Orexin-1 Receptor Antagonist SB-334867 Research Articles

Selective orexin 1 receptor antagonism does not affect effort-based responding for sucrose reward in rats.

In rodents, orexin neuropeptides regulate motivation and reward-seeking via orexin 1 receptor (OX1R) signaling in the mesolimbic dopaminergic system. This role is clearly established for rewards inherent to drugs of abuse but less so for natural rewards. Reported effects of the selective OX1R antagonist (SO1RA) SB-334867 on motivation for palatable food are ambiguous. In our experimental conditions neither SB-334867, nor two additional, structurally different SO1RAs, ACT-335827 and the clinical development candidate nivasorexant, affected effort-based responding for sucrose in rats. The positive control lisdexamfetamine, approved for psychiatric disorders associated with altered reward sensitivity such as binge eating disorder, increased effort-based responding.

Orexin-1 Receptor Antagonist SB-334867 Enhances Formalin-Induced Nociceptive Behaviors in Adult Male Rats.

Orexin (hypocretin) is one of the hypothalamic neuropeptides that plays a critical role in some behaviors including feeding, sleep, arousal, reward processing, and drug addiction. Neurons that produce orexin are scattered mediolaterally within the Dorsomedial Hypothalamus (DMH) and the lateral hypothalamus. In the current research, we assessed the impact of prolonged application of the antagonist of Orexin Receptor 1 (OXR1) on nociceptive behaviors in adult male rats. Sixteen Wistar rats received subcutaneous (s.c.) injections of the OXR1 antagonist, SB-334867 (20 mg/kg, i.p.), or its vehicle repetitively from Postnatal Day 1 (PND1)-PND30. On the 30th day following the final application of the OXR1 antagonist formalin-provoked pain was evaluated by injecting formalin. Administration of the OXR1 antagonist in the long-term augmented the formalin-provoked nociceptive behaviors in interphase and phase II of the formalin-induced pain. Current results showed that the continued inhibiting OXR1 might be implicated in formalin-induced nociceptive behaviors. Therefore, the present study highlighted the effect of orexin on analgesia.

Nasal administration of orexin A partially rescues dizocilpine-induced cognitive impairments in female C57BL/6 J mice

Sex difference has been reported in several behavioral endophenotypes of neuropsychiatric disorder in both rodents and humans. However, sex difference in cognitive symptoms associated with neuropsychiatric disorders has not been studied in detail. In this study, we induced cognitive impairment using the NMDA receptor antagonist, dizocilpine (MK-801), in male and female C57BL/6 J mice and performed a visual discrimination task in an automated touchscreen system. We found that discrimination performance decreased with increased doses of MK-801 in both sexes. However, female mice showed stronger deficit in discrimination performance than the male mice especially after administration of low (0.01 mg/kg) and high (0.15 mg/kg) doses of MK-801. Furthermore, we tested if administration of orexin A, orexin-1 receptor antagonist SB-334867 or orexin-2 receptor antagonist EMPA rescued MK-801 (0.15 mg/kg) induced cognitive impairment in visual discrimination. We found that nasal administration of orexin A partially rescued the cognitive impairment induced by MK-801 in females but not in males. Taken together, our data show that female C57BL/6 J mice are more sensitive compared to males to some doses of MK-801 in discrimination learning task and that orexin A partially rescues this cognitive impairment in females.

Blockade of the orexin 1-receptors and ‘cocaine- and amphetamine-regulated transcript’ in the nucleus accumbens shell alters impulse control in rats

