Noradrenergic modulation of dopamine transmission evoked by electrical stimulation of the locus coeruleus in the rat brain
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Norepinephrine (NE) and dopamine (DA), the two major catecholamines (CA) in the central nervous system (CNS), have been implicated in a variety of physiological functions and behaviors. Particularly, noradrenergic neurons of the locus coeruleus (LC) and the dopaminergic neurons of the ventral tegmental area (VTA) play an important roles in diverse neurological and psychiatric disorders such as Parkinson's disease, Alzheimer's dementia, and addiction. Although NE has been regarded as a regulator of DA functions in the brain, the underlying mechanisms of how NE regulates DA are still not well understood and remains controversial. Therefore, it is essential to better understand how the NE system modulates DA neuronal activity and impacts DA neurotransmission. The first goal of the research was to employ a novel method, in vivo fast-scan cyclic voltammetry (FSCV), with recently developed and modified ancillary tools to directly determine how the LC-NE system modulates neuronal activity of VTA-DA, as well as DA transmission in the anesthetized rat brain. For this study, the neurochemical features of NE in the VTA and DA in the nucleus accumbens (NAc), a key brain structure receiving dense dopaminergic innervation, evoked by electrical stimulation of the LC were characterized using dual-microelectrode FSCV techniques. DA and NE release evoked by the LC stimulation was measured simultaneously in the target brain regions with two separate carbon-fiber microelectrodes (CFM), which allowed direct comparison of their dynamic process and drug effects on them in same preparation. The second goal was to investigate how DA transmission in the NAc was regulated through, α1- and α2-adrenergic NE receptors expressed in the VTA. The results from pharmacological, anatomical and electrochemical studies show for the first time that i) electrical stimulation of LC evoked NE release in the VTA and DA release in the NAc and ii) DA release is regulated by both α1- and α2-adrenergic receptors whereas NE release is regulated by α2-adrenergic receptor but not by α1-adrenergic receptors. These results elucidate how the under-studied NE system of the brain modulates the DA system, potentially helping future investigations into the role of LC-NE in DA-related behaviors.