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The Pharmacology of Mianserin an Update R Br. J. clin. Pharmac. (1983) 15, 263S-268S THE PHARMACOLOGY OF MIANSERIN AN UPDATE R. J. MARSHALL Department of Pharmacology, Organon Laboratories Ltd., Newhouse, Lanarkshire MLI 5SH, Scotland, UK Introduction involved in the actions of both the classical tricyclic and newer atypical clinically effective antidepressant Since its introduction into clinical medicine, agents. My intention in this paper is to briefly mianserin hydrochloride has been shown to be a discuss some of these newer areas with special potent and useful treatment for depressive illness reference to mianserin. and seems to offer real advantages over the established tricyclic antidepressants in terms of fewer side-effects, lack of cardiotoxicity and greater Antagonism of presynaptic alpha-(@2) adrenoceptors safety in overdosage. In the proceedings of the last mianserin symposium published in this journal Although mianserin has been shown to be only (Peet & Turner, 1978), the pharmacology of weakly active (or inactive) in inhibiting in vivo brain mianserin pertaining to its mode of action was noradrenaline re-uptake (Leonard, 1974; Goodlet et succinctly reviewed in eight pages and pointed to al., 1977), there is good evidence that noradrenaline the atypical pharmacological profile of the drug in turnover and release are increased by the drug the standard battery of pharmacological tests for (Baumann & Maitre, 1977; Fludder & Leonard, predicting antidepressant activity (Table 1). Since 1979; Sugrue, 1980). The most likely mechanism then several comprehensive reviews on possible underlying these effects of mianserin is an mechanisms underlying antidepressant activity have antagonist action on the oc2-adrenoceptors which appeared (Sulser, 1979; Kostowski, 1981; Maj, are situated on the presynaptic nerve terminal and 1981; Waldmeier, 1981) and an excellent review of which regulate noradrenaline release [see Langer the pharmacology of mianserin published (van (1977) for a review]. Certainly the ability of Riezen et al., 1981). mianserin to potentiate noradrenaline-release The medicinal chemical design of potential evoked by K+ (Nickolson & Weiringa, 1981) or antidepressant agents has for many years been electrical stimulation (Baumann & Maitre, 1977) in dictated (some might even say hampered) by the brain slices suggests an o2-antagonist action. In 'biogenic amine hypotheses' [see Waldmeier (1981) addition, ligand-binding studies have shown that for a recent review] which broadly state that certain mianserin can effectively displace [3H] clonidine types of depression are associated with (or are due from rat cortex (Maggi et al., 1980; Tang & to) deficient noradrenergic and/or serotoninergic Seeman, 1980; Peroutka & Snyder, 1981) with Ki neurotransmission in certain areas of the brain. values between 12 and 35nM. It should be noted These views have been rigorously challenged or that in this respect mianserin is at least 20-100 modified over the last few years, partly on the times more potent than the tricyclic antidepressants grounds that chronic treatment of animals with (Maggi et al., 1980). The relevance of a2- clinically-active antidepressants produces quite adrenoceptor block to the actions of mianserin has different biochemical and pharmacological effects however been recently confused by the observation from those seen after acute dosing (e.g., U'Prichard in rats that chronic mianserin therapy (10mg/kg i.p. et al., 1978; Maj, 1981; Sugrue, 1981). In addition a for 15 days) potentiates the auto-inhibitory actions wealth of evidence suggests that mechanisms other of noradrenaline on superfused hypothalamic than neuronal amine re-uptake inhibition may be synaptosomes (Cerrito & Raiteri, 1981). These interesting results, which are shown in Figure 1, Table 1 Atypical pharmacological profile of mianserin suggest that the noradrenergic release system may in the rat become more sensitive to the negative feedback regulatory action of released noradrenaline following long-term blockade of the presynaptic o;2- Tricyclics Mianserin mianserin. Reserpine hypothermia Antagonism No effect adrenoceptors by Morphine catatonia Potentiation Inhibition The oc2-receptor blocking actions of mianserin are Apomorphine locomotion Potentiation No effect also readily demonstrated in sympathetically- Noradrenaline turnover Reduced Increased innervated peripheral tissues (Doxey et al., 1978; Tryptamine stereotypy Potentiation Inhibition Brown et al., 1980; Doggrell, 1980). The latter group of workers has compared the antagonist Adapted from Peet & Behagel (1978) actions of a series of antidepressant drugs on both 0306-5251/83/150263-06 $01.00 ©) The Macmillan Press Ltd., 1983 264S R.J. MARSHALL .., noradrenergic transmission arose from the observations that chronic administration of antidepressant drugs to animals leads to a decrease in the density and/or sensitivity of central j- adrenoceptors (Vetulani & Sulser, 1975; Vetulani et al., 1976; Banerjee et al., 1977; Wolfe et al., 1978). Chronic treatment of rats with mianserin results in an attenuation of noradrenaline-induced increases in cAMP without any apparent accompanying reduction in the number of 3-binding sites as assessed by ligand-binding (Mishra et al., 1980; r: Sellinger-Barnette et al., 1980).