Previous results suggest that extracellular dopamine (DA) in the rat cerebral cortex originates from dopaminergic and noradrenergic terminals. To further clarify this issue, dialysate DA, dihydroxyphenylacetic acid (DOPAC) and noradrenaline (NA) were measured both in the medial prefrontal cortex (mPFC) and in the occipital cortex (OCC), with dense and scarce dopaminergic projections, respectively. Moreover, the effect of the a 2 -adrenoceptor antagonist RS 79948 and the D 2 -receptor antagonist haloperidol on extracellular DA, DO-PAC and NA was investigated. Extracellular DA and DOPAC concentrations in the OCC were 43% and 9%, respectively, those in the mPFC. Haloperidol (0.1 mg/kg i.p.) increased DA and DOPAC (by 35% and 150%, respectively) in the mPFC, but was ineffective in the OCC. In contrast, RS 79948 (1.5 mg/kg i.p.) increased NA, DA and DOPAC, both in the mPFC (by approximately 50%, 60% and 130%, respectively) and the OCC (by approximately 50%, 80% and 200%, respectively). Locally perfused, the DA transporter blocker GBR 12909 (10 lM) was ineffective in either cortex, whereas desipramine (DMI, 100 lM) markedly increased extracellular NA and DA in both cortices. The weak haloperidol effect on DA efflux was not enhanced after DA-and NA-transporter blockade, whereas after DMI, RS 79948 markedly increased extracellular NA, and especially DA and DOPAC in both cortices. The results support the hypothesis that most extracellular DA in the cortex is co-released with NA from noradrenergic terminals, such co-release being primarily controlled by a 2 -adrenoceptors.
Our recent studies suggest that extracellular dopamine (DA) in the cerebral cortex not only originates from dopaminergic terminals but is also coreleased with noradrenaline (NA) from noradrenergic terminals [Devoto et al. (2001) Mol Psychiatry 6:657-664]. To further clarify this issue, the concentrations of extracellular DA, its deaminated metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), and NA were compared by microdialysis in the medial prefrontal cortex (mPFC), an area densely innervated by NA and DA neurons, and in the occipital cortex (OCC), equally innervated by NA but receiving scarce DA projections. Moreover, the effect of the alpha(2)-adrenoceptor agonist clonidine locally perfused into the locus coeruleus (LC) on extracellular NA, DA, and DOPAC in the mPFC, OCC, and ventral striatum was investigated. Consistent with the homogeneous NA innervation, extracellular NA concentration was similar in both cortices, while extracellular DA in the OCC, in spite of the scarce DA afference in this area, was only 37% lower than in the mPFC; extracellular DOPAC in the OCC was 81% lower than in the mPFC. Consistent with its ability to inhibit NA neurons, clonidine (10 microM) reduced extracellular NA by about 65 and 80% in the OCC and the mPFC, respectively, but also reduced extracellular DA by 70 and 50% in the OCC and the mPFC, respectively. Clonidine reduced DOPAC in the OCC (by about 40%) but not in the mPFC. In the ventral striatum clonidine reduced NA (by 30%) but not DA and DOPAC. After inhibition of the DA and NA transporter, by perfusing 100 microM desmethyl-imipramine into the mPFC, clonidine perfusion into the LC reduced extracellular NA and DA in the mPFC by about 50%. The results indicate that most of extracellular DA in the OCC and a significant portion in the mPFC reflect the activity of NA neurons and support the hypothesis that extracellular DA in the cerebral cortex may originate not only from DA but also from NA neurons.
The results suggest that clozapine, by inhibiting alpha(2)-adrenoceptors, co-releases DA and NA from noradrenergic terminals in the occipital cortex and that the same mechanism might be responsible for the concomitant increase of the two monoamines in the mPFC.
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