Although the catecholamine neurotransmitters norepinephrine (NE) and dopamine (DA) were originally thought to be the neurobiological substrates of reinforcement and reward, interest in norepinephrine (NE) declined following experimental results that shifted attention to a DA-centered hypothesis that has dominated the last few decades. However, a clear picture explaining the role of NE in reinforcement cannot be drawn from the available scientific literature because previous methodological limitations constrain definitive interpretations. Prior attempts to determine whether activation of locus coeruleus (LC) noradrenergic neurons can support operant behavior using intracranial electrical self-stimulation paradigms produced conflicting results, but these studies suffered from a lack of neural specificity;potential activation of fibers of passage and non- noradrenergic cells in the L region confound the data. Furthermore, they failed to recapitulate the endogenous phasic and tonic firing properties of LC neurons, and the contribution of other noradrenergic nuclei, including the A2 nucleus tractus solitarius (NTS) cells that project to the mesolimbic DA system, have not been assessed. In order to rigorously determine the role of noradrenergic neurons in reward and reinforcement, both neuron selectivity and firing rate and pattern must be accounted for. The proposed project will employ optogenetics to selectively activate noradrenergic neurons. By expressing the light-activated ion channel, channelrhodopsin 2 (ChR2), selectively in NE neurons of the LC (Aim 1) or A2 (Aim 2) brainstem nuclei, we will determine whether activation of these neurons at physiologically relevant firing frequencies can maintain operant behavior and produce a place preference. Completion of these studies will, for the first time, provide a comprehensive assessment of the noradrenergic component of the brain systems involved in reinforcement and reward.
The neurotransmitter dopamine is well known as the brain chemical of reward and pleasure, but its chemical relative, norepinephrine, may also regulate the brain response to rewarding events. Using state-of-the-art techniques, we will determine how norepinephrine contributes to reinforcement, which will improve our understanding of the brain's reward system.