Locus coeruleus neuronal activity and noradrenaline availability in the frontal cortex of rats chronically treated with imipramine: effect of alpha 2-adrenoceptor blockade.
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 alpha 2-adrenoceptors in the LC. Therefore, we have here studied the LC neuronal responsiveness to administration of the alpha 2-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 alpha 2-autoreceptors on LC neurons during chronic administration of NA reuptake inhibiting antidepressants. Moreover, the data suggest that addition of alpha 2-adrenoceptor antagonists may augment the clinical effect of such drugs in major depression.
Linnér
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Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Arborelius
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Nomikos
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Bertilsson
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Svensson
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D000317:Adrenergic alpha-Antagonists / Q000493:pharmacokinetics*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism*; D019329:Idazoxan / Q000494:pharmacology; D007099:Imipramine / Q000378:metabolism / Q000493:pharmacokinetics*; D008125:Locus Coeruleus / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D013997:Time Factors
D000317:Adrenergic alpha-Antagonists; D018341:Receptors, Adrenergic, alpha-2; D007099:Imipramine; D009638:Norepinephrine; D019329:Idazoxan