., 1979), mianserin and zimelidine (Mishra et al., 1980). However, fluoxetine, in contrast to zimelidine, is ineffective (Mishra et al., 1979). These observations have a number of ramifications regarding the ability of chronic antidepressants to induce a subsensitive adenylate cyclase system. A number of factors could account for the observed response. These include increased NE in the synaptic cleft, changes in receptor density, alterations in phosphodiesterase activity, changes in coupling factors and modification of properties of the cell membrane. The ability of long-term antidepressants to induce a subsensitive NE-stimulated adenylate cyclase system cannot be due solely to an increased availability of NE in the synaptic cleft as indicated by the effectiveness of iprindole (cf. Section 4.1.2.) and the specific 5-HT uptake inhibitor zimelidine. The ability of chronic nisoxetine to down-regulate adenylate cyclase functioning without changing the density of fl-adrenoceptors (cf. Section 5.12) indicates that both phenomena are not inter-dependent. Evidence that changes in fl-adrenoceptor binding and adenylate cyclase activity are not coupled is the observation that incubation of human astrocytoma cells with isopreterenol results in a rapid loss in adenylate cyclase activity with little change in fl-adrenoceptor binding (Su et al., 1979). Elucidating the mechanism of down-regulation of NE-stimulated adenylate cyclase systems by chronic antidepressants is an undoubted area of further research.

6.3. M A O INHIBITORS

Acutely administered MAO inhibitors enhance the response of the rat forebrain adenylate cyclase system to NE. In contrast, chronic pargyline or nialamide induce a subsensitive response (Vetulani et al., 1976b). It is of interest to note that the system is also down-regulated by repeated ECT (Vetulani and Sulser, 1975; Gillespie et al., 1979).

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6.4. LITHIUM The chronic administration of lithium at a dose achieving plasma levels in the upperrange of therapeutic concentrations attenuates the NE-stimulated adenylate cyclase in rat cortical slices. In contrast to NE receptor antagonists, compensatory supersensitivity does not develop (Ebstein et al., 1980). The lack of development of supersensitivity is consistent with the reports that chronic lithium has little effect on fl-adrenoceptor binding (cf. Section 5.2.4.). The reserpine-induced supersensitive response of cortical NEstimulated adenylate cyclase is prevented by the chronic administration of lithium at doses yielding plasma levels of the cation incapable of directly inhibiting the cyclase (Hermoni et al., 1980). 6.5. CONCLUSION

The observations that drugs such as reserpine which induce depressive reactions increase, and that drugs which alleviate the disease decrease, the sensitivity of the NEstimulated adenylate cyclase system emphasize the importance of the model. This is strengthened by the fact that a wide variety of antidepressant remedies have a common response i.e. a down-regulation of the system. The relevance of induced adrenoceptor subsensitivity will be discussed in greater depth in the Summary.

7. ELECTROPHYSIOLOGICAL AND BEHAVIORAL CORRELATES The relationship, if any, between the biochemical effects described above and changes in postsynaptic receptor functioning as studied by the use of electrophysiological and behavioral techniques is of obvious importance. A down-regulation in rat-brain fl-adrenoceptor sensitivity has been demonstrated electrophysiologically following chronic antidepressant administration. Long-term desipramine decreases the responsiveness of rat cerebellar Purkinje cells to iontophoretic NE. This is a fl-adrenoceptor mediated response and is the opposite of that seen in the acute situation (Siggins and Schultz, 1979). The sensitivity of rat cingulate cortical neurones to iontophoretic NE or GABA has been studied after the chronic administration of desipramine, chlorimipramine, maprotiline or tranylcypromine. A subsensitive response to NE, but not to GABA, was induced by all four antidepressants (Olpe and Schellenberg, 1980). Further evidence for a reduction in the overall functioning of central NE systems is the observation that the basal firing rate of rat hippocampal neurones is increased by chronic desipramine (Huang, 1979a). This system has an inhibitory NE input and acute desipramine facilitates NE inhibition (Huang, 1979b). In contrast to the lack of effect of chronic antidepressant administration on rat brain ~:-adrenoceptor binding (cf. Section 5.1.1.), long term administration of desipramine, imipramine, amitriptyline and iprindole, but not fluoxetine, is associated with an enhanced response to iontophoretic NE in the rat facial motor nucleus (Menkes et al., 1980). The excitation of facial motoneurones is facilitated by NE acting via an ~-adrenoceptor (McCall and Aghajanian (1979). An enhanced response to iontophoretic NE has also been observed in rat amygdaloid neurones after long-term desipramine, imipramine or iprindole. However, the receptors mediating the NE inhibition could not be classified as ~- or fl-adrenoceptors (Wang and Aghajanian, 1980). There is currently a lack of a suitable behavioral model for studying alterations in central fl-adrenoceptor functioning. Models which most likely reflect changes in postsynaptic ~x-adrenoceptor activity have been utilized. A clonidine-induced increase in spontaneous motor activity has been observed in rats treated chronically, but not acutely, with imipramine, amitriptyline or mianserin (Maj et al., 1979b). In a follow-up study, chronically administered tricyclic, e.g. amitriptyline and desipramine, and atypical antidepressants, e.g. iprindole and mianserin, were observed to enhance apomorphineinduced aggressive behavior in rats. Apomorphine-induced stereotypes were unaltered. In