- More recently it has been demonstrated that in rats treated for 10 days _> lU: ~~~~~~~~'IL.:-L;.i:j.:.ii L_ ;.S with mianserin (30mg/kg, s.c.) there is a marked decrease in the sensitivity of cingulate cortical Figure 1 Reduction by extracellular noradrenaline of neurones to microiontophoretically applied K + evoked [3H] noradrenaline release in noradrenaline (Olpe et al., 1981). This reduced hypothalamic synaptosomes from control rats (0) and sensitivity of cortical neurones to the depressant from animals chronically treated with mianserin(n). action of noradrenaline was not observed 24h after Control responses to K+ in absence of noradrenaline a single injection of mianserin or after chronic are shown for untreated (0) and mianserin-treated (A) treatment with the weak noradrenaline re-uptake animals. From Cerrito & Raiteri (1981), with inhibitor, iprindole (Figure 2). It is tempting to permission. speculate that the reduced 0-adrenoceptor sensitivity (assessed either by biochemical or acl (rat anococcygeus muscle) and ;2 (rat vas electrical measurements) observed in animals after deferens) adrenoceptors and concluded that 1) not chronic antidepressant treatment may be at least all antidepressants block o2-receptors, 2) none of partly produced by a desensitisation of the post- the antidepressants showed marked selectivity for synaptic 3-receptor caused by excessive levels of aC2-receptors, and 3) all the antidepressants studied noradrenaline in the synapse. However other were much weaker than phentolamine in blocking mechanisms cannot be excluded [see Sulser (1979) either cxl or a-adrenoceptors in these tissues (Table for a discussion]. 2). Using such peripheral test systems, compounds possessing selective x2-adrenoceptor antagonist properties have been identified (Chapleo et al., Interaction with serotoninergic transmission 1981; Michel & Whiting, 1981). Whether any of these compounds possess useful clinical Unlike many of the tricyclic antidepressants, antidepressant potency remains to be elucidated. mianserin does not inhibit neuronal 5-HT re-uptake in the brain (Raiteri et al., 1976; Goodlet et al., Down-regulation of P-adrenoceptors 1977). Although mianserin is a potent antagonist at 5-HT receptors in peripheral tissue (Vargaftig et al., The idea that depression is associated with an 1971; van Riezen, 1972) there remains some Ioverfunction' (rather than an 'underfunction') of controversy regarding its interaction with 5-HT Table 2 a-Adrenoceptor antagonist properties of antidepressants in peripheral tissues of the rat (Prejunctiona)c.2 (Post4junctionaboc. Ratio Rat vas deferens' Rat anococcygeusb pre/post Yohimbine 7.9 x 10-9 8.9x 10-7 113 Prazosin 2.9 x 10-6 1.4 x 10-9 0.0005 Amitriptyline 8.6 x 10-6 5.8x 10-8 0.007 Mianserin 6.5 x 10-7 1.8 x 10-7 0.28 Trazodone 1.1 x 10-6 1.8 x 10-7 0.16 Viloxazine 1.3 x 10-5 >3.5 x 10-s Adalpted from Brown et al. (1980). 'Molar concentration causing 20% cocaine reversal. bMolar pA2 versus noradrenaline contractions PHARMACOLOGY OF MIANSERIN 265S 100 Table 3 5-HT receptor antagonist properties of some antidepressants 90 80 EC50(mglkg) Tryptamine 70. 5-HTP head twitch convulsions Drug Mouse Rat Rat 60 Cyproheptadine 0.038 0.26 5.0 ,,- -/ Mianserin 0.094 0.84 1.5 50 .0 0 Amitriptyline 1.3 5.5 4.7 40 as 40 Trazodone 5.2 9.3 3.8 .=co ' 30 from Maj (1981) ._ Adapted ;r,C 20 0 0 c 10 co brain remain to be elucidated but it has been 40 0 I I a suggested (Maj, 1981) that 5-HT antagonists may 0. C, 100 release a 'serotoninergic brake' on noradrenergic c -b neurones, leading to an increased noradrenaline 90 turnover and availability (see Figure 3). .C0 80 0c 70 Histamine-receptor antagonism 60 - - - - 1It is well established that mianserin possesses potent 50 histamine-receptor antagonist properties in peripheral tissues (van Riezen et al., 1981). 40 Mianserin has a higher affinity (KB 10-9M) for histamine (H1) receptors in intestinal smooth 30 muscle than those (H2) in cardiac muscle 20 (KB-10-M). Several lines of evidence suggest that histamine may play some neurotransmitter role in 10 mammalian brain (Schwartz, 1977, 1979; Green et | |I I Ifi | t E | z al., 1979) and the presence of both types of 0 10 30 90 histamine receptors has been demonstrated [see 'Dose' of NE in nA Schwartz et al., (1981)].
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