Berridge, Craig W.

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 state-dependent 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.

The hypocretin/orexin (HCRT) neuropeptide system modulates behavioral state and state‐dependent processes via actions on multiple neuromodulatory transmitter systems. Recent studies indicate that HCRT selectively increases dopamine (DA) neurotransmission within the prefrontal cortex (PFC) and the shell subregion of the nucleus accumbens (NAs), but not the core subregion of the nucleus accumbens (NAc). The circuitry underlying the differential actions of HCRT across distinct DA systems is unclear. The current study examined whether HCRT preferentially activates PFC‐ and NAs‐projecting relative to NAc‐projecting DA neurons within the VTA. One week after infusion of the retrograde tracer fluorogold (FG) into the medial PFC, NAc or NAs, animals received a ventricular infusion of HCRT‐1. Subsequent analyses conducted across the rostral‐caudal extent of the VTA determined the degree to which: (i) Fos‐immunoreactivity (ir) was observed within tyrosine hydroxylase (TH)‐ir neurons; (ii) TH‐ir was observed within FG‐ir neurons; and (iii) Fos‐ir was observed within FG‐ir neurons. HCRT significantly increased Fos‐ir in VTA DA (TH‐ir) neurons, primarily in a restricted population of small‐to‐medium‐sized DA neurons located within the caudomedial VTA. Furthermore, within this region of the VTA, PFC‐ and NAs‐projecting TH‐ir neurons were more likely to contain Fos‐ir than were NAc‐projecting TH‐ir neurons. These results provide novel evidence that HCRT selectively activates PFC‐ and NAs‐projecting DA neurons within the VTA, and suggest a potential role for HCRT in PFC‐ and NAs‐dependent cognitive and/or affective processes. Moreover, these and other observations suggest that the dysregulation of HCRT–DA interactions could contribute to cognitive/affective dysfunction associated with a variety of behavioral disorders.