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rats treated chronically with amitriptyline, apomorphine-induced aggressive behavior was blocked by phenoxybenzamine (Maj et al., 1979c). These behavioral findings suggest that chronic antidepressant treatment is associated with an up-regulation in postsynaptic central ~-adrenoceptor functioning. Hence a good correlation exists between behavioral studies and the electrophysiological investigation cited above. The long-term administration of iprindole and a variety of tricyclic antidepressants, e.g. desipramine, chlorimipramine, imipramine and amitriptyline, results in an enhanced inhibitory response to iontophoretic 5-HT in rat hippocampal, ventral lateral geniculate and amygdaloid neurones (De Montigny and Aghajanian, 1978; Gallager and Bunney, 1979; Wang and Aghajanian, 1980). Moreover, chronic antidepressant administration is associated with an augmentation of the excitatory facilitatory action of 5-HT in the rat facial motor nucleus (Menkes et al., 1980). These observations would appear to be in harmony with behavioral findings as indicated by the enhanced behavioral response of rats to 5-hydroxytryptophan following chronic amitriptyline or mianserin (Molignicka and Klimek, 1979b). In addition, long-term administration of amitriptyline or imipramine to mice results in an augmented response to the 5-HT agonist 5-methoxy-N, N-dimethyltryptamine (Friedman and Dallob, 1979). Whereas acute imipramine, desipramine, amitriptyline or mianserin antagonizes the ability of i.v. 5-HT to induce sleep in young chicks, the chronic administration of the drugs is associated with an enhancement of the 5-HT induced depression (Jones, 1980). The apparent up-regulation in central 5-HT functioning following chronic antidepressant administration is in marked contrast to the findings of binding studies (cf. Sections 5.2.1. and 5.2.2.). 8. SUMMARY Acutely administered antidepressants possess a multiplicity of pharmacological actions. However, the fact that agents possessing similar pharmacological actions are devoid of antidepressant activity, together with the lack of correlation between doses required for acute pharmacological effects and clinical efficacy, suggest that the mechanism(s) of action of antidepressants cannot be directly attributed to the acute pharmacological properties of the drugs. The lag phase in onset of clinical effectiveness emphasizes the importance of adaptive changes following chronic antidepressant administration. The result obtained in any study investigating long-term drug treatment is dependent upon a number of factors. These include dosage, frequency and duration of administration and the time gap between cessation of administration and commencement, of experiment. The latter is extremely important. To assume that systems remain static for an indefinite period of time following cessation of treatment is invalid. For example, a rebound increase in rat locus coeruleus impulse flow occurs 2+48 hr after cessation of chronic imipramine administration (Svensson and Usdin, 1979). This can also be demonstrated neurochemically as evidenced by the overshoot in rat-brain M H P G and MHPG-SO4 content 36-48 hr after cessation of chronic desipramine treatment (Nielsen and Braestrup, 1977b; Sugrue, 1981a). Hence, if the time gap between the last injection and commencement of experiment is relatively long, one could well be studying a rebound phenomenon rather than a drug-induced adaptive change. Chronically administered antidepressants elicit a number of adaptive changes in presynaptic monoaminergic neurones. Such alterations can conceptually result in certain situations where neurotransmitter availability in the synaptic cleft is either enhanced or diminished. An example of the former is the induction of subsensitive ~2-adrenoceptors in rat brain by long-term desipramine. However, neurochemical studies suggest that this effect of desipramine is not shared by other antidepressants which markedly differ in their acute pharmacological profiles. Whereas acute mianserin blocks central ~2-adrenoceptors, this effect is lost following the chronic administration of the drug. These observations remain to be corroborated by electrophysiological data. Of interest, is the finding that the sensitivity of presynaptic DA receptors is down-regulated by the chronic administration of mianserin and tricyclic antidepressants. An example of chronic

