CNR - Institute of Neuroscience CNR
Institute of Neuroscience
 

Project

Role of biogenic amines in the mechanism of action of antipsychotic and antidepressant drugs

The main goal of this project is to clarify the neurochemical mechanisms and neuronal circuitries involved in the pathology of the main psychiatric diseases, such as depression and schizophrenia and to elucidate the mechanisms of action of psychotropic drugs. Using intracerebral microdialysis technique, our group contributed to shed light on the role of monoaminergic systems in the effects of antidepressant drugs.

Prefrontal Cortex and monoaminergic sistems

The prefrontal cortex is thought to play an important role in the pathogenesis of major psychiatric conditions and in the mechanism of drugs utilized for their treatment. This role might be related to an action on and to an interaction among the three monoaminergic inputs to the PFCX, noradrenergic (NA), serotonergic (5-HT) and dopaminergic (DA). Various antidepressants and antipsychotics have been shown to affect DA and NA transmission in the PFCX. While the effect of antidepressants on extracellular NA and/or 5-HT extends to all brain areas, being the result of a direct action on NA and 5-HT terminals, that on extracellular DA, being secondary to a NA/DA and 5-HT/DA interaction, is topographically specific. In the PFCX as well as in other areas where both catecholamines coexist, DA uptake by NA terminals through the NA transporter might contribute to the removal of DA from the extracellular fluid.

Different neurochemical effects of various antidepressant drugs

Although existing studies on the interaction between cortical DA and NA have been focussed on the PFCX, other cortical areas such as the occipital (OccCX) and parietal cortex (ParCX) show a coexistence of DA and NA terminals. We studied in these areas the effect of various drugs known to affect DA transmission in the PFCX showing the existence of unsuspected differences among different categories of antidepressants in their pattern of effects on cathecholamine transmission in the cerebral cortex. On this basis one might classify antidepressants into three categories: 1) those, like imipramine, that block both NET and SERT, or mianserin, that block α2 receptors, and increase extracellular DA in the PfCX as well as in isocortical areas such as the ParCX and OccCX; 2) those, like citalopram, that selectively block SERT and increase DA in isocortical areas but not in the PfCX; 3) those, like reboxetine and desipramine, that selectively block NET and increase DA preferentially, or, depending on the doses, selectively, in the PfCX. The observation of clear-cut topographic differences between the medial PFCX and isocortical areas in the neurochemical effects of NET and SERT blockers and α2 receptor antagonists could underlie differences in the therapeutic spectrum of these drugs.

Currently, our group is involved in two projects aimed at clarifying the neurochemical mechanisms involved in the "latency" to therapeutic effect of antidepressant drugs and the role of 5-HT6 receptors in psychiatric disorders.

Publications

  • Valentini V, Cacciapaglia F, Frau R, Di Chiara G (2005) Selective serotonin reuptake blockade increases extracellular dopamine in noradrenaline-rich isocortical but not prefrontal areas: dependence on serotonin-1A receptors and independence from noradrenergic innervation. J. Neurochem. 93:371-82.
  • Valentini V, Frau R, Di Chiara G (2004) Noradrenaline transporter blockers raise extracellular dopamine in medial prefrontal but not parietal and occipital cortex: differences with mianserin and clozapine. J. Neurochem. 88:917-27.

 

no PI photo

Gaetano Di Chiara

Contact information

email  E-mail

email  +39 0706758666

Participating staff

Valentina Valentini

Roberto Frau