Arousal and reward: a dichotomy in orexin function

doi:10.1016/j.tins.2006.08.002

Trends in Neurosciences

Volume 29, Issue 10, October 2006, Pages 571-577

https://doi.org/10.1016/j.tins.2006.08.002 Get rights and content

The orexins (or hypocretins) are neuropeptide transmitters made exclusively in hypothalamic neurons that have extensive CNS projections. Previous studies reported that this system is most strongly associated with feeding, arousal and the maintenance of waking. We review here recent studies that reveal a novel and important role for the orexin/hypocretin neuronal system in reward processing and addiction. We propose that the current evidence indicates a dichotomy in orexin function, such that orexin neurons in the lateral hypothalamus regulate reward processing for both food and abused drugs, whereas those in the perifornical and dorsomedial hypothalamus regulate arousal and response to stress. Evidence also indicates roles for lateral hypothalamus orexin neurons and ventral tegmental orexin receptors in reward-based learning and memory.

Introduction

During the development of addiction, occasional recreational use of drugs can expand into compulsive uncontrollable abuse of drugs. The treatment of addictions to drugs such as heroin and cocaine often fails, and a high percentage of addicts relapse or return to drug use after periods of abstinence ranging from days to years 1, 2, 3. Human studies have indicated that craving for drugs or relapse in abstinent addicts can be triggered by exposure to the drug, drug-associated environmental cues or stress [4]. This relapse behavior is robustly modeled in rodents and numerous studies have demonstrated that psychological or physical stress, presentation of cues previously associated with the drug, or administration of the drug itself can reinstate drug-seeking behavior, even in the absence of drug reward [4]. The neuroanatomical and neurochemical mechanisms associated with relapse have been intensively studied over the past 15 years [5], but a complete understanding of the process of relapse remains elusive and many gaps still linger in our knowledge of this subject. Recent data described in this review indicate that orexin systems have an important role in reward processing and drug relapse.

Section snippets

Functions of orexins

The orexins (also named hypocretins) were described by two groups in 1998, and comprise two distinct peptides (A and B, which are 33 and 28 amino acids in length, respectively) that have two distinct receptors 6, 7. Orexin-expressing neurons are predominantly located in the posterior hypothalamus and extend dorsally, medially and laterally from the fornix [8]. Although small in number, orexin neurons have extensive projections throughout CNS and affect a variety of homeostatic functions 9, 10.

Different populations of orexin neurons are involved in arousal versus reward

Narcoleptic patients are often treated using highly addictive amphetamine-like drugs [20] but they rarely become addicted to these drugs 21, 22. Furthermore, orexin knockout mice are less susceptible than wild-type animals to developing morphine dependence as measured by physical withdrawal responses [23]. This information, along with the aforementioned recent results of Harris et al. [11], indicates that orexins have functions in addition to feeding and arousal, and that they might have an

Role of orexin in stress and arousal

Stress also prominently stimulates drug relapse in abstinent addicts, an effect that is modeled in animal studies using footshock stress [27]. Importantly, Harris et al. showed that footshock at levels that produce reinstatement of drug-seeking behavior [27] activates orexin neurons in PFA–DMH but not those in the LH [11] (Figure 1). This finding is consistent with other reports showing that footshock, restraint or cold-exposure stress 28, 29 all increase Fos expression in PFA orexin neurons.

Role of orexins in feeding and reward

Anatomically, orexin neurons are in a good position to alter reward functioning. For instance, they heavily innervate both the dopamine-rich VTA and the nucleus accumbens (NAc) [36], structures that drive behaviors motivated by either food or drug rewards. Moreover, orexin receptors are expressed at high levels in both of these areas 37, 38, 39. Anatomical studies have further revealed that the shell region of the NAc might be more important for orexin-mediated behaviors than the core because

Role of orexins in reward conditioning

As we have already described, stimulation of LH orexin neurons, or infusions of orexin A into the VTA, can reinstate an extinguished preference for a morphine-associated environment [11]. These reinstatement effects could result from production of a stress-like state or by reactivation of the original reward-learning circuitry. Data we have reviewed here reveal that LH orexin neurons are not activated by stress, which leads us to favor the reactivation of the original circuitry. Results of

Concluding remarks

The name orexin comes from the word orexigenic, which means to stimulate appetite. Mounting evidence indicates that the LH orexin system not only stimulates appetite for food, but also can stimulate an appetite for other rewards such as abused drugs. Activation of these neurons seems to be necessary for learning to associate drug rewards with specific environmental cues. This effect might be mediated through the generation of synaptic plasticity involving glutamate receptors in VTA.

Acknowledgements

This work was supported by grants from the National Institutes of Health.

