Noradrenaline transporter blockers raise extracellular dopamine in medial prefrontal but not parietal and occipital cortex: differences with mianserin and clozapine

Abstract

This study compared the interaction between noradrenaline (NA) and dopamine (DA) mechanisms in the prefrontal (PFCX) and in the parietal (ParCX) and occipital (OccCX) cortex. The effect of reboxetine and desipramine, two NA transporter blockers, of mianserin, an antagonist of a 2 and 5-HT2 receptors, and of clozapine, an atypical antipsychotic, on dialysate DA in the medial PFCX, ParCX and OccCX was studied. We also assessed the influence of a prior 6-hydroxydopamine (6-OHDA) lesion of the dorsal noradrenergic bundle (DNAB) on the effect of reboxetine and clozapine on dialysate DA in the PFCX and ParCX. Systemic administration of reboxetine and desipramine dose-dependently increased dialysate DA in the PFCX but not in the ParCX and OccCX. In contrast, mianserin and clozapine raised dialysate DA in the ParCX and OccCX to an even larger extent than in the PFCX. 6-OHDA lesions of DNAB abolished the increase of dialysate DA elicited by reboxetine in the PFCX and by clozapine both in the PFCX and in the ParCX. It is concluded that, although PFCX and ParCX/OccCX share the presence of a strong control of DA transmission by NA through a 2 receptors, they differ in the extent to which DA is cleared from the extracellular compartment by uptake through the NA transporter. This process, although extensive in the PFCX, appears insignificant in the ParCX and OccCX, probably as a result of the higher ratio of NA to DA resulting in exclusion of DA from NA transporter.

A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

“…Furthermore, noradrenergic depletion of PFC attenuates cocaine CPP (64). At the transporter level, NET mediates DA clearance in the PFC (3)(4)(5)(6)(7)(8), underscoring the importance of NET function in controlling DA signaling. Thus, our finding that p38 MAPK inhibition or NET-Thr 30 intervention can attenuate cocaine CPP indicates a role for NET regulation in the PFC and in cocaine-reinforcing effects.…”

“…30 Peptide Blocks Cocaine-induced NET Up-regulation and Phosphorylation-Our previous study demonstrated that p38 MAPK activation mediates cocaine up-regulation of NET via NET-Thr 30 phosphorylation (1). Here we tested the effect of interrupting the Thr 30 motif using a TAT peptide two-way analysis of variance; Bonferroni's test: F (4,192) ϭ 1086 for drug, p ϭ 0.0001; F (6,192) strategy. Fig.…”

Neurocircuitry Underlying the Preferential Sensitivity of Prefrontal Catecholamines to Low-Dose Psychostimulants

“…Alternatively, this could reflect local action within the PFC and a unique sensitivity of PFC catecholamines to low concentrations of psychostimulants. For example, in the PFC the NE transporter (NET) has a prominent role in DA clearance from the extracellular space (Carboni et al, 2006(Carboni et al, , 1990Moron et al, 2002;Valentini et al, 2004). Evidence suggests that NE and DA binding to the NET is competitive, with increases in either NE or DA within the PFC elevating extracellular levels of the other transmitter (Bymaster et al, 2002;Schmeichel et al, 2012;Valentini et al, 2004).…”

Cocaine Up-regulation of the Norepinephrine Transporter Requires Threonine 30 Phosphorylation by p38 Mitogen-activated Protein Kinase

“…Studies using knock-out mice and/or pharmacological transporter blockade have provided strong evidence that extracellular DA clearance in the PFC is largely controlled by NET (41)(42)(43)(44)(45). In addition, a functional coupling exists between DA and NE transmission, and DA-related behavior at the transport level is linked to NET function (46).…”