Alpha-1 Adrenergic Receptors are Localized on Presynaptic Elements in the Nucleus Accumbens and Regulate Mesolimbic Dopamine Transmission

Brainstem noradrenergic neurons innervate the mesocorticolimbic reward pathway both directly and indirectly, with norepinephrine facilitating dopamine (DA) neurotransmission via alpha 1-adrenergic receptors (alpha 1ARs). Although alpha 1AR signaling in the prefrontal cortex (PFC) promotes mesolimbic transmission and drug-induced behaviors, the potential contribution of alpha 1ARs in other parts of the pathway, such as the ventral tegmental area (VTA) and nucleus accumbens (NAc), has not been investigated before. We found that local blockade of alpha 1ARs in the medial NAc shell, but not the VTA, attenuates cocaine- and morphine-induced locomotion. To determine the neuronal substrates that could mediate these effects, we analyzed the cellular, subcellular, and subsynaptic localization of alpha 1ARs and characterized the chemical phenotypes of alpha 1AR-containing elements within the mesocorticolimbic system using single and double immunocytochemical methods at the electron microscopic (EM) level. We found that alpha 1ARs are found mainly extra-synaptically in axons and axon terminals in the NAc and are enriched in glutamatergic and dopaminergic elements. alpha 1ARs are also abundant in glutamatergic terminals in the PFC, and in GABA-positive terminals in the VTA. In line with these observations, microdialysis experiments revealed that local blockade of alpha 1ARs attenuated the increase in extracellular DA in the medial NAc shell following administration of cocaine. These data indicate that local alpha 1ARs control DA transmission in the medial NAc shell and behavioral responses to drugs of abuse. Neuropsychopharmacology (2012) 37, 2161-2172; doi:10.1038/npp.2012.68; published online 16 May 2012