A role for lateral hypothalamic orexin neurons in reward seeking

Abstract

The lateral hypothalamus is a brain region historically implicated in reward and motivation, but the identity of the neurotransmitters involved are unknown. The orexins (or hypocretins) are neuropeptides recently identified as neurotransmitters in lateral hypothalamus neurons. Although knockout and transgenic overexpression studies have implicated orexin neurons in arousal and sleep, these cells also project to reward-associated brain regions, including the nucleus accumbens and ventral tegmental area. This indicates a possible role for these neurons in reward function and motivation, consistent with previous studies implicating these neurons in feeding. Here we show that activation of lateral hypothalamus orexin neurons is strongly linked to preferences for cues associated with drug and food reward. In addition, we show that chemical activation of lateral hypothalamus orexin neurons reinstates an extinguished drug-seeking behaviour. This reinstatement effect was completely blocked by prior administration of an orexin A antagonist. Moreover, administration of the orexin A peptide directly into the ventral tegmental area also reinstated drug-seeking. These data reveal a new role for lateral hypothalamus orexin neurons in reward-seeking, drug relapse and addiction.

Subchronic Cannabinoid Agonist (WIN 55,212-2) Treatment during Cocaine Abstinence Alters Subsequent Cocaine Seeking Behavior

“…Interestingly, the hypothalamic-pituitary-adrenal axis may have a common role in anxiety-related responses (Sinha et al, 2003), cue-induced reinstatement of extinguished cocaine seeking (Goeders and Clampitt, 2002), and behavioral effects of cannabinoids (Rodriguez de Fonseca et al, 1997). In this line, recent studies have shown that chronic cocaine exposure decreased the levels of CB1 receptor mRNA in the ventromedial hypothalamic nucleus (González et al, 2002b), which forms part of the hypothalamic-pituitary-adrenal axis, and that orexin neurons in the lateral hypothalamus, probably by a regulatory role of the endocannabinoid system (Hilairet et al, 2003), became activated by cues associated with cocaine and altered relapse (Harris et al, 2005). Future research will be needed to confirm this suspicion and to elucidate the role of these neural substrates in the neurobiological effects produced by pharmacological manipulation of the cannabinoid system.…”

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

“…Role m In satiety; m water reward (Horger et al, 1999;Kernie et al, 2000;Nakagawa et al, 2003); improvement in glucose metabolism (Tonra et al, 1999;Nakagawa et al, 2000;Ono et al, 2000) m Drug reward (Horger et al, 1999) K BDNF in mesolimbic pathways regulates appetitive behavior (Eisch et al, 2003;Itoh et al, 2004); BDNF within hypothalamus regulates energy balance by enhancing catabolic processes (Xu et al, 2003) K BDNF may play a role in behavioral sensitization to drugs (Guillin et al, 2001) and potentially to palatable food via its dopaminergic and opioidergic (Siuciak et al, 1994;Siuciak et al, 1995) effects Repeated exposure kIn the hippocampus (Molteni et al, 2002;Molteni et al, 2004) m In mesocorticolimbic areas including, hypothalamus (Meredith et al, 2002;Butovsky et al, 2005); m and upregulation of BDNF receptors during withdrawal (Toda et al, 2002;Grimm et al, 2003); incubation of drug craving, accompanied by m in BDNF (Grimm et al, 2003) BDNF gene knockout animals m In food intake and obesity (Lyons et al, 1999;Kernie et al, 2000;Rios et al, 2001;Xu et al, 2003) k Drug reward (Hall et al, 2003;Horger et al, 1999) Orexin m Food intake (Edwards et al, 1999;Harris et al, 2005) Relapse to drug seeking behavior (Harris et al, 2005) Activated by SGAs ( Ibanez-Rojo et al, 1993;Bencherif et al, 2005) are available, though, to extend preclinical palatable food opioid findings to humans. Neuroimaging studies in obese people reported in...…”

“…Through its hypothalamic effects, BDNF controls energy balance by enhancing catabolic processes (Xu et al, 2003). Similarly important are the actions of orexin neurons, situated in the LH and projecting to the NAc and VTA , to control food intake (Edwards et al, 1999;Harris et al, 2005) as well as drug reward and craving (Harris et al, 2005). In fact, a finding of a correlation between SGAs weight liability and the degree of LH orexin neurons stimulation ) is provocative and may offer important insights into homeostatic dysregulation associated with antipsychotic agents.…”

Overview of orexin/hypocretin system

“…Drugs of abuse stimulate this pathway, and orexin neurons have reciprocal connections with both the VTA and NAc. Orexin signaling has been reported to be critical for morphine-induced place preference and hyperlocomotion, and reinstatement of extinguished drug-seeking behavior in mice and rats (Harris et al, 2005;Narita et al, 2006). Notably, narcolepsy patients with daytime sleepiness who were treated with amphetamine-like stimulants and/or GHB for a long time rarely developed drug addiction (Guilleminault et al, 1974).…”