Excitatory orexinergic innervation of rat nucleus incertus – Implications for ascending arousal, motivation and feeding control

Błasiak, Anna; Siwiec, Marcin; Grabowiecka, Agnieszka; Blasiak, Tomasz; Czerw, Aleksandra; Błasiak, Ewa; Kania, Alan; Rajfur, Zenon; Lewandowski, M.H.; Gundlach, Andrew L.

doi:10.1016/j.neuropharm.2015.08.014

Cited by 40 publications

(44 citation statements)

References 83 publications

(116 reference statements)

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“…; Blasiak et al . , ), volume transmission by relaxin‐3 may occur (for review, see Agnati et al . ).…”

Section: Discussionmentioning

confidence: 99%

“…Experiments were performed during the light phase of the light-dark cycle as described by Blasiak et al (2015). In summary, rats (n = 66) were decapitated under deep isoflurane anaesthesia, and whole brains were dissected and submerged in ice-cold, low-sodium, high-magnesium artificial cerebrospinal fluid (ACSF) containing (mM): 185 sucrose, 25 NaHCO 3 , 3 KCl, 1.2 NaH 2 PO 4 , 2 CaCl 2 , 10 MgSO 4 and 10 glucose, pH 7.4; osmolality 290-300 mosmol kg −1 .…”

Section: Electrophysiologymentioning

confidence: 99%

“…For neural tracer injections, adult male Wistar rats (300 g; n = 3) were treated as described by Blasiak et al (2015). Under deep isoflurane anaesthesia, retrograde tracer (undiluted red fluorescent RetroBeads; LumaFluor, Naples, FL, USA) was injected into the PVN magnocellular part, using the following stereotaxic co-ordinates; anteroposterior −1.7 mm, mediolateral 0.4 mm and dorsoventral −7.8 mm from bregma (Paxinos & Watson, 2007).…”

Section: Immunohistochemistry and Neural Tract Tracingmentioning

confidence: 99%

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Inhibition of oxytocin and vasopressin neuron activity in rat hypothalamic paraventricular nucleus by relaxin‐3–RXFP3 signalling

Kania

Guguła

Grabowiecka

et al. 2017

The Journal of Physiology

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The paraventricular nucleus of the hypothalamus (PVN) plays an essential role in the control of food intake and energy expenditure by integrating multiple neural and humoral inputs. Recent studies have demonstrated that intracerebroventricular and intra-PVN injections of the neuropeptide relaxin-3 or selective relaxin-3 receptor (RXFP3) agonists produce robust feeding in satiated rats, but the cellular and molecular mechanisms of action associated with these orexigenic effects have not been identified. In the present studies, using rat brain slices, we demonstrated that relaxin-3, acting through its cognate G-protein-coupled receptor, RXFP3, hyperpolarized a majority of putative magnocellular PVN neurons (88%, 22/25), including cells producing the anorexigenic neuropeptides, oxytocin and vasopressin. Importantly, the action of relaxin-3 persisted in the presence of tetrodotoxin and glutamate/GABA receptor antagonists, indicating its direct action on PVN neurons. Similar inhibitory effects on PVN oxytocin and vasopressin neurons were produced by the RXFP3 agonist, RXFP3-A2 (82%, 80/98 cells). In situ hybridization histochemistry revealed a strong colocalization of RXFP3 mRNA with oxytocin and vasopressin immunoreactivity in rat PVN neurons. A smaller percentage of putative parvocellular PVN neurons was sensitive to RXFP3-A2 (40%, 16/40 cells). These data, along with a demonstration of abundant peri-PVN and sparse intra-PVN relaxin-3-immunoreactive nerve fibres, originating from the nucleus incertus, the major source of relaxin-3 neurons, identify a strong inhibitory influence of relaxin-3-RXFP3 signalling on the electrical activity of PVN oxytocin and vasopressin neurons, consistent with the orexigenic effect of RXFP3 activation observed in vivo.

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“…; Blasiak et al . , ), volume transmission by relaxin‐3 may occur (for review, see Agnati et al . ).…”

Section: Discussionmentioning

confidence: 99%

Section: Electrophysiologymentioning

confidence: 99%

Section: Immunohistochemistry and Neural Tract Tracingmentioning

confidence: 99%

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Inhibition of oxytocin and vasopressin neuron activity in rat hypothalamic paraventricular nucleus by relaxin‐3–RXFP3 signalling

Kania

Guguła

Grabowiecka

et al. 2017

The Journal of Physiology

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“…Relaxin-3 and RXFP3 knockout mice display reduced voluntary running wheel activity during the dark/active phase (Smith et al, 2012; Hosken et al, 2015) and activation of relaxin-3 receptors promotes arousal (Smith et al, 2013). Currently, there are no reports of a circadian rhythmicity in relaxin-3 levels, but sensitivity of relaxin-3 neurons to neuropeptides synthetized in a circadian manner, such as CRH and orexins (Blasiak et al, 2013, 2015) suggest that relaxin-3 expression and/or excitability of NI relaxin-3 neurons may vary over the 24-h cycle.…”

