Systemic and intrabasalis administration of the orexin-1 receptor antagonist, SB-334867, disrupts attentional performance in rats

Boschen, Karen E.; Fadel, Jim R.; Burk, Joshua A.

doi:10.1007/s00213-009-1596-2

Cited by 59 publications

(52 citation statements)

References 62 publications

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“…This interpretation questions the most recent observations claiming a role for Hcrt in cue- and context-driven cocaine seeking (Smith et al, 2009a,b), especially since the high doses of the Hcrt-1 receptor antagonist SB 334867 are known to induce sedative effects and attention deficits (Rodgers et al, 2001; Boschen et al, 2009). …”

Section: Discussion and Hypothesesmentioning

confidence: 65%

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The role of hypocretin in driving arousal and goal-oriented behaviors

2010

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The hypocretins (Hcrts), also called orexins, are two neuropeptides secreted by a few thousand neurons restricted to the lateral hypothalamus. The Hcrt peptides bind to two receptors located in nuclei associated with diverse cognitive and physiological functions. Experimental evidence has demonstrated that the physiological roles of hypocretins extend far beyond its initial role in food consumption, and has emerged as a key system in the fields of sleep disorders and drug addiction. Here, we discuss recent evidence demonstrating a key role of hypocretin in the motivation for reward seeking in general, and drug taking in particular, and we delineate a physiological framework for this peptidergic system in orchestrating the appropriate levels of alertness required for the elaboration and the execution of goal-oriented behaviors. We propose a general role for hypocretins in mediating arousal, especially when an organism must respond to unexpected stressors and environmental challenges, which serve to shape survival behaviors. We also discuss the limit of the current experimental paradigms to address the question of how a system normally involved in the regulation of vigilance states and hyperarousal may promote a pathological state that elicits compulsive craving and relapse to drug seeking.

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Section: Discussion and Hypothesesmentioning

confidence: 65%

“…Systemic or intracerebral administration of the Hcrtr-1 antagonist SB 334867 disrupted attentional performance in rats (Boschen et al, 2009). These observations strongly suggest a role for Hcrt in sustained attention, and possibly in the execution of goal-oriented behaviors.…”

Section: The Hypocretins and Attentional Processesmentioning

confidence: 99%

The role of hypocretin in driving arousal and goal-oriented behaviors

2010

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“…Hence, the data here obtained with SB-334867 and QNP in combination suggest that a dysfunctional inhibition of the cortical orexinergic system plays a significant role in the expression and modulation of dopaminergic-induced polydipsic behavior. It is noteworthy that QNP and SB-334867 present convergent effects in rats when tested in attention-requiring tasks, where they both produce a deterioration of performance (Pezze et al 2007;Boschen et al 2009). Apart from promoting and maintaining wakefulness, literature supports a prominent role of orexin peptides in cognition and attention, as suggested on neuroanatomical basis and confirmed by pharmacological studies (Lambe et al 2005;Deadwyler et al 2007;Morein-Zamir et al 2007;Pasumarthi and Fadel 2008).…”

Section: Discussionmentioning

confidence: 97%

Opposite roles of dopamine and orexin in quinpirole-induced excessive drinking: a rat model of psychotic polydipsia

et al. 2010

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“…Selective OXR-1 blockade was reported to reduce the ability of rats to discriminate visual signals in a two-lever sustained attention task (Boschen et al, 2009), and orexin inputs to the basal forebrain cholinergic system have been proposed to represent an anatomical substrate for the link between arousal and attention (Fadel and Burk, 2010). Although the rotarod is not comparable with a classical discrimination task, it is conceivable that rotarod performance requires a substantial level of attention from the rat to maintain stability on the rod, while it is rotating at increasing speed.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of the Dual Orexin Receptor Antagonist Almorexant and the GABAA-α1 Receptor Modulator Zolpidem, Alone or Combined with Ethanol, on Motor Performance in the Rat

Steiner

Lecourt

Strasser

et al. 2010

Neuropsychopharmacol

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Current insomnia treatments such as γ-aminobutyric acid (GABA) receptor modulators are associated with sedative and muscle-relaxant effects, which increase when drug intake is combined with alcohol. This study compared the novel sleep-enabling compound almorexant (ACT-078573-hydrochloride), a dual orexin receptor antagonist, with the positive GABA(A)-α1 receptor modulator zolpidem. Both compounds were administered alone or in combination with ethanol, and their effects on forced motor performance were determined in Wistar rats upon waking after treatment. To detect substance-induced sedation and myorelaxation, time spent on an accelerating rotating rod (rotarod) and forepaw grip strength were measured. Zolpidem (10, 30, and 100 mg/kg, p.o.) and ethanol (0.32, 1, and 1.5 g/kg, i.p.) dose-dependently decreased rotarod performance and grip strength, whereas almorexant (30, 100, and 300 mg/kg, p.o.) did not. Doses of ethanol (0.32 and 1 g/kg), which were ineffective when administered alone, showed interactions with zolpidem (10 and 30 mg/kg) leading to reduced rotarod performance and grip strength; in contrast, combination of ethanol (0.32 and 1 g/kg) with almorexant (100 and 300 mg/kg) did not reduce performance or grip strength below ethanol alone. We conclude that unlike zolpidem, almorexant does not interfere with forced motor performance or grip strength in the rat, nor does it further increase the sedative effects of ethanol. Our results suggest that the effect of almorexant can be immediately reversed to full alertness like under physiological sleep, and that almorexant is less likely to show strong sedation, excessive myorelaxation, or interaction with alcohol than commonly prescribed hypnotics such as zolpidem.

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Systemic and intrabasalis administration of the orexin-1 receptor antagonist, SB-334867, disrupts attentional performance in rats

Abstract: These findings suggest that orexins contribute to attentional processing, although neural circuits outside of basal forebrain corticopetal cholinergic neurons may mediate some of these effects.

Cited by 59 publications

References 62 publications

The role of hypocretin in driving arousal and goal-oriented behaviors

The role of hypocretin in driving arousal and goal-oriented behaviors

Opposite roles of dopamine and orexin in quinpirole-induced excessive drinking: a rat model of psychotic polydipsia

Differential Effects of the Dual Orexin Receptor Antagonist Almorexant and the GABAA-α1 Receptor Modulator Zolpidem, Alone or Combined with Ethanol, on Motor Performance in the Rat

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