Lateral hypothalamic orexin neurons are critically involved in learning to associate an environment with morphine reward

Harris, Glenda C.; Wimmer, Mathieu E.; Randall-Thompson, Jovita F.; Aston‐Jones, Gary

doi:10.1016/j.bbr.2007.05.025

Cited by 181 publications

(157 citation statements)

References 35 publications

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“…Orexin mRNA level modulated by expression of cocaine place preference was primarily found in the LH, whereas that in PFA-DMH was not affected, suggesting that LH orexin gene expression is involved in cocaine-conditioned behaviors in a region-specific manner. This observation is consistent with recent studies, showing that the cues previously conditioned with either cocaine or morphine reward (as measured by CPP) activated Fos-like immunoreactivity specifically within the LH orexin neurons of SD rats, whereas Fos expression in PFA-DMH orexin neurons was unaltered in response to these same cues (Harris et al, 2005(Harris et al, , 2007. Together, these results suggest that the orexin gene in LH neurons, as different from PFA-DMH subpopulations, responds to drug-induced reward processes.…”

Section: Discussionsupporting

confidence: 92%

Effects of cocaine place conditioning, chronic escalating-dose “binge” pattern cocaine administration and acute withdrawal on orexin/hypocretin and preprodynorphin gene expressions in lateral hypothalamus of Fischer and Sprague–Dawley rats

et al. 2008

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Recent evidence suggests an important role for hypothalamic orexins/hypocretins in modulation of drug reward and addiction-like behaviors in rodents. Our recent study has shown that the aversive state of arousal during acute morphine withdrawal is associated with increased orexin gene expression in lateral hypothalamus (LH) of Fischer 344 (F344) inbred rats, with no change in the expression of preprodynorphin (ppDyn), a gene co-expressed with LH orexin. Therefore, we determined whether orexin and ppDyn mRNA levels in LH or medial hypothalamus (including perifornical and dorsomedial areas) of F344 or Sprague-Dawley (SD) outbred rats, are altered following: 1) cocaine (10 mg/kg, i.p.) conditioned place preference (CPP); 2) chronic (14 days) cocaine exposure using both "binge" pattern administration in steady-dose (45 mg/kg/day) and escalating-dose (45 to 90 mg/kg/day) regimens; and 3) acute (1 day) and chronic (14 days) withdrawal from cocaine with opioid receptor antagonist naloxone treatment (1 mg/kg). We found that orexin mRNA levels were decreased after cocaine place conditioning in the LH of SD rats. A decreased LH orexin mRNA level was also observed after chronic escalating-dose cocaine (but not CPP pattern regimen without conditioning, or steady-dose regimen) in both strains. In F344 rats only, acute withdrawal from chronic escalating-dose cocaine administration resulted in increases in both LH orexin and ppDyn mRNA levels, which were unaltered by naloxone or after chronic withdrawal. Our results suggest that (1) alteration of LH orexin gene expression is region specific after cocaine place conditioning in SD rats and dose-dependent after chronic exposure in both strains; and (2) increased LH orexin and ppDyn gene expressions in F344 rats may contribute to negative affective states in cocaine withdrawal.

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Section: Discussionsupporting

confidence: 92%

Effects of cocaine place conditioning, chronic escalating-dose “binge” pattern cocaine administration and acute withdrawal on orexin/hypocretin and preprodynorphin gene expressions in lateral hypothalamus of Fischer and Sprague–Dawley rats

et al. 2008

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“…Previous experiments have shown an increase in c-Fos expression in LH neurons during renewal of extinguished sucrose (Hamlin et al, 2006), alcoholic beer (Hamlin et al, 2007), and cocaine seeking (Hamlin et al, 2008). These experiments show a causal role for LH in renewal across two different reward types, adding to a growing body of evidence that LH is important for learning about and responding to reward associated stimuli (Harris et al, 2005(Harris et al, , 2007.…”

Section: Discussionmentioning

confidence: 58%

“…To date there has been no investigation of the role of LH in renewal of extinguished drug seeking but a variety of additional lines of evidence support its potential involvement. For example, LH has long been implicated in regulating primary reward and feeding (Hoebel, 1979;Kelley, 2004) and, more recently, responding to drug-associated stimuli (Harris et al, 2005(Harris et al, , 2007. Moreover, the neuropeptide orexin, which originates in hypothalamus, has been implicated in reinstatement of drug seeking.…”

Section: Introductionmentioning

confidence: 99%

Lateral Hypothalamus Is Required for Context-Induced Reinstatement of Extinguished Reward Seeking

