The number of lateral hypothalamus orexin/hypocretin neurons contributes to individual differences in cocaine demand

Pantazis, Caroline B.; James, Morgan H.; Bentzley, Brandon S.; Aston‐Jones, Gary

doi:10.1101/547836

Cited by 8 publications

(6 citation statements)

References 47 publications

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“…The variable α has been shown repeatedly to correlate with drug-seeking for multiple drugs of abuse [61] and is associated with the propensity to develop a more severe SUD phenotype in cocaine self-administering rats [102]. Consistent with several previous studies indicating a functional dichotomy for LH versus DMH/PF orexin cells in reward and stress processes, respectively [60,64,103,104], we found that the number of LH (but not DMH/PF) orexin cells negatively correlated with heroin α. Interestingly, we observed no relationship between orexin cell numbers in either LH or DMH/PF and food α, indicating an apparent specific relationship between the LH orexin system in motivation for heroin. Moreover, positive correlations were observed between LH (but not DMH/PF) orexin cell numbers and heroin P max .…”

Section: Discussionsupporting

confidence: 88%

Oxytocin and orexin systems bidirectionally regulate the ability of opioid cues to bias reward seeking

et al. 2022

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As opioid-related fatalities continue to rise, the need for novel opioid use disorder (OUD) treatments could not be more urgent. Two separate hypothalamic neuropeptide systems have shown promise in preclinical OUD models. The oxytocin system, originating in the paraventricular nucleus (PVN), may protect against OUD severity. By contrast, the orexin system, originating in the lateral hypothalamus (LH), may exacerbate OUD severity. Thus, activating the oxytocin system or inhibiting the orexin system are potential therapeutic strategies. The specific role of these systems with regard to specific OUD outcomes, however, is not fully understood. Here, we probed the therapeutic efficacy of pharmacological interventions targeting the orexin or oxytocin system on two distinct metrics of OUD severity in rats—heroin choice (versus choice for natural reward, i.e., food) and cued reward seeking. Using a preclinical model that generates approximately equal choice between heroin and food reward, we examined the impact of exogenously administered oxytocin, an oxytocin receptor antagonist (L-368,899), and a dual orexin receptor antagonist (DORA-12) on opioid choice. Whereas these agents did not alter heroin choice when rewards (heroin and food) were available, oxytocin and DORA-12 each significantly reduced heroin seeking in the presence of competing reward cues when no rewards were available. In addition, the number of LH orexin neurons and PVN oxytocin neurons correlated with specific behavioral economic variables indicative of heroin versus food motivation. These data identify a novel bidirectional role of the oxytocin and orexin systems in the ability of opioid-related cues to bias reward seeking.

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Section: Discussionsupporting

confidence: 88%

Oxytocin and orexin systems bidirectionally regulate the ability of opioid cues to bias reward seeking

et al. 2022

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“…This could be done through targeted microinjections of an antisense morpholino into the NacC and vmCP followed by analysis of alcohol preference and consumption or by measuring the neuronal activity of these ectopic neurons after behaviour to determine if they are participating in local neural circuitry. 59 Although both clinical and animal studies have shown embryonic ethanol exposure to produce ectopic neurons in the brain, 21,22,62 this report provides new evidence in both rats and zebrafish for ectopic neurons that express specific peptides known to promote alcoholrelated behaviours. It also characterizes the morphology of these neurons, showing them to be mature neurons but different from normally located neurons, and it presents in zebrafish the first direct evidence that these ectopic neurons are functional and involved in mediating ethanol-induced disturbances in behaviour.…”

Section: Discussionmentioning

confidence: 77%

“…This difference is likely due to the fact that embryonic peptide neurons when differentiating from neural progenitor cells are more susceptible than mature neurons to drug‐induced disturbances. It is notable that these other substances administered at older ages, such as fentanyl 57 and cocaine, 59 stimulate the density of Hcrt neurons similar to the effects of embryonic ethanol exposure and animals with more motivation for these substances have a greater number of Hcrt neurons. This suggests that there are common underlying mechanisms mediating these drug effects on this neuropeptide neuronal population, which in turn drives behaviours related to substance use disorders.…”

Section: Discussionmentioning

confidence: 99%

Embryonic ethanol exposure induces ectopic Hcrt and MCH neurons outside hypothalamus in rats and zebrafish: Role in ethanol‐induced behavioural disturbances

et al. 2022

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Embryonic exposure to ethanol increases the risk for alcohol use disorder in humans and stimulates alcohol‐related behaviours in different animal models. Evidence in rats and zebrafish suggests that this phenomenon induced by ethanol at low‐moderate concentrations involves a stimulatory effect on neurogenesis and density of hypothalamic neurons expressing the peptides, hypocretin/orexin (Hcrt) and melanin‐concentrating hormone (MCH), known to promote alcohol consumption. Building on our report in zebrafish showing that ethanol induces ectopic expression of Hcrt neurons outside the hypothalamus, we investigated here whether embryonic ethanol exposure also induces ectopic peptide neurons in rats similar to zebrafish and affects their morphological characteristics and if these ectopic neurons are functional and have a role in the ethanol‐induced disturbances in behaviour. We demonstrate in rats that ethanol at a low‐moderate dose, in addition to increasing Hcrt and MCH neurons in the lateral hypothalamus where they are normally concentrated, induces ectopic expression of these peptide neurons further anterior in the nucleus accumbens core and ventromedial caudate putamen where they have not been previously observed and causes morphological changes relative to normally located hypothalamic neurons. Similar to rats, embryonic ethanol exposure at a low‐moderate dose in zebrafish induces ectopic Hcrt neurons anterior to the hypothalamus and alters their morphology. Notably, laser ablation of these ectopic Hcrt neurons blocks the behavioural effects induced by ethanol exposure, including increased anxiety and locomotor activity. These findings suggest that the ectopic peptide neurons are functional and contribute to the ethanol‐induced behavioural disturbances related to the overconsumption of alcohol.

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“…First, Ox1R signaling has been implicated in several psychiatric disorders that are commonly associated with deficient impulse control. Most notably, addiction is associated with higher numbers, activity and excitability of orexin cells (James et al, 2018b;Lawrence et al, 2006;Moorman et al, 2016;Pantazis et al, 2019;Thannickal et al, 2018;Yeoh et al, 2012Yeoh et al, , 2018, and SB is highly effective at reducing several addiction-related behaviors in rodents (Brodnik et al, 2018;Campbell et al, 2018;James et al, 2017James et al, , 2018aMartin-Fardon and Weiss, 2014a,b;Moorman et al, 2017;Perrey and Zhang, 2018;Schmeichel et al, 2017). Secondly, orexin neurons are interconnected with a variety of brain regions (e.g.…”

Section: Orexin Signaling and Inhibitory Controlmentioning

confidence: 99%

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

2020

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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.

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The number of lateral hypothalamus orexin/hypocretin neurons contributes to individual differences in cocaine demand

Cited by 8 publications

References 47 publications

Oxytocin and orexin systems bidirectionally regulate the ability of opioid cues to bias reward seeking

Oxytocin and orexin systems bidirectionally regulate the ability of opioid cues to bias reward seeking

Embryonic ethanol exposure induces ectopic Hcrt and MCH neurons outside hypothalamus in rats and zebrafish: Role in ethanol‐induced behavioural disturbances

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

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