Impulsivity is a multifaceted construct and alterations in impulsiveness are often associated with psychiatric diseases, including drug addiction and binge eating disorder. Impulse control involves several brain regions. The present study assessed the role of the orexigenic, appetite stimulating neuropeptide orexin (OX) and the anorexigenic, appetite reducing neuropeptide cocaine- and amphetamine-regulated transcript (CART) within the nucleus accumbens shell (NAcSh) in impulse control in rats. The animals were ranked for their trait impulsivity based on a screening in the 5-choice serial reaction time task (5-CSRTT). The rats’ performances were analysed after bilateral infusions of the OX 1-receptor antagonist SB-334867 (SB) and CART-antibodies (CART-ABs) into the NAcSh. After SB infusions, there was no change in premature responses observed on average. Further analysis revealed a negative linear correlation between the effect of intra-NAcSh SB infusions on premature responses and trait impulsivity. The effect of SB ranged from an increase, no change to a decrease in premature responses in the individual animals with increasing trait impulsivity. Infusions of CART-ABs led to consistently enhanced impulse control with fewer irrelevant actions, independent of trait impulsivity. These data suggest that both OX, especially OX A, and CART in the NAcSh, can be considered endogenous regulators of impulsive action, dependent on underlying impulsivity in the case of OX and independent from trait impulsivity in the case of CART.

Blockade of orexin receptor type-1 by SB-334867 and activation of orexin receptor type-2 attenuate morphine tolerance in rats.

The interaction of orexinergic neurons with the opioidergic system and their effects on morphine analgesia and tolerance have not been fully elucidated. The purpose of the study was to evaluate the effects of the orexin-1 and orexin-2 receptor (OX1R and OX2R) agonist and antagonist on morphine analgesia and tolerance in rats. A total of 90 Wistar albino male rats weighing 180-220 g wereused in the experiments. To induce morphine tolerance, rats were injected with a single dose of morphine (50 mg kg-1, s.c.) for 3 days. Morphine tolerance was assessed on day 4 in randomly selected rats by analgesia tests. In order to evaluate morphine tolerance situation, orexin-A, SB-334867, orexin-B andTCSOX2 29 were administered together with morphine for 3 days. The analgesic effects of orexin-A (10 μg kg-1), OXR1 antagonist SB-334867 (10 mg kg-1), OXR2 agonist orexin-B (15 μg kg-1), OXR2 antagonist TCS OX2 29 (0.5 mg kg-1) and morphine (5 mg kg-1) were measured at 15 or 30-min intervals by tail-flick and hot-plate antinociceptive tests. The results suggested that the combination of orexin-1 receptor antagonist SB-334867 and orexin-B with morphine significantly increased the analgesic effect compared to morphine-tolerant rats. In addition, administration of orexin-A and -B alone showed significant analgesic effects compared to the saline group. However, co-administration of orexin-A and -B with morphine didnot increase the analgesic efficacy of morphine. The results of this study demonstrated that co-administration of SB-334867 and orexin-B with morphine attenuated morphine tolerance. Further studies are needed to elucidate the details of the interaction between orexin receptors and the opioidergic system.

Orexin-1 receptor signaling in ventral tegmental area mediates cue-driven demand for cocaine.

Drug-associated sensory cues increase motivation for drug and the orexin system is importantly involved in this stimulus-enhanced motivation. Ventral tegmental area (VTA) is a major target by which orexin signaling modulates reward behaviors, but it is unknown whether this circuit is necessary for cue-driven motivation for cocaine. Here, we investigated the role of VTA orexin signaling in cue-driven motivation for cocaine using a behavioral economics (BE) paradigm. We found that infusion of the orexin-1 receptor (Ox1R) antagonist SB-334867 (SB) into VTA prior to BE testing reduced motivation when animals were trained to self-administer cocaine with discrete cues and tested on BE with those cues. SB had no effect when animals were trained to self-administer cocaine without cues or tested on BE without cues, indicating that learning to associate cues with drug delivery during self-administration training was necessary for cues to recruit orexin signaling in VTA. These effects were specific to VTA, as injections of SB immediately dorsal had no effect. Moreover, intra-VTA SB did not have an impact on locomotor activity, or low- or high-effort consumption of sucrose. Finally, we microinjected a novel retrograde adeno-associated virus (AAVretro) containing an orexin-specific short hairpin RNA (OxshRNA) into VTA to knock down orexin in the hypothalamus-VTA circuit. These injections significantly reduced orexin expression in lateral hypothalamus (LH)and decreased cue-driven motivation. These studies demonstrate a role for orexin signaling in VTA, specifically when cues predict drug reward.

