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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Annals of General Psychiatry Open Access 11 March 2019
Noradrenergic versus dopaminergic modulation of impulsivity, attention and monitoring behaviour in rats performing the stop-signal task
Psychopharmacology Open Access 17 May 2013
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Lindvall O, Björklund A, Divac I . Organisation of the catecholamine neurons projecting to the frontal cortex in the rat Brain Res 1978 142: 1–24
Fadda F, Gessa GL, Marcou M, Mosca E, Rossetti ZL . Evidence for dopamine autoreceptors in mesocortical dopamine neurons Brain Res 1984 293: 67–72
Bannon MJ, Roth RH . Pharmacology of mesocortical dopamine neurons Pharmacol Rev 1983 35: 53–68
Kilts CD, Anderson CM . Mesoamygdaloid dopamine neurons: differential rate of dopamine turnover in discrete amygdaloid nuclei of the rat brain Brain Res 1987 416: 402–408
Kawahara Y, Kawahara H, Westerink BHC . Comparison of the effects of hypotension and handling stress on the release of noradrenaline and dopamine in the locus coeruleus and medial prefrontal cortex of the rat Naunyn-Schmiedeberg's Arch Pharmacol 1999 360: 42–49
Feenstra MGP, Teske G, Botterblom MHA, De Bruin JPC . Dopamine and noradrenaline release in the prefrontal cortex of rats during classical aversive and appetitive conditioning to a contextual stimulus: interference by novelty effects Neurosci Lett 1999 272: 179–182
Westerink BHC, de Boer P, de Vries JB, Kruse CG, Long SK . Antipsychotic drugs induce similar effects on the release of dopamine and noradrenaline in the medial prefrontal cortex of the rat brain Eur J Pharmacol 1998 361: 27–33
Li X-M, Perry KW, Wong DT, Bymaster FP . Olanzapine increases in vivo dopamine and norepinephrine release in rat prefrontal cortex, nucleus accumbens and striatum Psychopharmacology 1998 136: 153–161
Tanda G, Bassareo V, Di Chiara G . Mianserin markedly and selectively increases extracellular dopamine in the prefrontal cortex as compared to the nucleus accumbens of the rat Psychopharmacology 1996 123: 127–130
Millan MJ, Gobert A, Rivet J-M, Adhumeau-Auclair A, Cussac D, Newman-Tancredi A et al. Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of α2-adrenergic and serotonin2C receptors: a comparison with citalopram Eur J Neurosci 2000 12: 1079–1095
Roberts DC, Zis AP, Fibiger HC . Ascending catecholamine pathways and amphetamine-induced locomotor activity: importance of dopamine and apparent non-involvement of norepinephrine Brain Res 1975 93: 441–454
Darracq L, Blanc G, Glowinski J, Tassin J-P . Importance of the noradrenaline-dopamine coupling in the locomotor activating effects of D-amphetamine J Neurosci 1998 18: 2729–2739
Arnsten AFT . Catecholamine regulation of the prefrontal cortex J Psychopharmacol 1997 11: 151–162
Carboni E, Tanda GL, Frau R, Di Chiara G . Blockade of the noradrenaline carrier increases extracellular dopamine concentrations in the prefrontal cortex: evidence that dopamine is taken up in vivo by noradrenergic terminals J Neurochem 1990 55: 1067–1070
Gresch PJ, Sved AF, Zigmond MJ, Finlay JM . Local influence of endogenous norepinephrine on extracellular dopamine in rat medial prefrontal cortex J Neurochem 1995 65: 111–116
Hertel P, Fagerquist MV, Svensson TH . Enhanced cortical dopamine output and antipsychotic-like effects of raclopride by α2 adrenoceptor blockade Science 1999 286: 105–107
Paxinos G, Watson C . The Rat Brain in Stereotaxic Co-ordinates Academic Press: New York 1997
Imperato A, Angelucci A, Casolini P, Zocchi A, Puglisi-Allegra S . Repeated stressful experiences differently affect limbic dopamine release during and following stress Brain Res 1992 577: 194–199
White FJ, Wang RY . Pharmacological characterisation of dopamine autoreceptors in the rat ventral tegmental area: microiontophoretic studies J Pharmacol Exp Ther 1984 231: 275–280
Roth RH, Suhr Y . Mechanism of the γ-hydroxybutyrate-induced increase in brain dopamine and its relationship to ‘sleep’ Biochem Pharmacol 1970 19: 3001–3012
Gessa GL, Devoto P, Diana M, Flore G, Melis M, Pistis M . Dissociation of haloperidol, clozapine and olanzapine effects on electrical activity of mesocortical dopamine neurons and dopamine release in the prefrontal cortex Neuropsychopharmacology 2000 22: 642–649
Svensson TH, Bunney BS, Aghajanian GK . Inhibition of both noradrenergic and serotonergic neurons in brain by the α-adrenergic agonist clonidine Brain Res 1975 92: 291–306
Ugedo L, Pineda J, Ruiz-Ortega JA, Martin-Ruiz R . Stimulation of locus coeruleus neurons by non-11/12-type imidazoline receptors: an in vivo and in vitro electrophysiological study Br J Pharmacol 1998 125: 1685–1694
Hertel P, Nomikos GG, Svensson TH . Idazoxan preferentially increases dopamine output in the medial prefrontal cortex at the nerve terminal level Eur J Pharmacol 1999 371: 153–158
Segal M, Pickel V, Bloom F . The projections of the nucleus Locus Coeruleus: an autoradiographic study Life Sci 1973 13: 817–821
Tanda G, Pontieri FE, Frau R, Di Chiara G . Contribution of blockade of the noradrenaline carrier to the increase of extracellular dopamine in the rat prefrontal cortex by amphetamine and cocaine Eur J Neurosci 1997 9: 2077–2085
Westerink BH, de Boer P, de Vries JB, Kruse CG, Long SK . Antipsychotic drugs induce similar effects on the release of dopamine and noradrenaline in the medial prefrontal cortex of the rat Eur J Pharmacol 1998 361: 27–33
Imperato A, Di Chiara G . Dopamine release and metabolism in awake rats after systemic neuroleptics as studied by trans-striatal dialysis J Neurosci 1984 5: 297–306
Imperato A, Tanda G, Frau R, Di Chiara G . Pharmacological profile of dopamine receptor agonists as studied by brain dialysis in behaving rats J Pharmacol Exp Ther 1987 245: 257–264
Svensson TH . Dysfunctional brain dopamine systems induced by psychotomimetic NMDA-receptor antagonists and the effects of antipsychotic drugs Brain Res Brain Res Rev 2000 31: 320–329
Svensson TH . Brain noradrenaline and the mechanism of action of antidepressant drugs Acta Psychiatr Scand Suppl 2000 402: 18–27
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.
About this article
Cite this article
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). https://doi.org/10.1038/sj.mp.4000904
- prefrontal cortex
- primary motor cortex
Developmental impact of glutamate transporter overexpression on dopaminergic neuron activity and stereotypic behavior
Molecular Psychiatry (2022)
Nature Reviews Neuroscience (2020)
Annals of General Psychiatry (2019)
Prenatal nicotine exposure decreases the release of dopamine in the medial frontal cortex and induces atomoxetine-responsive neurobehavioral deficits in mice