Differential regulation of phasic dopamine release in the forebrain by the VTA noradrenergic receptor signaling

Abstract

Phasic dopamine (DA) release from the ventral tegmental area (VTA) into forebrain structures is implicated in associative learning and conditional stimulus (CS)‐evoked behavioral responses. Mounting evidence points to noradrenaline signaling in the VTA as an important regulatory input. Accordingly, adrenergic receptor (AR) blockade in the VTA has been shown to modulate CS‐dependent behaviors. Here, we hypothesized that α1‐ and α2‐AR (but not β‐AR) activity preferentially modulates phasic, in contrast to tonic, DA release. In addition, these effects could differ between forebrain targets. We used fast‐scan cyclic voltammetric measurements in rats to assess the effects of intra‐VTA microinfusion of terazosin, a selective α1‐AR antagonist, on electrically evoked phasic DA release in the nucleus accumbens (NAc) core and medial prefrontal cortex (mPFC). Terazosin dose‐dependently attenuated phasic, but not tonic, DA release in the NAc core, but not in the mPFC. Next, we measured the effects of intra‐VTA administration of the α2‐AR selective antagonist RX‐821002 on evoked DA in the NAc core. Similar to the effects of α1‐AR blockade, intra‐VTA α2‐AR blockade with RX‐0821002 strongly and dose‐dependently attenuated phasic, but not tonic, DA release. In contrast, no regulation by RX‐821002 was observed in the mPFC. This effect was sensitive to intra‐VTA blockade of D2 receptors with raclopride. Finally, the β‐AR antagonist propranolol ineffectively modulated DA release in the NAc core. These findings revealed both α1‐ and α2‐ARs in the VTA as selective regulators of phasic DA release. Importantly, we demonstrated that AR blockade modulated mesolimbic, in contrast to mesocortical, DA release in previously unstudied heterogeneity in AR regulation of forebrain phasic DA.

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

“…It is important to note that the hypothesis that DA released by dopaminergic terminals in the mPFC may not be detectable by microdialysis does not contrast the notion that DA is tonically and phasically released by dopaminergic terminals in the mPFC (see Hauber, 2010 ), and that noradrenergic and dopaminergic systems interact reciprocally both at the level of the LC and VTA and at nerve terminal level in the mPFC ( Grenhoff et al, 1993 ; Guiard et al, 2008 ; Hauber, 2010 ; Mejias-Aponte, 2016 ; Xing et al, 2016 ; Park et al, 2017 ; Kielbinski et al, 2019 ). Indeed, the finding that both transient inactivation and denervation of noradrenergic neurons reduced the activity of DA neurons in the VTA is consistent with the view that NE exerts a tonic excitatory effect on VTA DA cells via α 1 -adrenoceptors ( Grenhoff et al, 1993 ; Grenhoff et al, 1993 ; Park et al, 2017 ; Kielbinski et al, 2019 ).…”

Alpha1-adrenergic receptor blockade in the ventral tegmental area attenuates acquisition of cocaine-induced pavlovian associative learning

“…Effect of intra-VTA α 1 -AR blockade on electrically evoked phasic DA release in the forebrain was performed as previously described for intra-VTA pharmacological manipulations ( Solecki et al, 2013 ; Kielbinski et al, 2019 ). We used within subject experiment design as previously described ( Wickham et al, 2015 ; Kielbinski et al, 2019 ). Rats were anesthetized (urethane 1.5 g/kg, ip.)…”

“…and placed in a stereotaxic frame to lower an electrode (bipolar, stainless-steel stimulating electrode, Plastics One, Roanoke, VA, United States) into the VTA (AP −5.2 mm, ML −1.0 mm, and DV between −7.6 and −8.5 mm). Next, a carbon fiber microelectrode [described in Kielbinski et al (2019) ] was lowered into the NAc core (AP +1.2 mm, ML −1.4 mm, and DV from −6.2 to −6.9 mm) and a reference electrode (Ag/AgCl) was placed in contralateral hemisphere. To induce redox reactions, a triangular waveform (−0.4 to +1.3 V and back to −0.4 V at a rate of 400 V/s, repeated at 100 ms intervals) was applied to the microelectrode.…”

“…To study the effects of intra-VTA prazosin administration, we used within subject experiment design as previously described ( Wickham et al, 2015 ; Kielbinski et al, 2019 ). Briefly, once stimulated DA was detected in the NAc core, minimum of six baseline dopamine samples were collected, followed by six samples after the intra-VTA PBS administration, additional six traces for second baseline prior to prazosin administration and final 6–12 traces after prazosin microinfusion.…”

“…Neurochemical and neurophysiological studies have since identified adrenergic receptors on both DA projection neurons and GABA interneurons as well as both excitatory and inhibitory afferent terminals ( Rommelfanger et al, 2009 ; Mitrano et al, 2012 ; Velásquez-Martinez et al, 2012 ; Velásquez-Martínez et al, 2015 ) with alpha 1 -adrenergic receptors (α 1 -ARs) in the VTA serving as putative regulators of phasic DA efflux in the nucleus accumbens (NAc) ( Goertz et al, 2015 ; Park et al, 2017 ). In our previous studies, we have shown that the mesolimbic VTA-NAc pathway, in contrast to the mesocortical (VTA–prefrontal cortex) pathway, is especially susceptible to modulation via intra-VTA α 1 -AR antagonists ( Kielbinski et al, 2019 ). We have also shown that α 1 -AR microinfusion into the VTA potently inhibits cocaine seeking under extinction conditions, while sparing natural reward processing, i.e., having no effect on food seeking ( Solecki et al, 2018 , 2019a ).…”