Role of lateral hypothalamic orexin neurons in reward processing and addiction

Abstract

SummaryOrexins (also known as hypocretins) are recently discovered neuropeptides made exclusively in hypothalamic neurons that have been shown to be important in narcolepsy/cataplexy and arousal. Here, we conducted behavioral, anatomical and neurophysiological studies that show that a subset of these cells, located specifically in lateral hypothalamus (LH), are involved in reward processing and addictive behaviors. We found that Fos expression in LH orexin neurons varied in proportion to preference for morphine, cocaine or food. This relationship obtained both in drug naïve rats and in animals during protracted morphine withdrawal, when drug preference was elevated but food preference was decreased. Recent studies showed that LH orexin neurons that project to ventral tegmental area (VTA) have 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, we found that stimulation of LH orexin neurons, or microinjection of orexin into VTA, reinstated an extinguished morphine preference. Most recently, using a self-administration paradigm we discovered that the Ox1 receptor antagonist SB-334867 (SB) blocks cocaine-seeking induced by discrete or contextual cues, but not by a priming injection of cocaine. 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. We also recently showed that orexin in VTA is necessary for learning a morphine place preference. These findings are consistent with results from others 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.

Accumbens Shell–Hypothalamus Interactions Mediate Extinction of Alcohol Seeking

“…This is in agreement with previous reports of c-Fos expression in PeF/LH orexin neurons following AcbSh injections of muscimol (Zheng et al, 2003;Baldo et al, 2004) and cue-induced reinstatement of ethanol seeking Dayas et al, 2008). Orexin neurons in LH may mediate reward-related behaviors such as reinstatement, whereas orexin neurons in DMH and PeF may mediate arousal (Harris et al, 2005;Harris and Aston-Jones, 2006;Aston-Jones et al, 2009). DMH and PeF orexin neurons are activated during periods of wakefulness, whereas LH neurons show no such variation (Estabrooke et al, 2001).…”

Aberrant Food Choices after Satiation in Human Orexin-Deficient Narcolepsy Type 1

“…These findings may help understand the phenomenon of overweight and obesity in these patients. In addition, this study shows an important role of orexin signaling in food-related reward processing-as previously found in animal studies [8][9][10][11][12] -which may have broader implications for the study of human eating behavior.…”

“…7 Besides its role in the control of vigilance, orexin neurotransmission is primarily important for mediating behavior under situations of high motivational relevance, including adapting homeostatic state and food-related motivation. [8][9][10][11][12] Orexin-producing neurons are influenced by appetite-regulating peptide hormones, i.e., inhibited by leptin and activated by ghrelin and low glucose levels. Therefore, it has been suggested that orexin neurons sense the metabolic and nutritional status of the individual and integrate this information to evoke the level of arousal necessary to maintain the energy balance.…”

Insular hypocretin transmission regulates nicotine reward

“…Conversely, chemical activation of hypocretin neurons, achieved by infusing the neuropeptide-Y Y4 receptor agonist rat pancreatic polypeptide into the LH, reinstated extinguished morphine seeking behavior in rats (10), an effect blocked by SB-334867 (10). Finally, hypocretin transmission at Hcrt-1 receptors plays a key role in cue-and stressinduced reinstatement of extinguished cocaine-and alcoholseeking behaviors (11)(12)(13)(14). Importantly, the role of hypocretin transmission in the motivational properties of nicotine has remained largely unexplored.…”