References (60)

B.C. Wallace
Psychological and environmental determinants of relapse in crack cocaine smokers
J. Subst. Abuse Treat.
(1989)
J.M. Bossert
Neurobiology of relapse to heroin and cocaine seeking: an update and clinical implications
Eur. J. Pharmacol.
(2005)
T. Sakurai
Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior
Cell
(1998)
T. Sakurai
Roles of orexin/hypocretin in regulation of sleep/wakefulness and energy homeostasis
Sleep Med. Rev.
(2005)
R.J. DiLeone
Lateral hypothalamic neuropeptides in reward and drug addiction
Life Sci.
(2003)
R.M. Chemelli
Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation
Cell
(1999)
L. Lin
The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene
Cell
(1999)
S. Nishino et al.
Pharmacological aspects of human and canine narcolepsy
Prog. Neurobiol.
(1997)
L. Lu
Effect of environmental stressors on opiate and psychostimulant reinforcement, reinstatement and discrimination in rats: a review
Neurosci. Biobehav. Rev.
(2003)
F. Sakamoto
Centrally administered orexin-A activates corticotropin-releasing factor-containing neurons in the hypothalamic paraventricular nucleus and central amygdaloid nucleus of rats: possible involvement of central orexins on stress-activated central CRF neurons
Regul. Pept.
(2004)

D.J. Macey

CRF and urocortin decreased brain stimulation reward in the rat: reversal by a CRF receptor antagonist

Brain Res.

(2000)

Y. Shaham

Stress-induced relapse to heroin and cocaine seeking in rats: a review

Brain Res. Rev.

(2000)

J. Fadel et al.

Anatomical substrates of orexin-dopamine interactions: lateral hypothalamic projections to the ventral tegmental area

Neuroscience

(2002)

P. Trivedi

Distribution of orexin receptor mRNA in the rat brain

FEBS Lett.

(1998)

A.J. Thorpe et al.

Orexin A in the nucleus accumbens stimulates feeding and locomotor activity

Brain Res.

(2005)

T.L. Horvath et al.

Input organization and plasticity of hypocretin neurons: possible clues to obesity's association with insomnia

Cell Metab.

(2005)

K.D. Carr

Augmentation of drug reward by chronic food restriction: behavioral evidence and underlying mechanisms

Physiol. Behav.

(2002)

S.L. Borgland

Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine

Neuron

(2006)

O. Selbach

Orexins/hypocretins cause sharp wave- and theta-related synaptic plasticity in the hippocampus via glutamatergic, GABAergic, noradrenergic, and cholinergic signaling

Neuroscience

(2004)

G.C. Harris

Glutamate-associated plasticity in the ventral tegmental area is necessary for conditioning environmental stimuli with morphine

Neuroscience

(2004)

J.H. Mendelson et al.

Management of cocaine abuse and dependence

N. Engl. J. Med.

(1996)

C.P. O’Brien

A range of research-based pharmacotherapies for addiction

Science

(1997)

Y. Shaham

The reinstatement model of drug relapse: history, methodology and major findings

Psychopharmacology (Berl.)

(2003)

L. de Lecea

The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity

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

(1998)

C. Peyron

Neurons containing hypocretin (orexin) project to multiple neuronal systems

J. Neurosci.

(1998)

L. de Lecea et al.

The hypocretins and sleep

FEBS J.

(2005)

G.C. Harris

A novel role for lateral hypothalamic orexin neurons in reward seeking

Nature

(2005)

B.K. Anand et al.

Hypothalamic control of food intake in rats and cats

Yale J. Biol. Med.

(1951)

J. Olds et al.

Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain

J. Comp. Physiol. Psychol.

(1954)

G.D. Petrovich et al.

Amygdala subsystems and control of feeding behavior by learned cues

Ann. N. Y. Acad. Sci.

(2003)

Cited by (497)

