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Evidence that cortical dopamine is a co-transmitter in noradrenergic neurons
No full textDopamine and noradrenaline in the prefrontal cortex modulate superior cognitive functions and are implicated in the aetiology of depressive and psychotic symptoms. Experimental evidence reveals parallel variations in extracellular concentration of both catecholamines in the cerebral cortex. In this review, data are presented suggesting that extracellular dopamine in the cerebral cortex originates not only from dopaminergic terminals but also from noradrenergic ones, where it acts both as precursor for noradrenaline and as co-transmitter. Since there lease of noradrenaline is controlled by alpha2-autoreceptors, it follows that release and extracellular concentration of both dopamine and noradrenaline in the cerebral cortex are controlled by alpha2-autoreceptors and noradrenaline transporter, whereas dopamine receptors and dopamine transporter do not seem to be involved in these processes. Atypical antipsychotics such as clozapine, and antidepressants such as mirtazapine, increase noradrenaline and dopamine release throughout the cerebral cortex, but not, or to a lesser extent, in subcortical areas. On the other hand, D2 selective drugs such as haloperidol, are potent in increasing dopamine levels in subcortical dopaminergic areas but are ineffective on dopamine and noradrenaline levels in the prefrontal cortex. Local stimulation or inhibition of locus coeruleus neurons by means of drug perfusion or electrical stimulation gives rise to parallel variations of noradrenaline and dopamine levels in the cerebral cortex, but not in prevalently dopaminergic subcortical areas. Extracellular dopamine of noradrenergic origin might represent the major portion of total extracellular dopamine not only in cortices with scarce dopaminergic innervation, such as the parietal and occipital cortex, but also in the densely innervated medial prefrontal cortex. In conclusion, drugs acting on the co-release mechanism of noradrenaline and dopamine may represent a tool with which to increase the selective output of dopamine in the cerebral cortex
On the origin of cortical dopamine: Is it a co-transmitter in noradrenergic neurons?
No full textDopamine (DA) and noradrenaline (NA) in the prefrontal cortex (PFC) modulate superior cognitive functions, and are involved in the aetiology of depressive and psychotic symptoms. Moreover, microdialysis studies in rats have shown how pharmacological treatments that induce modifications of extracellular NA in the medial PFC (mPFC), also produce parallel changes in extracellular DA. To explain the coupling of NA and DA changes, this article reviews the evidence supporting the hypothesis that extracellular DA in the cerebral cortex originates not only from dopaminergic terminals but also from noradrenergic ones, where it acts both as precursor for NA and as a co-transmitter. Accordingly, extracellular DA concentration in the occipital, parietal and cerebellar cortex was found to be much higher than expected in view of the scarce dopaminergic innervation in these areas. Systemic administration or intra-cortical perfusion of α2-adrenoceptor agonists and antagonists, consistent with their action on noradrenergic neuronal activity, produced concomitant changes not only in extracellular NA but also in DA in the mPFC, occipital and parietal cortex. Chemical modulation of the locus coeruleus by locally applied carbachol, kainate, NMDA or clonidine modified both NA and DA in the mPFC. Electrical stimulation of the locus coeruleus led to an increased efflux of both NA and DA in mPFC, parietal and occipital cortex, while in the striatum, NA efflux alone was enhanced. Atypical antipsychotics, such as clozapine and olanzapine, or antidepressants, including mirtazapine and mianserine, have been found to increase both NA and DA throughout the cerebral cortex, likely through blockade of α2-adrenoceptors. On the other hand, drugs selectively acting on dopaminergic transmission produced modest changes in extracellular DA in mPFC, and had no effect on the occipital or parietal cortex. Acute administration of morphine did not increase DA levels in the PFC (where NA is diminished), in contrast with augmented dopaminergic neuronal activity; moreover, during morphine withdrawal both DA and NA levels increased, in spite of a diminished dopaminergic activity, both increases being antagonised by clonidine but not quinpirole administration. Extensive 6-hydroxy dopamine lesion of the ventral tegmental area (VTA) decreases below 95% of control both intra- and extracellular DA and DOPAC in the nucleus accumbens, but only partially or not significantly in the mPFC and parietal cortex. The above evidence points to a common origin for NA and DA in the cerebral cortex and suggests the possible utility of noradrenergic system modulation as a target for drugs with potential clinical efficacy on cognitive functions
