Abstract
Orexin/hypocretin-containing neurons in lateral hypothalamus (LH) are implicated in the neurobiology of nicotine addiction. However, the neuroanatomical relationships between orexin-neurons/nerve fibers and nicotine-activated cells within the reward-addiction neurocircuitry is not known. In the present study in mice, we first used c-Fos immunohistochemistry to identify CNS cells stimulated by an acute single injection of nicotine (NIC, 2 mg/kg, IP). Sequential double-labelling was then performed to identify the location of orexin-containing neurons and nerve fibers with respect to NIC-induced c-Fos activated cells and/or tyrosine hydroxylase (TH) immunoreactive (IR) cells of the mesocorticolimbic reward-addiction pathways. Orexin-IR nerve fibers and terminals were detected at multiple sites of the NIC reward-addiction circuitry in close apposition to, and intermingled with, NIC-induced c-Fos-IR cells of locus coeruleus (LC), ventral tegmental area (VTA), nucleus accumbens (Acb), LH and paraventricular thalamic nucleus (PVT). Double-labelling of orexin with TH showed frequent contact between orexin-IR nerve fibers and noradrenergic cells of LC. However, there was infrequent contact between the orexinergic fibers and the TH-expressing dopaminergic cells of VTA, dorsal raphe nucleus (DR), posterior hypothalamus (DA11), arcuate hypothalamic nucleus (DA12) and periventricular areas (DA14). The close anatomical contact between orexinergic nerve fibers and NIC-activated cells at multiple sites of the reward-addiction pathways suggests that orexinergic projections from LH are likely to be involved in modulating activity of the neurons that are directly impacted by acute administration of nicotine.
Highlights
Orexins/hypocretins are excitatory neuropeptides synthesized by neurons located exclusively in three hypothalamic regions: Lateral Hypothalamus (LH), perifornical area and dorsomedial hypothalamus [1,2]
Consistent with previous immunohistochemical studies, orexin-containing neurons were present in the hypothalamus (HP) and they were restricted to the perifornical region, dorsomedial hypothalamic nucleus (DMH) and dorsal and lateral hypothalamus (DH, LH)
Orexin-containing nerve fibers were seen intermingled with nicotine hydrogen tartrate salt (NIC)–induced c-Fos activated cells at LH and at multiple other sites in hypothalamus, including the posterior hypothalamic area, ventromedial hypothalamic nucleus, arcuate hypothalamic nucleus and paraventricular hypothalamic nucleus (Figure 2)
Summary
Orexins/hypocretins are excitatory neuropeptides synthesized by neurons located exclusively in three hypothalamic regions: Lateral Hypothalamus (LH), perifornical area and dorsomedial hypothalamus [1,2] These neurons represent a relatively small number of cells, they project extensively to various brain regions and are implicated in a number of physiological functions, such as arousal, cognition, stress, appetite, metabolism and addiction [1,3,4,5,6,7,8,9]. Since noradrenergic cells of locus coeruleus (LC) and dopaminergic cells of ventral tegmental area (VTA) and other brain regions are among the main neurochemical substrates known to be impacted by nicotine, we evaluated noradrenergic and dopaminergic cells of the reward-addiction pathways as potential targets of orexinergic innervation in the CNS
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