The selective orexin 1 receptor antagonist SB-334867-A impairs acquisition and consolidation but not retrieval of spatial memory in Morris water maze
Introduction
A specific population of neurons located in the lateral and dorsomedial hypothalamus synthesize two neuropeptides, orexin-A (hypocretin-1) and orexin-B (hypocretin-2) [10], [26], [35], [36]. Both orexin-A and orexin-B are encoded by a single gene composed of two exons. The prepro-orexin messenger RNA (mRNA) encodes a 130-residue (rodent) or 131-residue (human) polypeptide, which has a typical secretory sequence and is cleaved to form mature orexin-A and orexin-B peptides [35], [37]. Orexinergic neurons widely project to the cerebral cortex, olfactory bulb, amygdala, septum, diagonal band of Broca, hippocampus, etc. [9], [10], [26], [30], [35]. The actions of these peptides are mediated by two membrane receptors, orexin 1 (OX1R), and orexin 2 (OX2R), that are coupled with G-proteins [35], [51]. While orexin-A has equal affinity at OX1R and OX2R, orexin-B has an appreciably greater (approximately 10-fold) affinity to OX2R [35], [41], [42]. In situ hybridization studies have shown that orexin receptors are expressed in some regions, in which dense orexin neuronal projections are observed. High levels of OX1R mRNA occur in the hippocampal formation (CA1, CA2, DG), tenia tecta, dorsal raphe nucleus and most prominently locus coeruleus (LC), while OX2R mRNA was found mainly in the cerebral cortex, nucleus accumbens, and subthalamic and paraventricular thalamic nuclei [22], [51]. The widespread projections of orexin containing neurons, coupled with the regional distribution of OX1R and OX2R, suggests that the endogenous orexins have diverse physiological functions including food intake [15], [35], arousal [9], sleep–waking cycle [31], [48], sleep disorder [17], drinking behavior [18], nociception [7], neuroendocrine functions [13], [19], [32], [45] and learning and memory [2], [4], [16], [46], [47]. Reports about the effect of orexins on learning and memory are controversial. Aou et al. have reported that i.c.v. administered orexin-A has produced memory impairment in water maze performance in a 2-day training protocol [4] but other reports show that i.c.v. administration of orexin-A and orexin-B facilitates avoidance learning in rats [46], [47]. Likewise, orexin-A improved learning and memory in SAMP8 mice: “an animal model of Alzheimer's disease” [16]. Also, it has been shown that orexin-A enhances normal long-term potentiation (LTP) in perforant path-dentate granule cell synapses in anesthetized rats [52]. Furthermore, our previous study has shown that blockade of CA1 region OX1Rs impaired memory processing in MWM task [2]. It has been reported that stimulation of the lateral hypothalamus area, the major source of orexinergic signaling, as well as various targets of orexinergic fibers such as the amygdala, LC and septum, modulates synaptic plasticity in the hippocampus [12], [29], [39], [53], a widely accepted cellular and molecular correlate of learning and memory [8], [10], [21].
The most potent and selective OX1R antagonist is SB-334867-A, which is at least 50-fold selective over OX2R [43]. Furthermore, this compound reaches maximal plasma and brain levels 0.5 h post-dosing and has a terminal elimination with half-life of approximately 4 h following systemic administration [14]. Therefore, SB-334867-A is increasingly being used as a tool to study not only receptor mediation of responses to administered peptides exogenously but also (when administered alone) to assess the physiological and behavioral significance of endogenous orexins [5], [33], [44]. However, it is likely that the systemic or i.c.v. administration of SB-334867-A may antagonize OX1Rs in many brain regions. Therefore, it cannot precisely assess the functions of specific region OX1Rs involved in learning and memory like dentate gyrus (DG), an integral neural substrate for spatial memory [20], [34], [49], [50]. Thus, in the present study, in order to avoid the nonspecific effects of systemic administration and extend the attempt for a better understanding of the functions of DG OX1Rs, we assessed the effects of intra-DG SB-334867-A treatment in three different memory processing stages on MWM task.
Section snippets
Animals
Ninety-five adult male albino Wistar rats (230–270 g) were obtained from Pasteur Institute, Iran. They were housed in a temperature (25 ± 2 °C) and humidity controlled room. The animals were maintained under a 12:12 h light/dark cycle, with lights on at 7:00 am. Food and water were provided ad libitum except for the periods of behavioral testing in MWM. The behavioral testing was done during the light phase. These animal experiments were carried out in accordance with recommendations from the
Experiment 1
The effects of intra-DG injection of SB-334867-A (1.5, 3, 6 μg/0.5 μl) or DMSO (0.5 μl) on acquisition in spatial information of MWM task was assessed. One-way ANOVA of the escape latency revealed significant differences between groups (F3,28 = 6.35; P = 0.002). Fig. 1A shows that SB-334867-A significantly increases escape latency in 1.5 (P < 0.05), 3 and 6 μg (P < 0.01) doses as compared with the DMSO group. The results of probe test have shown in Fig. 1B. One-way ANOVA revealed significant differences
Discussion
Our findings in the present study indicate: (1) There was no difference in the swimming speed of different doses of intra-DG administration of SB-334867-A in pre-training treated groups. (2) Pre-training administration of 3, 6 μg/0.5 μl SB-334 867-A but not 1.5 μg/0.5 μl could impair acquisition in MWM task. (3) Post-training administration of 3 and 6 μg/0.5 μl SB-334 867-A but not 1.5 μg/0.5 μl could impair consolidation in MWM task. (4) Fifteen minutes before probe trials, intra-DG administration of
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2022, Vitamins and HormonesCitation Excerpt :The beneficial or detrimental outcome of this receptor downregulation is under investigation, still, there is a report implying that in a hypoxia model of cultured rat hippocampal neurons, OXA increases hypoxia-induced neuronal damage via ERK 1/2 and involvement of PLCβ (Li et al., 2017). Orexin modulates synaptic transmission via predominant OX1Rs of the hippocampus (Akbari, Naghdi, & Motamedi, 2007). Recent studies have shown that OX1Rs couples with Gq/11 proteins, which increases protein kinase C (PKC) activity; and also associates with Gs proteins, increases protein kinase A (PKA) activity (Holmqvist et al., 2005), all of which leads to increases in the intracellular Ca2 + concentration (Kukkonen, Holmqvist, Ammoun, & Akerman, 2002) and facilitates the induction of LTP of the efficiency of excitatory transmission (Sil'kis, 2002).
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