Clinical usefulness of dual orexin receptor antagonism beyond insomnia: Neurological and psychiatric comorbidities
2024, Neuropharmacology
Orexin is a neurotransmitter produced by a small group of hypothalamic neurons. Besides its well-known role in the regulation of the sleep-wake cycle, the orexin system was shown to be relevant in several physiological functions including cognition, mood and emotion modulation, and energy homeostasis. Indeed, the implication of orexin neurotransmission in neurological and psychiatric diseases has been hypothesized via a direct effect exerted by the projections of orexin neurons to several brain areas, and via an indirect effect through orexin-mediated modulation of sleep and wake. Along with the growing evidence concerning the use of dual orexin receptor antagonists (DORAs) in the treatment of insomnia, studies assessing their efficacy in insomnia comorbid with psychiatric and neurological diseases have been set in order to investigate the potential impact of DORAs on both sleep-related symptoms and disease-specific manifestations. This narrative review aimed at summarizing the current evidence on the use of DORAs in neurological and psychiatric conditions comorbid with insomnia, also discussing the possible implication of modulating the orexin system for improving the burden of symptoms and the pathological mechanisms of these disorders. Target searches were performed on PubMed/MEDLINE and Scopus databases and ongoing studies registered on Clinicaltrials.gov were reviewed. Despite some contradictory findings, preclinical studies seemingly support the possible beneficial role of orexin antagonism in the management of the most common neurological and psychiatric diseases with sleep-related comorbidities. However, clinical research is still limited and further studies are needed for corroborating these promising preliminary results.
Orexin receptors in the hippocampal dentate gyrus modulated the restraint stress-induced analgesia in the animal model of chronic pain
2024, Behavioural Brain Research
Previous studies have shown that stressful stimuli induced an adaptive response of reduced nociception, known as stress-induced analgesia (SIA). Since orexin neuropeptides are involved in pain modulation, and orexin neurons, primarily located in the lateral hypothalamus (LH), project to various hippocampal regions, such as the dentate gyrus (DG), the current study aimed to examine the role of orexin receptors within the DG region in the restraint SIA in the animal model of chronic pain. One hundred-thirty adult male Wistar rats (230–250 g) were unilaterally implanted with a cannula above the DG region. Animals were given SB334867 or TCS OX2 29 (1, 3, 10, and 30 nmol, 0.5 µl/rat) into the DG region as orexin-1 receptor (OX1r) and orexin-2 receptor (OX2r) antagonists, respectively, five min before exposure to a 3-hour restraint stress (RS) period. Animals were then undergone the formalin test to assess pain-related behaviors as the animal model of chronic pain. The results showed that RS produces an analgesic response during the early and late phases of the formalin test. However, intra-DG microinjection of OX1r and OX2r antagonists attenuated the restraint SIA. OX2r antagonist was more potent than OX1r antagonist in the early phase of the formalin test, while OX1r antagonist was little more effective in the late phase. Predominantly, it could be concluded that the orexinergic system in the DG region might act as a potential endogenous pain control system and a novel target for treating stress-related disorders.
The cognitive (lateral) hypothalamus
2024, Trends in Cognitive Sciences
Despite the physiological complexity of the hypothalamus, its role is typically restricted to initiation or cessation of innate behaviors. For example, theories of lateral hypothalamus argue that it is a switch to turn feeding ‘on’ and ‘off’ as dictated by higher-order structures that render when feeding is appropriate. However, recent data demonstrate that the lateral hypothalamus is critical for learning about food-related cues. Furthermore, the lateral hypothalamus opposes learning about information that is neutral or distal to food. This reveals the lateral hypothalamus as a unique arbitrator of learning capable of shifting behavior toward or away from important events. This has relevance for disorders characterized by changes in this balance, including addiction and schizophrenia. Generally, this suggests that hypothalamic function is more complex than increasing or decreasing innate behaviors.
Lateral hypothalamus hypocretin/orexin glucose-inhibited neurons promote food seeking after calorie restriction
2023, Molecular Metabolism
The present study tests the hypothesis that changes in the glucose sensitivity of lateral hypothalamus (LH) hypocretin/orexin glucose-inhibited (GI) neurons following weight loss leads to glutamate plasticity on ventral tegmental area (VTA) dopamine neurons and drives food seeking behavior.
C57BL/6J mice were calorie restricted to a 15% body weight loss and maintained at that body weight for 1 week. The glucose sensitivity of LH hypocretin/orexin GI and VTA dopamine neurons was measured using whole cell patch clamp recordings in brain slices. Food seeking behavior was assessed using conditioned place preference (CPP).
1-week maintenance of calorie restricted 15% body weight loss reduced glucose inhibition of hypocretin/orexin GI neurons resulting in increased neuronal activation with reduced glycemia. The effect of decreased glucose on hypocretin/orexin GI neuronal activation was blocked by pertussis toxin (inhibitor of G-protein coupled receptor subunit Gα_i/o) and Rp-cAMP (inhibitor of protein kinase A, PKA). This suggests that glucose sensitivity is mediated by the Gα_i/o-adenylyl cyclase-cAMP-PKA signaling pathway. The excitatory effect of the hunger hormone, ghrelin, on hcrt/ox neurons was also blocked by Rp-cAMP suggesting that hormonal signals of metabolic status may converge on the glucose sensing pathway. Food restriction and weight loss increased glutamate synaptic strength (indexed by increased AMPA/NMDA receptor current ratio) on VTA dopamine neurons and the motivation to seek food (indexed by CPP). Chemogenetic inhibition of hypocretin/orexin neurons during caloric restriction and weight loss prevented these changes in glutamate plasticity and food seeking behavior.
We hypothesize that this change in the glucose sensitivity of hypocretin/orexin GI neurons may drive, in part, food seeking behavior following caloric restriction.
The role of orexin-1 receptors within the ventral tegmental area in the extinction and reinstatement of methamphetamine place preference
2023, Behavioural Brain Research
Targeting the orexin system has recently been identified as one of the promising options for treating drug addiction. It may be more feasible and achievable if we investigate the accurate function of the orexin system in brain areas implicated in reward and addiction, such as the ventral tegmental area (VTA) by animal reward models. This study investigated the contribution of the orexin system, mainly the orexin-1 receptors (OX1R) in the VTA, in the extinction and reinstatement of methamphetamine (METH) related memories in the conditioned place preference (CPP) model. Animals after the acquisition of METH place preference were subjected to two separate sets of extinction and reinstatement experiments to receive various concentrations of selective OX1R antagonist, SB334867 into the bilateral VTA before extinction sessions (1, 3, and 10 nmol/0.3 μl DMSO per side) or only on the reinstatement phase (3, 10, and 30 nmol/0.3 μl DMSO per side), respectively. Intra-VTA infusion of SB334867 throughout the extinction phase could remarkably facilitate the extinction process and decrease the maintenance of reinforcing effects of METH at the highest dosage (10 nmol; p < 0.0001). Data also indicated a single microinfusion of SB334867 into the VTA before reinstatement of the METH-seeking behavior could considerably prevent the relapse of previously formed reward-context memories (10 nmol; p < 0.01 and 30 nmol; p < 0.001). The present study provided evidence supporting the potential therapeutic effects of the orexin system modulation, specifically in the VTA, on different stages of METH-induced place preference.
The blockade of orexin receptors within the dentate gyrus of the hippocampus attenuated methamphetamine-induced reward learning during conditioning place preference
2023, Pharmacology Biochemistry and Behavior
Orexins and orexinergic receptors have been shown to play a critical role in reward processing and drug addiction. Previous studies showed that the orexinergic system in the dentate gyrus (DG) region of the hippocampus affects the conditioning (acquisition) and post-conditioning (expression) phases of morphine-induced conditioned place preference (CPP). The action of each orexin receptor within the DG during conditioning and expression phases for methamphetamine (METH)-induced CPP remains unclear. The present study aimed to determine the role of orexin-1 and -2 receptors in the hippocampal DG in METH CPP acquisition and expression. During the 5-day conditioning phase, rats received an intra-DG microinjection of SB334867, a selective orexin-1 receptor (OX1R) antagonist, or TCS OX2-29, a selective orexin-2 receptor (OX2R) antagonist, before injection of METH (1 mg/kg; sc). In different sets of animals on the expression day, rats received each antagonist before the CPP test. The results showed that SB334867 (3, 10, and 30 nmol) and TCS OX2-29 (3, 10, and 30 nmol) significantly decreased the acquisition of METH CPP during the conditioning phase. Furthermore, administration of SB 334867 (10 and 30 nmol) and TCS OX2-29 (3 and 10 nmol) on the post-conditioning day significantly reduced METH-induced CPP expression. The results also indicated that orexin receptors play a more critical role in the conditioning phase than in the expression phase. In summary, the orexin receptors in the DG play a crucial role in drug learning and memory and are essential for METH reward acquisition and expression.

