Orexins (synonymous with hypocretins) are recently discovered neuropeptides made exclusively in hypothalamus. Behavioral, anatomical and neurophysiological studies show that a subset of these cells, specifically those in lateral hypothalamus (LH), are involved in reward processing and addictive behaviors. Fos expression in LH orexin neurons varied in proportion to conditioned place preference (CPP) for morphine, cocaine or food. This relationship occurred both in drug naïve rats and in animals during protracted morphine withdrawal, when drug preference was elevated but food preference was decreased. Inputs to the LH orexin cell field from lateral septum and bed nucleus of the stria terminalis were Fos activated during cocaine CPP in proportion to the preference expressed in each animal. This implies that these inputs may be involved in driving the conditioned responses in LH orexin neurons. Related studies showed that LH orexin neurons that project to ventral tegmental area (VTA) had greater Fos induction in association with elevated morphine preference during protracted withdrawal than non-VTA-projecting orexin neurons, indicating that the VTA is an important site of action for orexin's role in reward processing. In addition, stimulation of LH orexin neurons, or microinjection of orexin into VTA, reinstated an extinguished morphine preference. In selfadministration studies, the orexin 1 receptor antagonist SB-334867 (SB) blocked cocaine-seeking induced by discrete or contextual cues previously associated with cocaine, but not by a priming injection of cocaine. There was no effect of SB on cocaine self-administration itself, indicating that it did not interfere with the drug's reinforcing properties. Neurophysiological studies revealed that locally applied orexin often augmented responses of VTA dopamine (DA) neurons to activation of the medial prefrontal cortex (mPFC), consistent with the view that orexin facilitates activation of VTA DA neurons by stimulus-reward associations. This LH-to-VTA orexin pathway was found to be necessary for learning a morphine place preference. These findings are consistent with results showing that orexin facilitates glutamate-mediated responses, and is necessary for glutamatedependent long-term potentiation in VTA DA neurons. We surmise from these studies that LH orexin neurons play an important role in reward processing and addiction, and that LH orexin cells are an important input to VTA for behavioral effects associated with reward-paired stimuli.

Orexins/hypocretins are hypothalamic peptides involved in arousal and wakefulness, but also play a critical role in drug addiction and reward-related behaviors. Here, we review the roles played by orexins in a variety of animal models of drug addiction, emphasizing both commonalities and differences for orexin’s involvement in seeking of the major classes of abused drugs, as well as food. One common theme that emerges is an involvement of orexins in drug seeking triggered by external stimuli (e.g., cues, contexts or stressors). We also discuss the functional neuronal circuits in which orexins are embedded, and how these circuits mediate addiction-related behaviors, with particular focus on the role of orexin and glutamate interactions within the ventral tegmental area. Finally, we attempt to contextualize the role of orexins in reward by discussing ways in which these peptides, expressed in only a few thousand neurons in the brain, can have such wide-ranging effects on behavior.

Orexins (also named hypocretins) are recently discovered neuropeptides made exclusively in the hypothalamus. Recent studies have shown that orexin cells located specifically in lateral hypothalamus (LH) are involved in motivated behavior for drugs of abuse as well as natural rewards. Administration of orexin has been shown to stimulate food consumption, and orexin signaling in VTA has been implicated in intake of high-fat food. In self-administration studies, the orexin 1 receptor antagonist SB-334867 (SB) attenuated operant responding for high-fat pellets, sucrose pellets and ethanol, but not cocaine, demonstrating that signaling at orexin receptors is necessary for reinforcement of specific rewards. The orexin system is also implicated in associations between rewards and relevant stimuli. For example, Fos expression in LH orexin neurons varied in proportion to conditioned place preference (CPP) for food, morphine, or cocaine. This Fos expression was altered accordingly for CPP administered during protracted abstinence from morphine or cocaine, when preference for natural rewards was decreased and drug preference was increased. Additionally, orexin has been shown to be involved in reward-stimulus associations in the self-administration paradigm, where SB attenuated cue-induced reinstatement of extinguished sucrose-or cocaineseeking. Although the specific circuitry mediating the effects of orexin on food reward remains unknown, VTA seems likely to be a critical target for at least some these orexin actions. Thus, recent studies have established a role for orexin in reward-based feeding, and further investigation is warranted for determining whether function/dysfunction of the orexin system may contribute to the overeating associated with obesity.

Orexins (also called hypocretins) have been shown to be importantly involved in reward and addiction, but little is known about the circuitry that regulates orexin neuronal activity during drug-seeking behaviors. Here, we examined inputs to the lateral hypothalamic (LH) orexin cell field from the lateral septum (LS) using tract-tracing and Fos immunohistochemistry after cocaine (10mg/kg) conditioned place preference (CPP) in Sprague Dawley rats. We found that neurons in rostral LS (LSr) that project to LH are Fos-activated in proportion to cocaine CPP, and that inhibition of LSr neurons with local baclofen and muscimol microinjection (0.3/0.03 nmol) blocks expression of Fos in LH orexin cells and cocaine preference. In addition, using local inactivation in LS and orexin antisense Morpholinos in LH, we found that LSr influences on LH orexin neurons are critical for the expression of cocaine preference. These results indicate that LSr activates LH orexin neurons during cocaine place preference, and that this circuit is essential for expression of cocaine place preference.

SignificanceWith the imminent increase of the elderly population worldwide, Alzheimer’s disease (AD) is one of the most significant medical problems in modern society. Although nonselective histone deacetylase (HDAC) proteins delineate a promising druggable target and nonselective HDAC inhibitors have been shown effective for other indications, they present a wide spectrum of side-effects. Selective inhibition of HDAC isoforms may, however, greatly eliminate such toxicities while presenting improved efficacy. We demonstrate that RGFP-966, a selective HDAC3 inhibitor, decreases accumulation of proteins relevant for AD pathophysiology and alleviates memory impairment in an AD mouse model. The presented work provides evidence for a crucial role of HDAC3 in mediating AD-like pathology and opens an avenue for the discovery of epigenetic therapeutics for AD.