Section: Central Regulation Of Food Intake: the Interaction Of Orexigmentioning

confidence: 99%

Interactions of Circadian Rhythmicity, Stress and Orexigenic Neuropeptide Systems: Implications for Food Intake Control

et al. 2017

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Many physiological processes fluctuate throughout the day/night and daily fluctuations are observed in brain and peripheral levels of several hormones, neuropeptides and transmitters. In turn, mediators under the “control” of the “master biological clock” reciprocally influence its function. Dysregulation in the rhythmicity of hormone release as well as hormone receptor sensitivity and availability in different tissues, is a common risk-factor for multiple clinical conditions, including psychiatric and metabolic disorders. At the same time circadian rhythms remain in a strong, reciprocal interaction with the hypothalamic-pituitary-adrenal (HPA) axis. Recent findings point to a role of circadian disturbances and excessive stress in the development of obesity and related food consumption and metabolism abnormalities, which constitute a major health problem worldwide. Appetite, food intake and energy balance are under the influence of several brain neuropeptides, including the orexigenic agouti-related peptide, neuropeptide Y, orexin, melanin-concentrating hormone and relaxin-3. Importantly, orexigenic neuropeptide neurons remain under the control of the circadian timing system and are highly sensitive to various stressors, therefore the potential neuronal mechanisms through which disturbances in the daily rhythmicity and stress-related mediator levels contribute to food intake abnormalities rely on reciprocal interactions between these elements.

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“…Hcrt/ox signals through two excitatory G-protein coupled receptors (OX 1 R, OX 2 R) and enhances neuronal excitability in catecholamine-producing cell types (Blasiak et al 2015; Borgland et al 2006; Brown et al 2001; Eriksson et al 2001; Hagan et al 1999). Notably, fiber immunoreactivity and receptor mRNA analyses revealed dense innervation across midbrain regions including ventral tegmental area (VTA), and hcrt/ox transmission was initially found to underlie arousal and appetite (Fadel and Deutch 2002; Marcus et al 2001; Peyron et al 1998).…”

Section: Introductionmentioning

confidence: 99%

Role of hypocretin/orexin receptor blockade on drug-taking and ultrasonic vocalizations (USVs) associated with low-effort self-administration of cathinone-derived 3,4-methylenedioxypyrovalerone (MDPV) in rats

et al. 2017

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Rationale Synthetic psychostimulant abuse, including cathinone-derived 3,4-methylenedioxypyrovalerone (MDPV), continues to increase in many countries. Similar to cocaine but with greater potency, MDPV elicits a transient sympathomimetic response by blocking cellular uptake of dopamine (DA) and norepinephrine (NE)—administration in some users is reported as euphoria-inducing much like cocaine and amphetamine. Pharmacological agents that disrupt excitatory transmission onto midbrain DA-producing neurons, including hypothalamic hypocretin/orexin (hcrt/ox) receptor antagonists, present attractive targets to aide abstinence maintenance by reducing psychostimulant-associated reward and reinforcement. Objective The present study sought to assess the degree to which suvorexant, a dual hcrt/ox receptor antagonist, influences drug-taking as well as ultrasonic vocalizations (USVs) associated with MDPV self-administration. Methods Rats were trained to self-administer MDPV (~0.03 mg/kg/inf, 3-s) for 14 days under a fixed-ratio 1 schedule of reinforcement, and effects of suvorexant (0, 3, 10, 30 mg/kg, i.p.) on drug-taking was assessed. USVs were recorded during a 30-minute pre-lever period as well as during 2-hours of MDPV self-administration. Results We observed that suvorexant modestly suppressed the number of MDPV infusions earned. Notably, we observed that suvorexant reduced 50-kHz USVs associated with pre- and post-lever time-points but did not noticeably alter call type profiles. Upon comparison of the two measures, we observed trending positive associations between suvorexant-induced changes in drug-taking and 50-kHz USVs. Conclusions Results from this exploratory study provide support for: (1) studying how suvorexant may provide benefit to humans with stimulant use disorders, (2) identifying a potential role for orexin transmission in cathinone abuse, and (3) further interrogating the potential utility of rat USVs to predict drug consumption in preclinical models of substance use disorders.

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Excitatory orexinergic innervation of rat nucleus incertus – Implications for ascending arousal, motivation and feeding control

Cited by 40 publications

References 83 publications

Inhibition of oxytocin and vasopressin neuron activity in rat hypothalamic paraventricular nucleus by relaxin‐3–RXFP3 signalling

Inhibition of oxytocin and vasopressin neuron activity in rat hypothalamic paraventricular nucleus by relaxin‐3–RXFP3 signalling

Interactions of Circadian Rhythmicity, Stress and Orexigenic Neuropeptide Systems: Implications for Food Intake Control

Role of hypocretin/orexin receptor blockade on drug-taking and ultrasonic vocalizations (USVs) associated with low-effort self-administration of cathinone-derived 3,4-methylenedioxypyrovalerone (MDPV) in rats

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