Intermittent self-administration of fentanyl induces a multifaceted addiction state associated with persistent changes in the orexin system.

The orexin (hypocretin) system plays a critical role in motivated drug taking. Cocaine self-administration with the intermittent access (IntA) procedure produces a robust addiction-like state that is orexin-dependent. Here, we sought to determine the role of the orexin system in opioid addiction using IntA self-administration of fentanyl. Different groups of male rats were either given continuous access in 1-h period (short access [ShA]), 6-h period (long access [LgA]), or IntA (5 min of access separated by 25 min of no access for 6 h) to fentanyl for 14 days. IntA produced a greater escalation of fentanyl intake, increased motivation for fentanyl on a behavioral economics task, persistent drug seeking during abstinence, and stronger cue-induced reinstatement compared with rats given ShA or LgA. We found that addiction behaviors induced by IntA to fentanyl were reversed by the orexin-1 receptor antagonist SB-334867. IntA to fentanyl was also associated with a persistent increase in the number of orexin neurons. Together, these results indicate that the IntA model is a useful tool in the study of opioid addiction and that the orexin system is critical for the maintenance of addiction behaviors induced by IntA self-administration of fentanyl.

Persistent effects of the orexin-1 receptor antagonist SB-334867 on naloxone precipitated morphine withdrawal symptoms and nociceptive behaviors in morphine dependent rats

Aim of the study In this study, we investigated the effect of long-term administration of orexin receptor 1 (OXR1) antagonist on naloxone-precipitated morphine withdrawal symptoms and nociceptive behaviors in morphine-dependent rats. Materials and methods Wistar rats received subcutaneous (s.c.) injections of morphine (6, 16, 26, 36, 46, 56, and 66 mg/kg, 2 ml/kg) at an interval of 24 h for 7 days. In chronic groups, the OXR1 antagonist, SB-334867 (20 mg/kg, i.p.), or its vehicle, was injected repetitively from postnatal day 1 (PND1)-PND23 and then for the following seven days before each morphine injection. Meanwhile, in acute groups, SB-334867, or its vehicle, was administered before each morphine injection. In groups of rats that were designated for withdrawal experiments, naloxone (2.5 mg/kg, i.p.) was administered after the last injection of morphine. In the formalin-induced pain, the effect of OXR1 inhibition on the antinociceptive effects of morphine was measured by injecting formalin after the final morphine injection. Results Animals that received long-term SB-334867 administration before morphine injection demonstrated a significant reduction in chewing, defecation, diarrhea, grooming, teeth chattering, wet-dog shake, and writhing. Inhibiting OXR1 for a long time increased formalin-induced nociceptive behaviors in interphase and phase II of the formalin-induced pain. Conclusions Our results indicated that the inhibition of OXR1 significantly reduces the development of morphine dependence and behavioral signs elicited by the administration of naloxone in morphine-dependent rats. Furthermore, the prolonged blockade of OXR1 might be involved in formalin-induced nociceptive behaviors.

Sex Differences in Demand for Highly Palatable Foods: Role of the Orexin System.

