Regulation of dopamine release by striatal adrenoceptors

Striatal dopamine (DA) is critical to the regulation of action selection and motivation. DA neurons have extensively branched axons which afford axonal regulation of DA release by diverse striatal neuromodulators including acetylcholine (ACh), GABA and adenosine, which regulate the amplitude and activity-sensitivity of DA release. Adrenoceptors are expressed throughout the striatum but their role, and that of norepinephrine (NE) as a potential striatal neuromodulator, is poorly understood. Given only a sparse norepinephrinergic input of the striatum but the dense innervation by DA, the endogenous ligand for striatal adrenoceptors might not be NE, but DA. We tested firstly whether striatal adrenoceptors regulate DA release in acute slices from mouse brain by detecting electrically evoked DA release using fast-scan cyclic voltammetry following the pharmacological manipulation of adrenoceptors. The α1-receptor agonist phenylephrine decreased DA release evoked by single electrical pulses by ~30% in the dorsolateral striatum (DLS) and nucleus accumbens core (NAc), and increased the pulse-number-dependence of DA release in NAc but not DLS. Conversely, in the NAc, β-receptor agonist isoproterenol increased DA release evoked by single electrical pulses by ~10%. These data suggest that striatal α1- and β-adrenoceptors can modulate DA signalling. Ongoing experiments are investigating whether regulation is direct on DA axons or via other neuromodulatory circuits (e.g. ACh, GABA), whether the GPCR activation-based NE sensor GRABNE2h has utility in detecting NE against the background of DA, and whether DA or NE can be the endogenous ligand for striatal adrenoceptors.