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Evidence for co-release of noradrenaline and dopamine from noradrenergic neurons in the cerebral cortex


The aim of this study was to determine whether extracellular dopamine (DA) in the prefrontal cortex (PFC) might originate other than from DA neurons, also from noradrenergic (NA) ones. To this aim, we compared the levels of DA and NA in the dialysates from the PFC, a cortical area innervated by NA and DA neurons, and cortices that receive NA but minor or no DA projections such as the primary motor, the occipital-retrosplenial, and the cerebellar cortex. Moreover, the effect of α2-ligands and D2-ligands that distinctly modify NA and DA neuronal activity on extracellular NA and DA in these areas was studied. Extracellular NA concentrations were found to be similar in the different cortices, as expected from the homogeneous NA innervation, however, unexpectedly, also DA concentrations in the PFC were not significantly different from those in the other cortices. The α2-adrenoceptor agonist clonidine, intraperitoneally (i.p.) injected or locally perfused into the PFC, reduced not only extracellular NA levels, as expected from its ability to inhibit NA neuron activity, but also markedly reduced extracellular DA levels. Conversely, the α2-adrenoceptor antagonist idazoxan, i.p. injected or locally perfused into the PFC, not only increased extracellular NA levels, in line with its ability to activate NA neuron activity, but also increased those of DA. Conversely, in contrast to its ability to inhibit DA neuronal activity, the D2 receptor agonist quinpirole only modestly and transiently reduced extracellular DA levels, while γ-butyrolactone failed to modify DA levels in the PFC; conversely, haloperidol, at variance from its ability to activate DA neurons, failed to significantly modify extracellular DA levels in the PFC. Both haloperidol and quinpirole were totally ineffective after local perfusion into the PFC. Systemically injected or locally perfused, clonidine and idazoxan also modified both DA and NA concentrations in dialysates from primary motor, occipital-retrosplenial and cerebellar cortices as observed in the PFC. Finally, i.p. injected or locally perfused, clonidine reduced and idazoxan increased extracellular NA levels in the caudate nucleus, but neither α2-ligand significantly modified extracellular DA levels. Our results suggest that extracellular DA in the PFC, as well as in the other cortices, may depend on NA rather than DA innervation and activity. They suggest that dialysate DA reflects the amine released from NA neurons as well, where DA acts not only as NA precursor but also as co-transmitter. The co-release of NA and DA seems to be controlled by α2-receptors located on NA nerve terminals.

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The authors thank Dr MA Casu for the skilful performance of histological analysis, and Laboratorio Farmaceutico CT (Sanremo, IM, Italy) for the generous gift of γ-butyrolactone. This study was partially supported by a grant from the European Community, the Italian Government and the Regione Sardegna through the POP Sardegna.

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Correspondence to P Devoto.

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Devoto, P., Flore, G., Pani, L. et al. Evidence for co-release of noradrenaline and dopamine from noradrenergic neurons in the cerebral cortex. Mol Psychiatry 6, 657–664 (2001).

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  • microdialysis
  • clonidine
  • idazoxan
  • quinpirole
  • haloperidol
  • γ-butyrolactone
  • cerebellum
  • prefrontal cortex
  • primary motor cortex

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