The noradrenaline–dopamine interaction in the rat medial prefrontal cortex studied by multi-probe microdialysis

doi:10.1016/S0014-2999(01)00863-9

European Journal of Pharmacology

Volume 418, Issue 3, 27 April 2001, Pages 177-186

https://doi.org/10.1016/S0014-2999(01)00863-9 Get rights and content

Abstract

Multi-probe microdialysis was used to investigate the interaction between the release of noradrenaline and dopamine in the medial prefrontal cortex. Retrograde microdialysis was used to stimulate or inhibit the activity of the locus coeruleus for a restricted period of time, and the response of extracellular noradrenaline and dopamine in the ipsilateral and contralateral medial prefrontal cortex was recorded with microdialysis probes. Infusion of clonidine into the locus coeruleus (100 μM for 45 min) suppressed noradrenaline release and slightly inhibited dopamine release in the ipsilateral medial prefrontal cortex. Application of carbachol to the locus coeruleus (100 μM for 45 min) stimulated both the noradrenaline and dopamine release in the ipsilateral medial prefrontal cortex. No changes were seen in the contralateral medial prefrontal cortex. In the ipsilateral nucleus accumbens, extracellular noradrenaline levels increased, but dopamine levels remained unchanged. Application to the locus coeruleus (during 10 min) of the glutamate receptor agonists N-methyl-d-aspartate (NMDA) (300 μM) or kainate (100 μM) strongly increased extracellular noradrenaline and dopamine levels in the ipsilateral medial prefrontal cortex. However, in the contralateral probe the release of dopamine (but not of noradrenaline) was also stimulated. Application of carbachol to the locus coeruleus was used as a model to further investigate the presumed noradrenaline–dopamine interaction. In a series of dual-probe experiments, α₁-, α₂-, and β-adrenoceptor antagonists (prazosin, idazoxan, propranolol) or a reuptake-inhibitor (nomifensine) was administered during carbachol stimulation of the locus coeruleus. Prazosin and propranolol were administered systemically in a dose of 3 mg/kg, whereas idazoxan (10 μM) and nomifensine (100 μM) were infused into the medial prefrontal cortex. However, none of these pretreatments modified the effects of the control carbachol-infusions. The results did not identify a receptor-interaction or a common reuptake site that explained the presumed interaction between dopamine and noradrenaline in the medial prefrontal cortex. Therefore, the noradrenaline–dopamine interaction hypothesis could not be confirmed or refuted.

Introduction

Dopamine and noradrenaline neurons that project to the frontal cortex are implicated in various complex types of behavior such as cognitive processes, arousal, stress responses, anxiety and fear Foote et al., 1983, Aston Jones et al., 1991, Berridge and Foote, 1991, Tassin, 1992. The noradrenaline and dopamine neurons converge in the medial prefrontal cortex, and there is growing evidence for an interaction between the release of various catecholamines in this brain region. An anatomical connection at the level of the ventral tegmental area has been proposed Tassin et al., 1986, Tassin, 1992, Grenhoff et al., 1993, whereas others have emphasized that a common reuptake site for noradrenaline and dopamine could explain the interaction Carboni et al., 1990, Gresch et al., 1995, Yamamoto and Novotney, 1998. An example of the supposed interaction is the recent observation that a number of typical and atypical antipsychotics induced similar changes in the release of noradrenaline and dopamine in the medial prefrontal cortex Li et al., 1998, Westerink et al., 1998.

The nature of the noradrenaline–dopamine interaction in the cortex is not fully understood. In this study, we used multi-probe microdialysis to further investigate this issue. To this end, a microdialysis probe was implanted in the vicinity of the locus coeruleus. The probe was used to infuse compounds that stimulate or inhibit locus coeruleus activity. A second probe, which was used to record extracellular dopamine and noradrenaline, was implanted in the ipsilateral medial prefrontal cortex. In additional experiments, a third probe was placed in the contralateral medial prefrontal cortex.

The noradrenaline–dopamine interaction hypothesis was further investigated by stimulating or inhibiting the activity of the locus coeruleus, for a restricted period of time, and by recording the response of extracellular noradrenaline and dopamine in the ipsilateral medial prefrontal cortex.

Various pharmacological agents known to affect the electrical activity of noradrenergic locus coeruleus neurons (clonidine, carbachol, N-methyl-d-aspartate (NMDA) and kainate) were infused in the vicinity of this nucleus and bilateral changes in extracellular noradrenaline and dopamine were recorded in the medial prefrontal cortex.

Infusion of carbachol into the locus coeruleus stimulated the release of noradrenaline as well as dopamine in the medial prefrontal cortex. No contralateral effects were seen. The noradrenaline–dopamine interaction was specific for the cortical area and was not observed in the nucleus accumbens.

Next, infusion of carbachol (for 45 min) into the locus coeruleus was used as a model to further investigate the mechanism of the noradrenaline–dopamine interaction. In a series of dual-probe experiments, α₁- and α₂- and β-adrenoceptor antagonists or a reuptake-inhibitor was administered, during concurrent stimulation of the locus coeruleus with carbachol.

Section snippets

Animals, drug treatment and doses

Male albino rats of a Wistar-derived strain (285–320 g; Harlan, Zeist, The Netherlands) were used for the experiments. The rats were housed in plastic cages (35×35×40 cm) and had free access to food and water.

The following drugs were used: clonidine HCl, carbachol, NMDA, nomifensine maleate, prazosin HCl, (±)-propranolol HCl, kainate (all purchased from Research Biochemicals, Natick, MA). Idazoxan was purchased from Sigma (St. Louis, MO, USA). Except prazosin and propranolol (which were

Basal values

The basal values of noradrenaline in the left and right prefrontal cortex did not differ. Separate control experiments (saline injections) were not included. Mean basal values were (±S.E.M.), in the presence of 10 μM nomifensine, noradrenaline 4.95±0.33 fmol/min (n=43) and dopamine 4.86±0.57 fmol/min (n=43). The basal values of the various experimental groups were not statistically different; therefore, there were grouped together. Basal values in the absence of nomifensine were noradrenaline

Discussion

Various authors have speculated about a coupling between the release of noradrenaline and dopamine in the medial prefrontal cortex Tassin et al., 1986, Carboni et al., 1990, Tassin, 1992, Grenhoff et al., 1993, Gresch et al., 1995, Yamamoto and Novotney, 1998. A possible direct interaction between these neurons has important pharmacological implications, because it means that psychotropic drugs that modify cortical noradrenaline release will also modify dopamine activity. Here, we used

Acknowledgements

The present study was supported by a grant from Solvay Pharmaceuticals, Weesp, The Netherlands.

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The noradrenaline–dopamine interaction in the rat medial prefrontal cortex studied by multi-probe microdialysis

Abstract

Introduction

Section snippets

Animals, drug treatment and doses

Basal values

Discussion

Acknowledgements

Prog. Brain Res.

Eur. J. Pharmacol.

Brain Res.

Brain Res. Mol. Brain Res.

Brain Res.

Eur. J. Pharmacol.

Effects of locus coeruleus activation on electroencephalographic activity in neocortex and hippocampus

J. Neurosci.

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.

Pharmacological analysis of a cholinergic receptor mediated regulation of brain norepinephrine neurons

J. Neural Transm.

Nucleus locus coeruleus: new evidence of anatomical and physiological specificity

Physiol. Rev.

Noradrenergic modulation of midbrain dopamine cell firing elicited by stimulation of the locus coeruleus in the rat

J. Neural Transm. Gen. Sect.