2009

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We studied the role of lateral hypothalamus (LH) in context-induced reinstatement (renewal) of reward seeking. Rats were trained to respond for 4% (v/v) alcoholic beer or 10% (w/v) sucrose reward in one context (Context A) before extinction training in a second context (Context B). On test, rats were returned to the training context, A (ABA), or the extinction context, B (ABB). Return to the training context (ABA) produced robust reinstatement. Reversible inactivation of LH via baclofen/muscimol infusion prevented context-induced reinstatement of beer and sucrose seeking. This prevention was specific to bilateral infusions into LH. We then used the retrograde neuronal tracer cholera toxin b subunit (CTb) combined with detection of the c-Fos protein to identify activated afferents to LH during contextinduced reinstatement of beer seeking. Double labeling for c-Fos and CTb revealed a significant recruitment of LH-projecting neurons in nucleus accumbens shell (AcbSh) during reinstatement. These afferents could be classified into two anatomically and functionally distinct groups. First, afferents in the ventral AcbSh projecting to LH were activated during reinstatement. Second, afferents in the dorsomedial AcbSh projecting to LH were activated during test in the extinction context. These recruitments were specific to an AcbSh-LH pathway because they were not observed following CTb injection into the immediately adjacent perifornical hypothalamus. These results show that LH is critical for context-induced reinstatement of reward seeking and that parallel striatal-hypothalamic pathways are recruited following return to the training versus extinction contexts.

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“…The rewarding effects of morphine were absent in mice deficient in the prepro-hypocretin gene tested in a place conditioning procedure (18). Lesions of hypocretin-enriched areas of the LH blocked a conditioned place preference for morphine (19). 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).…”

Section: Discussionmentioning

confidence: 99%

Insular hypocretin transmission regulates nicotine reward

Hollander

Cameron

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

272

263

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Damage to the insular cortex can profoundly disrupt tobacco addiction in human smokers, reflected in spontaneous cessation of the tobacco habit and persistently decreased urge to smoke. Little is known concerning the neurobiological mechanisms through which the insula may control the maintenance of the tobacco habit. Emerging evidence suggests that hypocretin (orexin) transmission may play an important role in drug reinforcement processes, but its role in the rewarding actions of nicotine, considered the key addictive component of tobacco smoke, remains largely unexplored. Here we show that blockade of hypocretin transmission at hypocretin-1 (Hcrt-1; orexin-1) receptors decreases i.v. nicotine self-administration in rats and the motivation to obtain the drug. Blockade of Hcrt-1 receptors also abolished the stimulatory effects of nicotine on brain reward circuitries, as measured by reversal of nicotine-induced lowering of intracranial self-stimulation thresholds. In addition, we show that hypocretin-containing fibers innervate the insula, Hcrt-1 receptors are located on insular cells, and blockade of Hcrt-1 receptors in the insula but not in the adjacent somatosensory cortex decreases nicotine self-administration. These data demonstrate that insular hypocretin transmission plays a permissive role in the motivational properties of nicotine, and therefore may be a key neurobiological substrate necessary for maintaining tobacco addiction in human smokers.craving ͉ orexin ͉ self-administration ͉ intracranial self-stimulation C igarette smoking is one of the largest preventable causes of death and disease in developed countries, and accounts for approximately 440,000 deaths and $160 billion in health-related costs annually in the United States (1). Despite the well known negative health consequences of the tobacco smoking habit, only approximately 10% of smokers who attempt to quit annually remain abstinent after 1 year, highlighting the persistence of the smoking habit. The insula is a cortical brain region involved in processing interoceptive information related to emotional and motivational states to facilitate maintenance of physiological homeostasis (2). This brain region may also regulate the experience of conscious urges and cravings (2-4). It was recently reported that damage to the insula in human smokers resulted in a profound disruption of tobacco addiction characterized by spontaneous cessation of the smoking habit and a low urge to smoke thereafter (3). Conversely, abstinence-induced cigarette craving in smokers is highly correlated with activation of the insular cortex (5). The neurobiological mechanisms through which the insula regulates the persistence of the tobacco habit remain unclear.Nicotine is a major reinforcing constituent of tobacco responsible for the smoking habit in humans (6). In common with other major drugs of abuse, nicotine can directly stimulate reward circuitries in the brain (7), and obtaining the reward-enhancing effects of nicotine may contribute to the persistence of the tobacco ...

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Lateral hypothalamic orexin neurons are critically involved in learning to associate an environment with morphine reward

Cited by 181 publications

References 35 publications

Effects of cocaine place conditioning, chronic escalating-dose “binge” pattern cocaine administration and acute withdrawal on orexin/hypocretin and preprodynorphin gene expressions in lateral hypothalamus of Fischer and Sprague–Dawley rats

Effects of cocaine place conditioning, chronic escalating-dose “binge” pattern cocaine administration and acute withdrawal on orexin/hypocretin and preprodynorphin gene expressions in lateral hypothalamus of Fischer and Sprague–Dawley rats

Lateral Hypothalamus Is Required for Context-Induced Reinstatement of Extinguished Reward Seeking

Insular hypocretin transmission regulates nicotine reward

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