BackgroundThe prevalence of eating disorders, including binge eating disorder, is significantly higher in women. These findings are mirrored by preclinical studies, which indicate that female rats have a higher preference for palatable food and show greater binge-like eating compared with male rats.MethodsHere, we describe a novel within-session behavioral-economic paradigm that allows for the simultaneous measurement of the intake at null cost (Q0) and normalized demand elasticity (α) of 3 types of palatable food (low fat, high fat, and chocolate sucrose pellets) via demand curve analysis. In light of evidence that the orexin (hypocretin) system is critically involved in reward and feeding behaviors, we also examined the role of orexin function in sex differences of economic demand for palatable foods.ResultsThe novel within-session behavioral-economic approach revealed that female rats have higher intake (demand) than males for all palatable foods at low cost (normalized to body weight) but no difference in intake at higher prices, indicating sex-dependent differences in the hedonic, but not motivational, aspects of palatable food. Immediately following behavioral-economic testing, we observed more orexin-expressing neurons and Fos expression (measure of recent neural activation) in these neurons in female rats compared with male rats. Moreover, the orexin-1 receptor antagonist SB334867 reduced both low- and high-cost intake for palatable food in both male and female rats.ConclusionsThese findings provide evidence of higher demand at low prices for palatable food in females and indicate that these behavioral differences may be associated with sexual dimorphism in orexin system function.

Persistent effects of the orexin-1 receptor antagonist SB-334867 on motivation for the fast acting opioid remifentanil

The orexin (hypocretin) system is multifaceted, and regulates sleep-wake cycles, nociception, endocrine function and reward-seeking behavior. We have established an important role for this system in motivation for drugs of abuse. The orexin-1 receptor (Ox1R) antagonist SB334867 (SB) reduces seeking of drug reward under conditions of high motivation. There is some evidence that the effects of systemic SB on reward seeking persist beyond the pharmacological availability of the drug, however the time course of these effects is not well characterized, nor is it known whether similar persistent effects are observed following intraparenchymal injections. Here, we used a behavioral economics paradigm, which allows for repeated testing of drug motivation across consecutive days, to examine the persistent effects of acute systemic and local treatment with SB on motivation for the short-acting μ‐opioid receptor agonistremifentanil. Systemic injections of SB immediately prior to behavioral testing reduced motivation for remifentanil; this effect was sustained on a subsequent test at 24 h, but not on a third test at 48 h. When injected into ventral pallidum (VP) the effects of SB were more persistent, with reduced motivation observed for up to 48 h. We next made SB injections into VP 24 h prior to behavioral testing; this produced effects that persisted for at least 72 h post-treatment. Cued reinstatement of extinguished remifentanil seeking was also attenuated by pretreatment with SB 24 h earlier. These data indicate that the effects of SB on opioid seeking behavior persist beyond the bioavailability of the compound. These observations have important ramifications for the future clinical use of orexin receptor antagonists for the treatment of addiction.

The orexin-1 receptor antagonist SB-334867 reduces motivation, but not inhibitory control, in a rat stop signal task

There is considerable clinical interest in the neuropeptide orexin/hypocretin for its ability to regulate motivation and reward as well as arousal and wakefulness. For instance, antagonists for the orexin-1 receptor (OxR1) are thought to hold great promise for treating drug addiction and disorders associated with overeating, as these compounds repeatedly have been found to suppress seeking of various drugs of abuse as well as highly palatable foods in preclinical models. Given the hypothesized role of OxR1 signaling in cue-driven motivation, an outstanding question is whether pharmacologically blocking this receptor affects cognitive functioning. Response inhibition – the ability to cancel ongoing behavior – is one aspect of cognitive control that may be particularly relevant. Response inhibition deficits are commonly associated with a range of psychiatric disorders and neurological diseases, including substance use disorders and obesity. Moreover, OxR1 signaling recently has been implicated in waiting impulsivity, another aspect of inhibitory control. Here, we investigated the effects of the OxR1 antagonist SB-334867 on response inhibition in a rat version of the stop-signal reaction time task. Results show that acutely blocking OxR1 had minimal effects on response inhibition or attentional functioning. In contrast, this manipulation reduced motivation to perform the task and earn food rewards, consistent with other recent findings. These results add to the growing body of literature implicating OxR1 in the regulation of motivation and suggest that effects of pharmacological compounds such as SB-334867 on drug-seeking behavior are not related to effects on response inhibition.

Demand elasticity predicts addiction endophenotypes and the therapeutic efficacy of an orexin/hypocretin-1 receptor antagonist in rats.

