Review article| Volume 52, ISSUE 10, P921-926, November 15, 2002

Timing is everything: does the robust upregulation of noradrenergically regulated plasticity genes underlie the rapid antidepressant effects of sleep deprivation?


      The mechanisms by which sleep deprivation brings about rapid antidepressant effects remain to be elucidated. Biological rhythms have the capacity to temporally dissociate biochemical processes, and imposing a temporal coincidence on normally dissociated events can have striking and unexpected effects. In this context, it is noteworthy that the locus coeruleus (LC) noradrenergic projection is quiescent only during rapid-eye-movement (REM) sleep, when the target tissues display their greatest sensitivity; indeed, the temporal dissociation between the firing of the LC noradrenergic neurons and the sensitivity of its postsynaptic targets in the cortex may have considerable relevance for the antidepressant effects of sleep deprivation. Sleep deprivation rapidly upregulates several plasticity-related genes, effects that are noradrenergically mediated; these are the very same genes that are upregulated by chronic antidepressants. Thus, activating the norepinephrine system during REM sleep (by infusing an α2 antagonist) may allow an interaction with a primed, sensitized postsynaptic milieu, thereby rapidly increasing the expression of plasticity genes and consequently a rapid antidepressant response.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Bourne H.R.
        • Nicoll R.
        Molecular machines integrate coincident synaptic signals.
        Cell. 1993; 72: 65-75
        • Cirelli C.
        • Tononi G.
        Differential expression of plasticity-related genes in waking and sleep and their regulation by the noradrenergic system.
        J Neurosci. 2000; 20: 9187-9194
        • Cirelli C.
        • Tononi G.
        Gene expression in the brain across the sleep-waking cycle.
        Brain Res. 2000; 885: 303-321
        • Duman R.S.
        Synaptic plasticity and mood disorders.
        Mol Psychiatry. 2002; 7: S29-S34
        • Frazer A.
        • Benmansour S.
        Delayed pharmacological effects of antidepressants.
        Mol Psychiatry. 2002; 7: S23-S28
        • Goodwin F.K.
        • Jamison K.R.
        Manic-Depressive Illness. Oxford University Press, Inc, New York1990
        • Hyman S.E.
        • Nestler E.J.
        Initiation and adaptation.
        Am J Psychiatry. 1996; 153: 151-162
        • Ikonomov O.C.
        • Manji H.K.
        Molecular mechanisms underlying mood stabilization in manic-depressive illness.
        Am J Psychiatry. 1999; 156: 1506-1514
        • Manji H.K.
        • Duman R.S.
        Impairments of neuroplasticity and cellular resilience in severe mood disorder.
        Psychopharmacol Bull. 2001; 35: 5-49
      1. Manji HK, Quiroz JA, Sporn J, Payne JL, Zarate CA, Denicoff K, et al (2002, in press): Enhancing synaptic plasticity and cellular resilience to develop novel, improved therapeutics for difficult to treat depression. Biol Psychiatry.

        • Nestler E.J.
        • Gould E.
        • Manji H.
        • Bucan M.
        • Duman R.S.
        • Gershenfeld H.K.
        • et al.
        Preclinical models.
        Biol Psychiatry. 2002; 52: 503-528
        • Neumeister A.
        • Praschak-Rieder N.
        • Hesselmann B.
        • Vitouch O.
        • Rauh M.
        • Barocka A.
        • et al.
        Effects of tryptophan depletion in drug-free depressed patients who responded to total sleep deprivation.
        Arch Gen Psychiatry. 1998; 55: 167-172
        • Rensing L.
        • Meyer-Grahle U.
        • Ruoff P.
        • et al.
        Biological timing and the clock metaphor.
        Chronobiol Int. 2001; 18: 329-369
        • Ringel B.L.
        • Szuba M.P.
        Potential mechanisms of the sleep therapies for depression.
        Depress Anxiety. 2001; 14: 29-36
      2. Rush AJ and Ryan ND (2002): Current and Emerging Therapeutics for Depression. In: KL Davis, DS Charney, JT Coyle, CB Nemeroff, editors. Neurosychopharmacology—the Fifth Generation of Progress. Philadelphia: Lippincott Williams and Wilkins, pp 1081–1098.

        • Siegel J.M.
        • Rogawski M.A.
        A function for REM sleep.
        Brain Res. 1988; 472: 213-233
        • Siuciak J.A.
        • Lewis D.R.
        • Wiegand S.J.
        • Lindsay R.M.
        • et al.
        Antidepressant-like effect of brain-derived neurotrophic factor (BDNF).
        Pharmacol Biochem Behav. 1997; 56: 131-137
        • Smolensky M.
        Circadian rhythms in medicine.
        CNS Spectrums. 2001; 6: 467-482
        • Szabo S.T.
        • Blier P.
        Response of the norepinephrine system to antidepressant drugs.
        CNS Spectrums. 2001; 6: 679-684
        • Troncone L.R.
        • Braz S.
        • Benedito M.A.
        • Tufik S.
        • et al.
        REM sleep deprivation induces a decrease in norepinephrine-stimulated 3H-cyclic AMP accumulation in slices from rat brain.
        Pharmacol Biochem Behav. 1986; 25: 223-225
        • Wirz-Justice A.
        • Tobler I.
        • Kafka M.S.
        • Naber D.
        • Marangos P.J.
        • Borbely A.A.
        • Wehr T.A.
        • et al.
        Sleep deprivation.
        Psychiatry Res. 1981; 5: 67-76
        • Wirz-Justice A.
        • Van den Hoofdakker R.H.
        Sleep deprivation in depression.
        Biol Psychiatry. 1999; 46: 445-453
        • Wu J.C.
        • Bunney W.E.
        The biological basis of an antidepressant response to sleep deprivation and relapse.
        Am J Psychiatry. 1990; 147: 14-21