Abstract
Background: Previous studies indicate a reduced feedback inhibition of brain noradrenaline
(NA) neurons in the locus coeruleus (LC) during chronic administration of antidepressants
which inhibit the NA reuptake mechanism due to functional downregulation of somatodendritic
α2-adrenoceptors in the LC. Therefore, we have here studied the LC neuronal responsiveness
to administration of the α2-adrenoceptor antagonist idazoxan (IDA) after both short-term and long-term imipramine
(IMI) administration.
Methods: Rats were treated for different periods with systemic IMI. In these rats,
basal activity of central noradrenergic function and the effect of IDA was assessed
by means of extracellular single-cell recording from LC neurons and in vivo microdialysis of extracellular NA levels in the frontal cortex (FC).
Results: The average firing rate of LC neurons was significantly reduced in rats by
short-term IMI treatment compared with long-term treatment. The output of NA in the
FC of all IMI-treated animals was significantly increased compared with saline-treated
rats. Moreover, the enhancing effect of IDA on both the firing rate of LC neurons
and the cortical NA output was larger in rats after long-term treatment with IMI than
after short-term administration.
Conclusions: Our results clearly support the notion of development of functional downregulation
of α2-autoreceptors on LC neurons during chronic administration of NA reuptake inhibiting
antidepressants. Moreover, the data suggest that addition of α2-adrenoceptor antagonists may augment the clinical effect of such drugs in major depression.
Keywords
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 accessOne-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:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Monitoring extracellular norepinephrine in brain using in vivo microdialysis and HPLC-EC.in: Robinson T.E. Justice J.B. Microdialysis in the Neurosciences. Elsevier, Amsterdam1991: 253-274
- 5-HT1A receptor antagonists increase the activity of serotonergic cells in the dorsal raphe nucleus in rats treated acutely or chronically with citalopram.Naunyn-Schmiedeberg’s Arch Pharmacol. 1995; 352: 157-165
- The 5-HT1A receptor antagonist (s)-UH-301 augments the increase in extracellular concentrations of 5-HT in the frontal cortex produced by both acute and chronic treatment with citalopram.Naunyn-Schmiedeberg’s Arch Pharmacol. 1996; 353: 630-640
- Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors.Arch Gen Psychiatry. 1994; 51: 248-251
- Chronic treatment with fluvoxamine increases extracellular serotonin in frontal cortex but not in raphe nuclei.Synapse. 1992; 15: 243-245
- Electrophysiological investigations of the effect of repeated zimelidine administration on serotonergic neurotransmission in the rat.J Neurosci. 1983; 3: 1270-1278
- Stress antidepressant drugs and the locus coeruleus.Brain Res Bull. 1994; 35: 545-556
- Steady state concentrations of imipramine and its metabolites in relation to the sparteine/debrisoquine polymorphism.Eur J Clin Pharmacol. 1986; 30: 679-684
- Effects of desipramine and maprotiline on the coeruleus-cortical noradrenergic system in anaesthetized rats.Eur J Pharmacol. 1996; 312: 189-193
- Effects of a selective 5-HT reuptake blocker, citalopram, on the sensitivity of 5-HT autoreceptors.Naunyn Schmiedeberg’s Arch Pharmacol. 1986; 333: 342-348
Cremers TIFH, de Boer P, Westerink BHC, Wikström H (1998): Relevance of SSRI plasma concentrations in relation to apparent serotonergic autoreceptor activation and chronic treatment regimens. Soc Neurosci Abstr 24(1):439.15, p. 1112.
- Serotonin function and the mechanism of antidepressant action.Arch Gen Psychiatry. 1990; 47: 411-418
- Monoamines and the mechanism of antidepressant action.Psychopharmacol Bull. 1993; 29: 389-396
- Presynaptic Alpha-2 adrenoceptors play a major role in the effects of IDA on cortical noradrenaline release (as measured by in vivo dialysis) in the rat.J Pharmacol Exp Ther. 1987; 241: 642-649
- α2-adrenoceptors and I2 sites in the mammalian central nervous system.Pharmacol Ther. 1995; 68: 175-208
- α2-adrenergic receptor blockade markedly potentiates duloxetine- and fluoxetine-induced increases in noradrenaline, dopamine, and serotonin levels in the frontal cortex of freely moving rats.J Neurochem. 1997; 69: 2616-2619
- Effects of amphetamine on single cell activity in a catecholamine nucleus, the locus coeruleus.Nature. 1971; 234: 100-102
- Serotonin 5-HT1A autoreceptor blockade potentiates the ability of the 5-HT reuptake inhibitor citalopram to increase nerve terminal output of 5-HT in vivo.J Neurochem. 1993; 60: 776-779
- Chronic treatment with citalopram facilitates the effect of a challenge dose on cortical serotonin output.Eur J Pharmacol. 1994; 260: 243-246
- Effects of acute and repeated administration of antidepressant drugs on extracellular levels of 5-hydroxytryptamine measured in vivo.J Pharmacol Exp Ther. 1995; 274: 866-876
- Effects of long term desipramine administration on noradrenergic neurotransmission.J Pharmacol Exp Ther. 1991; 257: 1081-1090
- Measurement of endogenous noradrenaline release in the rat cerebral cortex in vivo by transcortical dialysis.J Neurochem. 1986; 46: 1794-1801
- Somatodendritic α2-adrenoceptors in the locus coeruleus are involved in the in vivo modulation of cortical noradrenaline release by the antidepressant desipramine.J. Neurochem. 1998; 71: 790-798
- Modulation of catecholamine release by α2-adrenoceptors and I1-imidazoline receptors in rat brain.Brain Res. 1997; 744: 216-226
- Tricyclic antidepressants.Eur J Pharmacol. 1975; 32: 302-312
- The Rat Brain in Stereotaxic Coordinates. 2nd ed. Academic Press, Sydney, Australia1986
- Stimulatory effects of clonidine, cirazoline and rilmenidine on locus coeruleus noradrenergic neurones.Naunyn Schmiedeberg’s Arch Pharmacol. 1993; 348: 134-140
- Effect of long-term administration of duloxetine on the function of serotonin and noradrenaline terminals in the rat brain.Naunyn-Schmiedeberg’s Arch Pharmacol. 1998; 357: 600-610
- Attenuated feed-back inhibition of brain serotonin synthesis following chronic administration of imipramine.Naunyn-Schmiedeberg’s Arch Pharmacol. 1978; 302: 115-118
- Feedback inhibition of brain noradrenaline neurons by tricyclic antidepressants.Science. 1978; 202: 1089-1091
- Alpha-adrenoceptor mediated inhibition of brain noradrenergic neurons after acute and chronic treatment with tricyclic antidepressants.in: Usdin E. Kopin I.J. Barchas J. Catecholamines Basic and Clinical Frontiers. Pergamon Press, New York1979: 672-674
- Electrophysiology of brain noradrenaline neurons and the mode of antidepressant drugs.in: Briley M. Montgomery S. Antidepressant Therapy at the Dawn of the 3rd Millennium. Martin Dunitz Ltd, London, England1998: 19-35
- Chronic desipramine and fluoxetine differentially affect extracellular dopamine in the rat prefrontal cortex.Psychopharmacol. 1996; 127: 83-87
- Antidepressant action on brain noradrenergic neurons.J Pharmacol Exp Ther. 1990; 253: 833-840
Article info
Publication history
Accepted:
May 12,
1999
Received in revised form:
April 30,
1999
Received:
February 12,
1999
Identification
Copyright
© 1999 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