Behavioral economics is a powerful, translational approach for measuring drug demand in both humans and animals. Here, we asked if demand for cocaine in rats with limited drug experience could be used to identify individuals most at risk of expressing an addiction phenotype following either long- or intermittent access self-administration schedules, both of which model the transition to uncontrolled drug-seeking. Because the orexin-1 receptor antagonist SB-334867 (SB) is particularly effective at reducing drug-seeking in highly motivated individuals, we also asked whether demand measured after prolonged drug experience could predict SB efficacy. Demand elasticity (α) measured immediately following acquisition of cocaine self-administration ('baseline α') was positively correlated with α assessed after 2w of long- or intermittent access. Baseline α also predicted the magnitude of compulsive responding for cocaine, drug-seeking in initial abstinence and cued reinstatement following long-, intermittent- or standard short access. When demand was measured after these differential access conditions, α predicted the same addiction endophenotypes predicted by baseline α, as well as primed reinstatement and the emergence of negative emotional mood behavior following abstinence. α also predicted the efficacy of SB, such that high demand rats showed greater reductions in motivation for cocaine following SB compared to low demand rats. Together, these findings indicate that α might serve as a behavioral biomarker to predict individuals most likely to progress from controlled to uncontrolled drug use, and to identify individuals most likely to benefit from orexin-based therapies for the treatment of addiction.

Activation of orexin-1 receptors in the amygdala enhances feeding in the diet-induced obesity rats: Blockade with μ-opioid antagonist

Obesity has become a global problem due to its sharply increased prevalence and associated complications. Orexin and opioid signaling can regulate feeding behavior and represent potential therapeutic targets for obesity. In the present experiment, we sought to ascertain the effects of orexin-A and μ-opioid signaling regulation in the basomedial amygdala (BMA) on feeding and investigate the physiology of gastric distension (GD)-responsive neurons in a diet-induced obesity (DIO) and diet-induced obesity resistance (DR) rat model. Intra-BMA infusions of orexin-A increased the firing of BMA GD neurons and increased food intake, and that these effects could be abolished by pretreatment with the orexin-1 receptor (OX-1R) antagonist SB334867, these effects could also be somewhat attenuated by co-administration of naloxone. In the DIO and DR rats, mRNA expression of OX-1R and μ-opioid receptors were increased in the BMA. Our results strongly suggest that orexin-A and opioid signaling in the BMA play a major role in regulating GD neuronal excitability and feeding behavior in obesity.

Orexin-A and endocannabinoid signaling regulate glucose-responsive arcuate nucleus neurons and feeding behavior in obese rats

Obesity is a global public health problem. Orexin and endocannabinoid signaling in the hypothalamus have been shown to regulate feeding and are promising molecular targets for obesity treatment. In this study, we attempted to analyze effects of orexin-A and endocannabinoid signaling modulation in the arcuate nucleus (Arc) on feeding and glucose-responsive (GR) neurons physiology in a diet-induced obesity (DIO) and diet-induced obesity resistant (DR) rat model. Administration of orexin-A or cannabinoid receptor type-1 (CB1R) antagonist AM251 altered the firing of GR neurons in the Arc. The effects of orexin-A were eliminated by pre-administrating orexin-1 receptor (OX-1R) antagonist SB334867, respectively. Behavioral studies showed that orexin-A increased food intake, while AM251 reduced feeding. Histological studies showed that mRNA and protein expression of OX-1R (orexin-1 receptor) and CB1R were increased in the Arc of DIO and DR rats. Our results strongly suggest that orexin-A and endocannabinoid signaling in Arc plays an important role in regulating GR neuronal excitability and food intake in obesity.

