Noradrenergic terminals are the primary source of α2-adrenoceptor mediated dopamine release in the medial prefrontal cortex

Abstract

In various psychiatric disorders, deficits in dopaminergic activity in the prefrontal cortex (PFC) are implicated. Treatments involving selective augmentation of dopaminergic activity in the PFC primarily depend on the inhibition of α2-adrenoreceptors singly or in combination with the inhibition of the norepinephrine transporter (NET). We aimed to clarify the relative contribution of dopamine (DA) release from noradrenergic and dopaminergic terminals to DA output induced by blockade of α2-adrenoreceptors and NET. To this end, we assessed whether central noradrenergic denervation modified catecholamine output in the medial PFC (mPFC) of rats elicited by atipamezole (an α2adrenoreceptor antagonist), nisoxetine (an NET inhibitor), or their combination. Intraventricular administration of antidopamine-beta-hydroxylase-saporin (aDBH) caused a loss of DBH-positive fibers in the mPFC and almost total depletion of tissue and extracellular NE level; however, it did not reduce tissue DA level but increased extracellular DA level by 70% in the mPFC. Because noradrenergic denervation should have caused a loss of NET and reduced NE level at α2-adrenoceptors, the actual effect of an aDBH-induced lesion on DA output elicited by blockade of α2adrenoceptors and NET was evaluated by comparing denervated and control rats following blockade of α2adrenoceptors and NET with atipamezole and nisoxetine, respectively. In the control rats, extracellular NE and DA levels increased by approximately 150% each with 3 mg/kg atipamezole; 450% and 230%, respectively, with 3 mg/kg nisoxetine; and 2100% and 600%, respectively, with combined atipamezole and nisoxetine. In the denervated rats, consistent with the loss of NET, nisoxetine failed to modify extracellular DA level, whereas atipamezole, despite the lack of NE-induced stimulation of α2-adrenoceptors, increased extracellular DA level by approximately 30%. Overall, these results suggest that atipamezole-induced DA release mainly originated from noradrenergic terminals, possibly through the inhibition of α2-autoreceptors. Furthermore, while systemic and local administration of the α2adrenoceptor agonist clonidine into the mPFC of the controls rats reduced extracellular NE level by 80% and 60%, respectively, and extracellular DA level by 50% and 60%, respectively, it failed to reduce DA output in the denervated rats, consistent with the loss of α2-autoreceptors. To eliminate the possibility that denervation reduced DA release potential via the effects at dopaminergic terminals in the mPFC, the effect of systemic administration of the D2-DA antagonist raclopride (0.5 mg/kg IP) on DA output was analyzed. In the control rats, raclopride was found to be ineffective when administered alone, but it increased extracellular DA level by 380% following NET inhibition with nisoxetine. In the denervated rats, as expected due to the loss of NET, raclopride-alone or with nisoxetineincreased DA release to approximately the same level as that observed in the control rats after NET inhibition. Overall, these re...

Noradrenergic Source of Dopamine Assessed by Microdialysis in the Medial Prefrontal Cortex

“…Importantly, the loss of NET provides a likely explanation for why noradrenergic denervation failed to reduce extracellular DA in the mPFC (Harik, 1984;Carboni et al, 1990;Pozzi et al, 1994;Valentini et al, 2004;Masana et al, 2011;Devoto et al, 2015;Devoto et al, 2019), in apparent contradiction with our hypothesis that noradrenergic terminals supply extracellular DA in the mPFC. Indeed, in accord with this hypothesis, transient inactivation of noradrenergic neurons by clonidine perfusion into the LC, a condition in which NET activity is Dialysate levels are means ± SEM of values obtained in 9 control and 11 nisoxetine-perfused rats.…”

“…As Table 1 shows, consistent with earlier results (Devoto et al, 2015;Devoto et al, 2019), the ICV injection of aDBH (0.5 µg/5µl) depleted tissue and extracellular NE almost totally and did not modify tissue DA and DOPAC. Notably, in apparent contrast to our hypothesis that noradrenergic terminals supply DA in the mPFC, noradrenergic denervation did not reduce extracellular DA (actually increased it by about 38%) and reduced extracellular DOPAC by 50%.…”

“…Moreover, consistent with the hypothesis that cortical DA measured by microdialysis originates from noradrenergic terminals, the D2 receptor agonist quinpirole, both given systemically or locally perfused into the mPFC, failed to modify extracellular DA in the mPFC in control rats but, opposite to raclopride, reduced extracellular DA after NET was inactivated by nisoxetine or eliminated by noradrenergic denervation, in line with the hypothesis that extracellular DA from dopaminergic terminals may be detected when DA clearance is impaired. Notably, as expected from the hypothesis that extracellular DA in the mPFC derives from noradrenergic terminals, in a previous study (Devoto et al, 2019) the a 2 -adrenoceptor agonist clonidine was found to reduce extracellular DA in the mPFC of control rats but to be ineffective after noradrenergic denervation with aDBH.…”

Long-Term Treatment with Fluvoxamine Decreases Nonmotor Symptoms and Dopamine Depletion in a Postnatal Stress Rat Model of Parkinson’s Disease

“…Generally, we found reduced DA levels in the striatum and prefrontal cortex of maternally separated (MS) rats when compared to nonseparated (NS) rats. These results were predictable as previous studies showed that chronic stress (including maternal separation) leads to central dopaminergic denervation in brain areas implicated in movement, learning and memory, or motivation [1,[92][93][94]. In an animal model of PD, 6-OHDA selectively uptaken by dopaminergic neurons via DA transporters can exacerbate the harmful effects of chronic stress leading to apoptotic cell death in the striatum and related brain areas including the prefrontal cortex and hippocampus [12,95,96].…”

Dopamine and Noradrenaline in the Brain; Overlapping or Dissociate Functions?

“…(4) Electrical stimulation of the LC did not change DA concentration in striatum but significantly increased NA level in this region (Devoto et al, 2005a,b). 5Selective lesion studies and specific disruption of catecholamine production in VTA and LC confirmed that noradrenergic terminals are the main source of dopamine in cortical regions (Pozzi et al, 1994;Devoto et al, 2008Devoto et al, , 2015Devoto et al, , 2019Smith and Greene, 2012). Moreover, several medications for neuropsychiatric conditions increase both DA and NA in the brain (Devoto et al, 2006).…”