Methods and Findings in Experimental and Clinical Pharmacology
Vol. 25, Suppl. A, 2003
ISSN 0379-0355
Copyright 2003 Prous Science, S.A.
CCC: 0379-0355/2003
http://www.prous.com

Noradrenergic System Implications in Depressive Disorders

J.J. Meana

Department of Pharmacology, University of the Basque Country (UPV/EHU), Spain

A deficit of monoaminergic neurotransmission in the CNS is thought to be the underlying cause of depressive disorders. Although evidence exists for the participation of other mechanisms such as stress and a neurodegenerative/neurotrophic unbalance, the treatment of depressive disorders has focused on modulation of serotonin (5-HT) and/or noradrenaline (NA) neurotransmission.

The a₂-adrenoceptor plays a role as the common link between the 5-HT and NA systems. Thus, a₂-adrenoceptors act as autoreceptors or heteroreceptors on NA and 5-HT nerve terminals, respectively. Moreover, 5-HT afferents modulate the firing activity of locus coeruleus (LC), the main noradrenergic nucleus in the CNS, and NA afferents regulate the activity of 5-HT neurones, located in the raphe nuclei. Additionally, a₂-adrenoceptors are expressed as somatodendritic autoreceptors on LC neurones, exerting a tonic inhibitory modulation of noradrenergic activity in vivo. Several studies have demonstrated that a₂-adrenoceptor density (receptor radioligand binding, immunoblot protein expression) and functional activity ([³⁵S]GTPgammaS binding stimulation by agonists) are enhanced in postmortem brains of subjects who suffer from depression. Downregulation of a₂-adrenoceptor density and desensitization of a₂-adrenoceptor-mediated responses in the CNS are common responses to chronic treatment with antidepressant drugs that increase synaptic noradrenaline (NA). In fact, a₂-adrenoceptor antagonists (mirtazapine, mianserine) have been developed as clinically effective antidepressant drugs. However, the hypothetical modulation and the mechanism through which selective 5-HT reuptake inhibitors (SSRI) modify a₂-adrenoceptors remain unsolved.

Over the last few years, we have studied the changes induced by acute and chronic administration of the antidepressant citalopram, as a representative of SSRI drugs, on NA neurotransmission in the rat brain. Extracellular NA is monitored by in vivo microdialysis simultaneously in the LC and in the cingulate cortex (Cg), a projection area arising from the LC. a₂-adrenoceptor desensitization can be evaluated by analyzing responses of NA concentrations to administration of the a₂-adrenoceptor agonist clonidine. Electrophysiological recording of noradrenergic activity is performed through collaboration with another research group (Dr. L. Ugedo).

Local administration by reversal dialysis of citalopram (0.1-100 mM) in the LC increases NA in the LC and decreases NA in the Cg. The increase of NA in the LC is promoted by local 5-HT reuptake inhibition, as this effect is abolished by pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine. The NA decrease in the Cg induced by local citalopram in the LC is mediated through somatodendritic a₂-adrenoceptors that inhibit LC firing activity, and subsequently, NA release in terminal areas. Thus, concomitant administration of the a₂-adrenoceptor antagonist RS79948 does not modify citalopram's effect on NA in the LC, but abolishes it in the Cg. Consequently, the extracellular firing activity of LC neurones decreases following local citalopram perfusion. Systemic administration of citalopram at a 10 mg/kg i.p. dose, but not at 5 mg/kg i.p., produces similar findings.

Previous findings are similar to those obtained with low systemic administration of the NA uptake inhibitors desipramine and reboxetine (1 mg/kg) or with local perfusion into the LC of these drugs.

In the presence of the 5-HT₃ antagonist MDL72222 (1 mM) in the LC, citalopram does not modify NA in the LC and no changes are obtained in the Cg. In contrast, in the presence of the 5-HT_1/2 antagonist methiothepin (1 mM), the effect of citalopram is maintained. Furthermore, administration of the 5-HT₃ agonist drug m-chloro-phenyl-biguanide into the LC increases NA in the area. Therefore, the 5-HT receptor that modulates extracellular NA in the LC seems to correspond to the 5-HT₃ subtype.

Local administration of citalopram into the Cg increases NA in the area. This increase is abolished in the presence of MDL72222, suggesting a stimulatory role of 5-HT₃ receptors on NA release in terminal areas. The inhibitory effect of systemic administration of citalopram (10 mg/kg ip) on NA in the Cg is modified to a stimulatory effect in the presence of MDL72222 (1 mM) in the LC, confirming the previous suggestion.

As opposed to acute effects, chronic administration of citalopram (5 mg/kg ip, 14 days) increases extracellular NA concentrations in the Cg without changes in the LC. The increase in NA is not observed in the 24 h following the last dose. Under such treatment conditions, a₂-adrenoceptor sensitivity was quantified 48 h after the last administration of citalopram.

Clonidine (0.3 mg/kg i.p.) induced a lower decrease of NA in the Cg in chronic citalopram-treated (29 + 18%) rats than in chronic saline-treated rats (61 + 7%). No differences (42 + 8% and 44 + 8%, respectively) were observed in the LC. This finding could represent desensitization of a₂-adrenoceptors located at somatodendritic levels on LC neurones and/or desensitization of a₂-adrenoceptors located on noradrenergic terminals in the Cg. In order to clarify this fact, extracellular recording of LC firing activity and inhibitory dose-response curves to clonidine administration (0.625-20 mg/kg i.v.) were performed. No desensitization of somatodendritic a₂-adrenoceptors that control LC firing activity were obtained, which establishes the main role of terminal a₂-adrenoceptors located on noradrenergic terminals in the response of these autoreceptors to the chronic administration of citalopram.

The finding of a₂-adrenoceptor desensitization following chronic administration of the SSRI citalopram is similar to that obtained previously with chronic administration of desipramine and clorgyline, which increase synaptic concentrations of NA. The results suggest that, independent of the pharmacological mechanism of action, antidepressant drugs are able to downregulate and desensitize a₂-adrenoceptors in brain areas with noradrenergic innervation.

ACKNOWLEDGMENTS

This work was supported by MCyT (SAF 2001-0553) and UPV/EHU (13588/2001).

Methods and Findings in Experimental and Clinical Pharmacology Vol. 25, Suppl. A, 2003
ISSN 0379-0355 Copyright 2003 Prous Science, S.A. CCC: 0379-0355/2003 http://www.prous.com