Estimation of endogenous noradrenaline release in rat brain in vivo using [³H]RX 821002

Noradrenaline plays an important role in many normal brain functions, e.g., attention, memory, and emotion. Dysfunction in the noradrenergic system is thought to lead to a number of abnormal brain conditions. The lack of suitable in vivo tracers to monitor noradrenaline release, levels, and regulation has hampered our fully understanding the roles that it plays in the brain. Presented here are data showing that the in vivo binding of the 2-adrenoceptor antagonist [3H]RX 821002 is sensitive to endogenous noradrenaline. Elevation of extracellular noradrenaline, using three different pharmacological challenges in rat, led to a reduction in the binding potential (BP) of [3H]RX 821002 when compared with vehicle controls. The challenges used were i.p. administration of D-amphetamine, the imidazoline2 binding site-selective ligand BU224, and L-deprenyl. Of the cortical regions measured, the reduction in BP reached significance in the anterior cingulate cortex for all of these pharmacological challenges. These initial observations in rat indicate that labelling of the 2-adrenoceptors with RX 821002 can be used to estimate changes in extracellular noradrenaline concentration in the cortex. This has the potential to enable the investigation of the role that noradrenaline plays both in the normal and abnormal brain and, if the ligand can be radiolabelled with a suitable positron-emitting isotope at high specific radioactivity, it could be an invaluable PET tracer.