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drug administration being associated with a possible diminished availability of neurotransmitter in the synaptic cleft is the situation occurring after the long-term administration of specific inhibitors of 5-HT uptake. The ability of such compounds on acute administration to enhance 5-HT functioning is absent following their chronic administration. In spite of continued monoamine uptake inhibition, the failure of the agents to augment 5-HT functioning is conceivably due to a diminished release of the monoamine stemming from the prolonged reduction in synthesis following long-term drug treatment. The chronic administration of antidepressants is also associated with a number of postsynaptic adaptive changes. Such alterations can occur independently of presynaptic changes. For example, chronic iprindole down-regulates postsynaptic /3-adrenoceptor functioning in spite of the fact that the drug appears to be devoid of effect on the NE presynaptic neurone. In contrast to drugs used in the treatment of unipolar depression, viz. tricyclics and MAO inhibitors, lithium is relatively ineffective in eliciting changes in receptor density. However, of interest is the ability of the cation to attenuate pharmacologically induced supersensitive NE, DA and 5-HT receptors. Hence, it is feasible that lithium functions as a general dampener of aberrant monoaminergic functioning. Central postsynaptic monoaminergic functioning is modulated by long-term tricyclic and atypical antidepressant administration. The observations of drug-induced decreased cortical 5-HT2 receptor binding and of the augmentation of both inhibitory and excitatory 5-HT functioning, as shown electrophysiologically, are intriguing. The extension of these studies to alternative forms of antidepressant therapy, e.g. MAO inhibitors and ECT, is awaited with interest. A critical problem in elucidating the significance of such observations is the lack of a 5-HT coupled receptor system analogous to the NE-coupled adenylate cyclase model. A key observation is the down-regulation of the rat brain NE-coupled adenylate cyclase system following chronic treatment with a wide variety of therapies, e.g. tricyclics, atypical antidepressants, MAO inhibitors and ECT. A decreased sensitivity of central postsynaptic /?-adrenoceptors has been confirmed electrophysiologically. In general terms, the down-regulation of the NE-coupled adenylate cyclase system can be correlated with a decrease in jq-adrenoceptor binding density. However, nisoxetine, zimelidine, and possibly mianserin, are exceptions. This suggests that both phenomena are not necessarily interdependent and that the antidepressant-induced downregulation may be effected by an action other than at the coupling step. Studies investigating postsynaptic adrenoceptor functioning in depressives have resulted in equivocal observations. Studies utilizing peripheral systems suggest the presence in depressives of subsensitive and supersensitive /~- and ~-adrenoceptors respectively. In contrast, the use of the hypothalamic-pituitary axis points to the presence of subsensitive ~-adrenoceptors. The precise link between these observations and the loci of antidepressant action are tenuous. While cross-species extrapolations must be treated with caution, the observation that chronically administered antidepressants down-regulate central NE functioning permits the speculation that depression may, in part, be related to a functional hyperactivity of NE neuronal systems. The hypersensitive receptors may serve to amplify incoming stimuli and hence result in a central excitability. Thus a hyperresponsive catecholaminergic system may be an underlying cause of depression (Segal et al., 1974). Antidepressant administration may clinically result in a desensitization of enhanced NE receptor functioning thus causing a reduction in the postulated amplification mechanism that translates sensory input into physiological and behavioral events (Sulser, 1978; Sulser et al., 19781. Thus current thinking is diametrically opposite to the original catecholamine hypothesis of depression which attributed the illness to a deficiency of the monoamine at central synapses. In spite of the profound advancements in our knowledge of the pharmacological effects of antidepressants, the precise identity of the neurotransmitter(s) involved in their mechanism(s) of action remains elusive. The picture is further complicated by the complex

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anatomical, physiological and biochemical inter-connections among central putative neurotransmitter and modulatory systems. Depression is not a homogeneous entity. Despite the biochemical and clinical evidence for NE- and 5-HT-mediated depressions, the possibility cannot be ignored that antidepressants may act by a common, as yet unknown, mechanism of action. Determining the mechanism(s) of action of antidepressants is a key goal in unravelling the etiology of the disease. Acknowledgement---Sincerest thanks are extended to Claudine Kratz for her invaluable secretarial assistance.

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