Failure by tricyclic antidepressants to affect the increase of dopamine extracellular concentrations produced by haloperidol in the caudate and accumbens nuclei of rats
No full textCo-release of dopamine and noradrenaline from noradrenergic neurons in the cerebral cortex: implication for the neurobiology of psychiatric disorders
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Labetalol blockade of central alpha- and beta-noradrenergic receptors in rat brain homogenates
No full textDisulfiram and diethylditiocarbamate intoxication affects the storage and release of striatal dopamine
No full textDopamine-beta-hydroxylase inhibition potentiates cocaine effect on dopamine release in the medial prefrontal cortex
No full textStimulation of the locus coeruleus elicits noradrenaline and dopamine release in the medial prefrontal and parietal cortex
No full textOur previous studies have suggested that dopamine and noradrenaline may be coreleased from noradrenergic nerve terminals in the cerebral cortex. To further clarify this issue, the effect of electrical stimulation of the locus coeruleus on extracellular noradrenaline, dopamine and DOPAC in the medial prefrontal cortex, parietal cortex and caudate nucleus was analysed by microdialysis in freely moving rats. Stimulation of the locus coeruleus for 20 min with evenly spaced pulses at 1 Hz failed to modify cortical catecholamines and DOPAC levels. Stimulation with bursts of pulses at 12 and 24 Hz increased, in a frequency-related manner, not only noradrenaline but also dopamine and DOPAC in the two cortices. In both cortices noradrenaline returned to baseline within 20 min of stimulation, irrespective of the stimulation frequency, whereas dopamine returned to normal within 20 and 60 min in the medial prefrontal cortex and within 60 and 80 min in the parietal cortex after 12 and 24 Hz stimulation, respectively. DOPAC remained elevated throughout the experimental period. Phasic stimulation of the locus coeruleus at 12 Hz increased noradrenaline in the caudate nucleus as in the cerebral cortices but was totally ineffective on dopamine and DOPAC. Tetrodotoxin perfusion into the medial prefrontal cortex dramatically reduced noradrenaline and dopamine levels and suppressed the effect of electrical stimulation. These results indicate that electrical stimulation-induced increase of dopamine is a nerve impulse exocytotic process and suggest that cortical dopamine and noradrenaline may be coreleased from noradrenergic terminals
The dopamine beta-hydroxylase inhibitor nepicastat increases dopamine release and potentiates psychostimulant-induced dopamine release in the prefrontal cortex
No full textThe dopamine-beta-hydroxylase inhibitor nepicastat has been shown to reproduce disulfiram ability to suppress the reinstatement of cocaine seeking after extinction in rats. To clarify its mechanism of action, we examined the effect of nepicastat, given alone or in association with cocaine or amphetamine, on catecholamine release in the medial prefrontal cortex and the nucleus accumbens, two key regions involved in the reinforcing and motivational effects of cocaine and in the reinstatement of cocaine seeking.
Nepicastat effect on catecholamines was evaluated by microdialysis in freely moving rats.
Nepicastat reduced noradrenaline release both in the medial prefrontal cortex and in the nucleus accumbens, and increased dopamine release in the medial prefrontal cortex but not in the nucleus accumbens. Moreover, nepicastat markedly potentiated cocaine-and amphetamine-induced extracellular dopamine accumulation in the medial prefrontal cortex but not in the nucleus accumbens. Extracellular dopamine accumulation produced by nepicastat alone or by its combination with cocaine or amphetamine was suppressed by the alpha(2)-adrenoceptor agonist clonidine.
It is suggested that nepicastat, by suppressing noradrenaline synthesis and release, eliminated the alpha(2)-adrenoceptor mediated inhibitory mechanism that constrains dopamine release and cocaine-and amphetamine-induced dopamine release from noradrenaline or dopamine terminals in the medial prefrontal cortex
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