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Mercè MasanaNoradrenergic contribution to mesocortical but not mesolimbic- dopamine transmission in the rat: Implications in schizophrenia and depression

Abstract :

Atypical antipsychotic drugs such as clozapine show superior efficacy over classical dopamine (DA) D2 blockers (e.g. haloperidol) in the treatment of schizophrenia, particularly in the improvement of negative symptoms and cognitive deficits.
This clinical superiority may be related to the increase of DA transmission in prefrontal cortex (PFC) produced by atypical, but not classical antipsychotic drugs. Moreover, dopaminergic (DA) transmission is emerging as a new target to improve depression treatments. In fact, a multi-target drug treatment approach is becoming a common clinical practice to improve the outcome in major depression, particularly in more resistant cases. For example, drugs like triple re-uptake inhibitors act on dopaminergic, serotonergic (5-HT) and noradrenergic (NE) systems, and interestingly, these new compounds appear to be superior in terms of shortest time onset of therapeutic benefit.

Our aim is to selectively increase cortical DA. Thus, we systemically characterized the regulation of DA output in the mesocortical and mesolimbic dopaminergic neuronal pathways. In particular, we studied the role of DA and NE transporter (DAT and NET, respectively) on DA reuptake, and also the NE neuronal contribution to DA co-release, either in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) of rats. The main result was that a combination treatment, which includes a NET inhibitor and a α2-adrenergic antagonist, was able to evoke a selective enhancement of extracellular DA concentration in mPFC of rats, but not in NAc. Additionally, we examined whether these combination treatment could augment the effects of antipsychotic and antidepressants drugs on DA release in PFC using in vivo microdialysis. We also tested if this effect was behaviorally and histochemically relevant, using the forced swimming test and c-Fos mRNA expression.

In summary, we propose the combination treatment with a NET inhibitor and a α2-adrenergic antagonist may offer new perspectives to improve the antipsychotic and antidepressant treatment effects, by enhancing cortical catecholamine transmission.

Selected publications

Selective enhancement of mesocortical dopaminergic transmission by noradrenergic drugs: therapeutic opportunities in schizophrenia. Masana M, Bortolozzi A, Artigas F. Int J Neuropsychopharmacol. 2011 Feb;14(1):53-68. Epub 2010 Aug 12.

Dopamine release induced by atypical antipsychotics in prefrontal cortex requires 5-HT(1A) receptors but not 5-HT(2A) receptors. Bortolozzi A, Masana M, Díaz-Mataix L, Cortés R, Scorza MC, Gingrich JA, Toth M, Artigas F. Int J Neuropsychopharmacol. 2010 Nov;13(10):1299-314. Epub 2010 Feb 17.

Giovanni Marsicano