P.4.e.009 - Facilitation of contextual fear extinction by orexin-1 receptor antagonism is associated with the activation of specific amygdala cell subpopulations

Background Orexins are hypothalamic neuropeptides recently involved in the regulation of emotional memory. The basolateral amygdala, an area orchestrating fear memory processes, appears to be modulated by orexin transmission during fear extinction. However, the neuronal types within the basolateral amygdala involved in this modulation remain to be elucidated. Methods We used retrograde tracing combined with immunofluorescence techniques in mice to identify basolateral amygdala projection neurons and cell subpopulations in this brain region influenced by orexin transmission during contextual fear extinction consolidation. Results Treatment with the orexin-1 receptor antagonist SB334867 increased the activity of basolateral amygdala neurons projecting to infralimbic medial prefrontal cortex during fear extinction. GABAergic interneurons expressing calbindin, but not parvalbumin, were also activated by orexin-1 receptor antagonism in the basolateral amygdala. Conclusions These data identify neuronal circuits and cell populations of the amygdala associated with the facilitation of fear extinction consolidation induced by the orexin-1 receptor antagonist SB334867.

The effect of orexin-A on motor and cognitive functions in a rat model of Parkinson’s disease

Objective: The aim of this study was to evaluate the effect of orexin-A (OX-A) and the orexin-1 receptor antagonist SB-334867 (SB) on motor and cognitive functions in a rat model of Parkinson’s disease. Methods: Parkinson was induced by intracerebroventricular (i.c.v) injection of 6- hydroxydopamine (6-OHDA) (200 μg/rat). 72 h later, the treatment was initiated by i.c.v administration of SB (30 nmol/rat) and/or OX-A (0.3 nmol/rat) for 10 days. Motor functions were monitored using rotarod and hanging tests. Cognitive function was assessed by passive avoidance test (Shuttle box). Results: OX-A administration in 6-OHDA treated rats remarkably increased the time which animals run on rod (in rotarod test) and also the latency to fall (in hanging test) (P < 0.01 and P < 0.001, respectively). Conversely, administration of SB in 6-OHDA-treated rats decreased the mentioned indices (P < 0.05 for latency to fall). Administration of agonist and/or antagonist of orexin-1 receptors had no significant effect on 6-OHDA induced cognitive impairment in rats. Conclusion: Results of this study suggest that the orexinergic system might be involved in sensory-motor deficits of Parkinson’s disease.

Facilitation of Contextual Fear Extinction by Orexin-1 Receptor Antagonism Is Associated with the Activation of Specific Amygdala Cell Subpopulations

BackgroundOrexins are hypothalamic neuropeptides recently involved in the regulation of emotional memory. The basolateral amygdala, an area orchestrating fear memory processes, appears to be modulated by orexin transmission during fear extinction. However, the neuronal types within the basolateral amygdala involved in this modulation remain to be elucidated.MethodsWe used retrograde tracing combined with immunofluorescence techniques in mice to identify basolateral amygdala projection neurons and cell subpopulations in this brain region influenced by orexin transmission during contextual fear extinction consolidation.ResultsTreatment with the orexin-1 receptor antagonist SB334867 increased the activity of basolateral amygdala neurons projecting to infralimbic medial prefrontal cortex during fear extinction. GABAergic interneurons expressing calbindin, but not parvalbumin, were also activated by orexin-1 receptor antagonism in the basolateral amygdala.ConclusionsThese data identify neuronal circuits and cell populations of the amygdala associated with the facilitation of fear extinction consolidation induced by the orexin-1 receptor antagonist SB334867.

Orexin‐A increases the firing activity of hippocampal CA1 neurons through orexin‐1 receptors

