Abstract
The mesolimbic reward pathway arising from dopaminergic (DA) neurons of the ventral tegmental area (VTA) has been strongly implicated in reward processing and drug abuse. In rodents, behaviors associated with this projection are profoundly influenced by an orexinergic input from the lateral hypothalamus to the VTA. Because the existence and significance of an analogous orexigenic regulatory mechanism acting in the human VTA have been elusive, here we addressed the possibility that orexinergic neurons provide direct input to DA neurons of the human VTA. Dual-label immunohistochemistry was used and orexinergic projections to the VTA and to DA neurons of the neighboring substantia nigra (SN) were analyzed comparatively in adult male humans and rats. Orexin B-immunoreactive (IR) axons apposed to tyrosine hydroxylase (TH)-IR DA and to non-DA neurons were scarce in the VTA and SN of both species. In the VTA, 15.0±2.8% of TH-IR perikarya in humans and 3.2±0.3% in rats received orexin B-IR afferent contacts. On average, 0.24±0.05 and 0.05±0.005 orexinergic appositions per TH-IR perikaryon were detected in humans and rats, respectively. The majority (86–88%) of randomly encountered orexinergic contacts targeted the dendritic compartment of DA neurons. Finally, DA neurons of the SN also received orexinergic innervation in both species. Based on the observation of five times heavier orexinergic input to TH-IR neurons of the human, compared with the rat, VTA, we propose that orexinergic mechanism acting in the VTA may play just as important roles in reward processing and drug abuse in humans, as already established well in rodents.
Highlights
The neuropeptides orexin A and orexin B have been implicated in a variety of behavioral states including feeding [1], sleep and arousal [2], reward processing and drug abuse [3]
Based on the similar neuroanatomical features of these orexinergic pathways in the two species, with about five times higher relative incidences of orexinergic contacts on individual ventral tegmental area (VTA) DA neurons in humans than in rats, we propose that orexin actions in the VTA may be critically involved in reward processing and drug addiction in the human, as it has been established well in rodents
The regional density of tyrosine hydroxylase (TH)-IR cell bodies detectable in the VTA of the human was much lower than in the rat, resulting in lower numbers of DA cells analyzed in the human VTA
Summary
The neuropeptides orexin A and orexin B ( known as hypocretin 1 and hypocretin 2) have been implicated in a variety of behavioral states including feeding [1], sleep and arousal [2], reward processing and drug abuse [3]. The perikarya of orexin synthesizing neurons are located in the dorsal medial hypothalamus, perifornical area and the lateral hypothalamus [1,5,6,7] Their axonal projections to the midbrain ventral tegmental area (VTA) [7,8,9] have been implicated in the wide effects of orexins on the mesolimbic reward pathway [7,9,10]. Based on the similar neuroanatomical features of these orexinergic pathways in the two species, with about five times higher relative incidences of orexinergic contacts on individual VTA DA neurons in humans than in rats, we propose that orexin actions in the VTA may be critically involved in reward processing and drug addiction in the human, as it has been established well in rodents
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