Hypocretin/Orexin Selectively Increases Dopamine Efflux within the Prefrontal Cortex: Involvement of the Ventral Tegmental Area

Abstract

Hypocretins (HCRTs) modulate a variety of behavioral and physiological processes, in part via interactions with multiple ascending modulatory systems. Further, HCRT efferents from the lateral hypothalamus innervate midbrain dopamine (DA) nuclei, and DA cell bodies express HCRT receptors. Combined, these observations suggest that HCRT may influence behavioral state and/or statedependent processes via modulation of DA neurotransmission. The current studies used in vivo microdialysis in the unanesthetized rat to first characterize the effect of intracerebroventricular infusion of HCRT-1 (0.07, 0.7 nmol) on extracellular levels of DA within the prefrontal cortex (PFC) and nucleus accumbens (Acc). Electroencephalographic/electromyographic measures of sleep-wake state were collected along with select behavioral measures (eg locomotor activity, grooming). HCRT-1 dose-dependently increased PFC dialysate DA levels, and these increases were closely correlated with increases in time spent awake. In contrast, Acc DA levels were unaffected. Additional studies examined whether HCRT-1 acts directly within the ventral tegmental area (VTA) to selectively increase PFC DA efflux and modulate behavioral state. Unilateral infusion of HCRT-1 (0.1, 1.0 nmol) within the VTA increased PFC, but not Acc, DA levels. Importantly, intra-VTA infusion of HCRT-1 increased the time spent awake and grooming. Moreover, HCRT-induced increases in both time spent awake and time spent grooming were significantly correlated with post-infusion PFC DA levels. The current observations predict a prominent modulatory influence of HCRT on PFC-dependent cognitive and affective processes that results, in part, from actions within the VTA. Additionally, these observations suggest that the activation of VTA DA neurons contributes to the behavioral state-modulatory actions of HCRT.

Systemic and Nasal Delivery of Orexin-A (Hypocretin-1) Reduces the Effects of Sleep Deprivation on Cognitive Performance in Nonhuman Primates

“…However, the relative financial expense and the lack of bioavailability of orexin-A coupled with drastically different potency when injected i.v. versus centrally (Kiyashchenko et al, 2001;Vittoz and Berridge, 2006) has precluded systemic orexin-A as a candidate for controlling the effects of sleep deprivation (Hara et al, 2001). We show here that these limitations can be greatly overcome by delivering orexin-A via nasal spray which proved superior to systemically delivered orexin-A both in terms of enhancing performance in sleep-deprived monkeys as well as reversing the effects on altered CMRglc levels in key brain areas affected by sleep deprivation.…”

“…Receptors for orexin-A are located on neurons in many different brain regions making it possible for this peptide, once released, to activate a large number of areas affected by sleep and sleep deprivation (Hagan et al, 1999;Bourgin et al, 2000;Kilduff and Peyron, 2000;Piper et al, 2000;Gerashchenko et al, 2001;Yoshida et al, 2001;Wu et al, 2002;Peever et al, 2003;Lee et al, 2005;Mileykovskiy et al, 2005;Vittoz and Berridge 2006), It has recently been shown that manipulation of this system via administration of a orexin antagonist can increase sleep in rats, dogs and humans (Brisbare-Roch et al, 2007). The loss of orexin cells has been shown to cause human and animal narcolepsy (Chemelli et al, 1999;Lin et al, 1999;Nishino et al, 2000;Peyron et al, 2000;Thannickal et al, 2000;Gerashchenko et al, 2001;Wu et al, 2002;Mieda et al, 2004).…”

Orexin Mediates the Expression of Precipitated Morphine Withdrawal and Concurrent Activation of the Nucleus Accumbens Shell

“…Examination of the effects of intra-VTA orexin on DA levels in the Acb has yielded mixed results. While some results suggest a link (53), others report that orexin action in the VTA results in increased prefrontal cortex DA levels with no change in Acb DA levels (54). Moreover, previous evidence suggests that the VTA may not play a role in morphine withdrawal.…”

The Orexin-1 Receptor Antagonist SB-334867 Blocks the Effects of Antipsychotics on the Activity of A9 and A10 Dopamine Neurons: Implications for Antipsychotic Therapy

“…Activity of A10 dopamine cells has been hypothesized to be important for enabling of motor, cognitive, and motivational behavior (Schultz, 1998;Datla et al, 2002) and may be one pathway by which endogenous orexin enhances arousal. Indeed, recent data have shown that orexin increases dopamine efflux in the PFC via activation of the VTA (Vittoz and Berridge, 2006). Thus, it could be hypothesized that orexin-1 receptor antagonists would block the effects of physiological stimulation (such as might occur during periods of arousal) of this pathway in the behaving animal.…”