Orexins including two peptides, orexin-A and orexin-B, are produced in the posterior lateral hypothalamus. Much evidence has indicated that central orexinergic systems play numerous functions including energy metabolism, feeding behavior, sleep/wakefulness, and neuroendocrine and sympathetic activation. Morphological studies have shown that the hippocampal CA1 regions receive orexinergic innervation originating from the hypothalamus. Positive orexin-1 (OX1 ) receptors are detected in the CA1 regions. Previous behavioral studies have shown that microinjection of OX1 receptor antagonist into the hippocampus impairs acquisition and consolidation of spatial memory. However, up to now, little has been known about the direct electrophysiological effects of orexin-A on hippocampal CA1 neurons. Employing multibarrel single-unit extracellular recordings, the present study showed that micropressure administration of orexin-A significantly increased the spontaneous firing rate from 2.96 ± 0.85 to 8.45 ± 1.86 Hz (P < 0.001) in 15 out of the 23 hippocampal CA1 neurons in male rats. Furthermore, application of the specific OX1 receptor antagonist SB-334867 alone significantly decreased the firing rate from 4.02 ± 1.08 to 2.11 ± 0.58 Hz in 7 out of the 17 neurons (P < 0.05), suggesting that endogenous orexinergic systems modulate the firing activity of CA1 neurons. Coapplication of SB-334867 completely blocked orexin-A-induced excitation of hippocampal CA1 neurons. The PLC pathway may be involved in activation of OX1 receptor-induced excitation of CA1 neurons. Taken together, the present study's results suggest that orexin-A produces excitatory effects on hippocampal neurons via OX1 receptors. © 2016 Wiley Periodicals, Inc.

Role of the orexin (hypocretin) system in contextual fear conditioning in rats

Orexin (hypocretin) neurons located in the posterior hypothalamus send projections to multiple areas of the brain involved in arousal and experimental evidence indicates that these neurons play a role in the physiological and behavioral responses to stress. This study was done to determine if the orexin system was involved in mediating the fear associated with shock context (5×2s of 1.5mA). First, real-time RT-PCR was used to examine changes in the mRNA levels for prepro-orexin (ppOX), the orexin-1 receptor (OX1R) and the orexin-2 receptor (OX2R) at two weeks post-shock. We found that the mRNA levels for ppOX and OX1R were increased in the posterior hypothalamus of shocked rats. In contrast, no significant difference was found in the midline thalamus or the locus coeruleus/parabrachial region. Second, the study examined if systemic injections of antagonists for orexin receptors attenuated the freezing related to contextual fear. The OX1R antagonist SB334867 (20 or 30mg/kg; i.p.) decreased freezing while the same doses of the OX2R antagonist TCSOX229 had no effect. The dual orexin antagonist TCS1102 (20mg/kg; i.p.) also decreased the freezing to the shock context. The results of the present study show upregulation of orexin activity and of the OX1R in the hypothalamus following exposure of rats to footshocks and highlight a specific role of OX1R in contextual fear.

Ventral tegmental area orexin 1 receptors promote palatable food intake and oppose postingestive negative feedback.

Hypothalamic orexin neurons project to numerous brain areas, including the ventral tegmental area (VTA), which is involved in motivation and food-seeking behavior. Here we address how exogenously administered orexin-A and endogenous orexin 1 receptor (OX1R) activation in the VTA affects feeding behavior. We hypothesized that orexin-A and OX1R antagonist SB334867 delivered to the VTA, at doses that were subthreshold for effect when injected into the ventricle, would affect intake of palatable foods in multiple test situations. We first used a hedonic feeding model in which satiated rats selectively consume a high-fat diet (HFD). Intra-VTA orexin-A stimulated additional consumption of chow and increased HFD intake in this model. In ad libitum-fed rats given daily 30-min test sessions, intra-VTA orexin-A also increased intake of HFD and 0.1 M sucrose. Further analysis of licking patterns revealed that that VTA orexin-A increased meal size and licking burst size only toward the end of the meal. Consistent with this finding, a subthreshold dose of VTA orexin-A prevented intake suppression induced by gastrointestinal nutrient infusion. Surprisingly, intra-VTA orexin-A had no effect on operant responding for sucrose pellets on a progressive ratio schedule of reinforcement. A role for endogenous VTA OX1R stimulation is supported by our finding that bilateral VTA injection of the selective OX1R antagonist SB334867 suppressed 0.1 M sucrose intake. Together, our data suggest that OX1R activity in the VTA facilitates food intake, potentially by counteracting postingestive negative feedback that would normally suppress feeding later in a meal.