View all citing articles on Scopus

View full text

Trends in Neurosciences

ReviewArousal and reward: a dichotomy in orexin function

Introduction

Section snippets

Functions of orexins

Different populations of orexin neurons are involved in arousal versus reward

Role of orexin in stress and arousal

Role of orexins in feeding and reward

Role of orexins in reward conditioning

Concluding remarks

Acknowledgements

J. Subst. Abuse Treat.

Eur. J. Pharmacol.

Cell

Sleep Med. Rev.

Life Sci.

Cell

Cell

Prog. Neurobiol.

Neurosci. Biobehav. Rev.

Regul. Pept.

Brain Res.

Brain Res. Rev.

Neuroscience

FEBS Lett.

Brain Res.

Cell Metab.

Physiol. Behav.

Neuron

Neuroscience

Neuroscience

Management of cocaine abuse and dependence

N. Engl. J. Med.

A range of research-based pharmacotherapies for addiction

Science

The reinstatement model of drug relapse: history, methodology and major findings

Psychopharmacology (Berl.)

The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity

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

Neurons containing hypocretin (orexin) project to multiple neuronal systems

J. Neurosci.

The hypocretins and sleep

FEBS J.

A novel role for lateral hypothalamic orexin neurons in reward seeking

Nature

Hypothalamic control of food intake in rats and cats

Yale J. Biol. Med.

Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain

J. Comp. Physiol. Psychol.

Amygdala subsystems and control of feeding behavior by learned cues

Ann. N. Y. Acad. Sci.

Review
Arousal and reward: a dichotomy in orexin function