Temporal sequence of changes in central noradrenergic system of rat after prolonged antidepressant treatment: Receptor desensitization and neurotransmitter interactions

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Abstract

It has been shown that different receptor components may be involved in the adaptive changes occurring in noradrenergic (NE) neurones after prolonged periods of exposure to antidepressant drugs. In this report the desensitization of NE-coupled adenylate cyclase (NE-AC), β-adrenergic receptors and [3H]imipramine ([3H]-IMI or [3H]desipramine ([3H]DMI) binding sites have been temporally correlated with in vivo changes of NE utilization. Normetanephrine (NMN) was measured as indicator of NE synaptic events involved in antidepressant action. Concentrations of normetanephrine were increased after acute desipramine (DMI), viloxazine and mianserin administration. Following 3 days of treatment, the antidepressant-induced increase of normetanephrine became tolerant and NE neurones were resistant to the antidepressant effect until the 15th day of treatment. After two weeks, DMI elicited a significant decrease in the content of normetanephrine. A different pattern of changes has been found in the temporal modification of [3H]IMI recognition sites, β-adrenoceptors and NE-AC activity after chronic DMI treatment. Binding sites and receptors were down regulated after 10 days of treatment preceding the decrease in normetanephrine content. No down-regulation was observed in [3H]-DMI binding sites. Studies on the effects of antidepressants during brain maturation revealed that the mechanisms which cause desensitization of β-receptors and [3H]-IMI binding sites appear in the early stages of postnatal life. Since [3H]-IMI and [3H]-DMI recognition sites have been shown to be located on serotonergic (5-HT) and noradrenergic neurones respectively, the interactions between NE and 5-HT neurones could represent possible mechanisms implicated in receptor desensitization. The experiments presented involving lesions of 5-HT neurones have clearly demonstrated that NE release in rat cerebral cortex is under a tonic serotonergic influence. Alterations in the chemico-physical properties of the synaptic membranes might be also taken in consideration for the mechanisms underlying receptor modulation. In fact, evidence is provided that in neural tissue phospholipid methylation can be affected. In conclusion, the temporal sequence of changes in cortical noradrenergic neurones, after chronic antidepressant treatment, has demonstrated that integrated mechanisms are operative for the function of the overall system.

References (79)

  • D.A. Pasquier et al.

    Dorsal raphe, substantia nigra and locus coeruleus: interconnections with each other and the neostriatum

    Brain Res. Bull.

    (1977)
  • R. Raisman et al.

    Specific tricyclic antidepressant binding sites in rat brain characterized by high-affinity [3H]-imipramine binding

    Eur. J. Pharmac.

    (1980)
  • B. Renaud et al.

    Effects of 5,7-dihydroxytryptamine on tyrosine-hydroxy-lase activity in central catecholaminergic neurones of the rat

    Biochem. Pharmac.

    (1975)
  • R. Schwarcz et al.

    Striatal lesions with kainic acid; neurochemical characteristics

    Brain Res.

    (1977)
  • C.B. Smith et al.

    α2-adrenoceptors in rat brain are decreased after long-term tricyclic antidepressant drug treatment

    Brain Res.

    (1981)
  • C. Spyraki et al.

    Functional evidence for subsensitivity of noradrenergic alphas-receptors after chronic desipramine treatment

    Life Sci.

    (1980)
  • M.F. Sugrue

    The inability of chronic mianserin to block central alpha2-adrenoceptors

    Eur. J. Pharmac.

    (1980)
  • M. Van Wijk et al.

    Metabolism of centrally released noradrenaline by extraneuronal monoamine oxidase and catechol-O-methyltransferase

    Brain Res.

    (1976)
  • R.Y. Wang et al.

    Denervation supersensitivity to serotonin in rat forebrain single cell studies

    Brain Res.

    (1979)
  • J. Axelrod

    Methylation reactions in the formation and metabolism of catecholamines and other biogenic amines

    Pharmac. Rev.

    (1966)
  • S.P. Banerjee et al.

    Development of beta-adrenergic receptor sub-sensitivity by antidepressants

    Nature, Lond.

    (1977)
  • P.A. Bauman et al.

    Blockade of presynaptic alpha receptors and of amine uptake in the rat brain by the antidepressant mianserin

    Archs Pharmac.

    (1977)
  • D.S. Bennet et al.

    Schedule of appearance of 5-hydroxytryptamine and associated enzymes in the developing rat brain

    J. Neurochem.

    (1965)
  • F. Brandao et al.

    The role of neuronal and extraneuronal systems in the metabolism of adrenaline and noradrenaline released from nerve terminals by electrical stimulation

    Naunyn-Schmiedebergs Arch. Pharmac.

    (1980)
  • S.T. Broitman et al.

    Effects of chronic imipramine and chlomipramine oral administrtion on maternal behavior and litter development

    Psychopharmacology

    (1978)
  • N. Brunello et al.

    Different synaptic location of mianserin and imipramine binding sites

    Science

    (1982)
  • D.B. Bylund et al.

    Beta-adrenergic receptor binding in membrane preparations from mammalian brain

    Molec. Pharmac.

    (1976)
  • L.A. Chiodo et al.

    Repeated tricyclies induce a progressive dopamine autoreceptor subsensitivity independent of daily treatment

    Nature

    (1980)
  • D.M. Chuang et al.

    A biochemical study of receptor internalization during β-adrenergic receptor desensitization in frog erythrocytes

    Molec. Pharmac.

    (1980)
  • J.T. Coyle et al.

    Development of the uptake and storage of L-3H-norepinephrine in the rat brain

    J. Neurochem.

    (1971)
  • F.T. Crews et al.

    Presynaptic alphareceptor subsensitivity after long-term antidepressant treatment

    Science

    (1978)
  • F.T. Crews et al.

    Identification and properties of methyltransferases that synthetize phosphatidilcholine in rat brain synaptosomes

    J. Neurochem.

    (1980)
  • V. Cuomo et al.

    Enduring behavioral and biochemical effects in the adult rat after prolonged postnatal administration of haloperidol

    Psychopharmacology

    (1981)
  • F.S. De la Londe et al.

    The role of monoamine oxidase in the response of the isolated central artery of the rabbit ear to tyramine

    Br. J. Pharmac.

    (1970)
  • G.M. Drew et al.

    Pharmacological characterization of alpha-adrenoceptors which mediate clonidine-induced sedation

    Br. J. Pharmac.

    (1975)
  • W. Feniuk et al.

    Preliminary characterization of the presynaptic receptor for 5-HT in dog isolated saphenous vein

    Br. J. Pharmac.

    (1979)
  • J.M. Fludder et al.

    Chronic effects of mianserin on noradrenaline metabolism in the rat brain: evidence for a presynaptic alpha-adrenolitic action in vivo

    Psychopharmacology

    (1979)
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    Present address: Fidia Research Laboratories, Abano Terme, Italy.

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