Orexin neuropeptides modulate the hippocampal-dependent memory through basolateral amygdala interconnections.

Orexin neuropeptides have functional roles in hippocampal-dependent memory formation via the consolidation and retrieval of passive avoidance and spatial memories. The effects of these neuropeptides have been confirmed on the induction of long-term potentiation (LTP). The orexinergic system seems to have modulatory effects by sending projection fibers to several brain parts, such as the hippocampus and amygdala. Orexin neuropeptides activate the neural circuits of the basolateral amygdala during different arousal events with various emotional loads. Therefore, this system plays a vital role in creating appropriate behavioral reactions and responses particular to the situation. This review aimed to report new progression and advances in the hippocampus function in memory by focusing on its relationship with the amygdala through the orexinergic system.

The role of interaction between orexin receptors and ß2 adrenergic receptors in basolateral amygdala in dentate gyrus synaptic plasticity in male rats.

Orexin receptors expressed in basolateral amygdala (BLA) have been proposed for memory processing and hippocampal plasticity. There are several investigations about the effect of the adrenergic system in BLA on memory enhancement. However, there is no information about the molecular basis of this effect. Adrenergic and orexinergic fibers are found in BLA. In this study, the effects of both adrenergic and orexinergic systems were investigated on the amygdala function. To this end, the selective beta 2 adrenergic agonist (clenbuterol) and orexin receptors' antagonists (OX1R and OX2R, SB-334867-A and TCS-OX2-29, respectively) were administered into the BLA, then the high frequency stimulation (200-Hz) was applied to the perforant pathway and the synaptic plasticity of the dentate granular cells was studied in anaesthetized rats. Clenbuterol injection into the BLA enhanced the population spike (PS) component of LTP in the dentate gyrus (DG), as compared to that observed after dimethyl sulfoxide treatment. In addition, after orexin 1 or 2 receptor antagonists (SB-334867-A and TCS-OX2-29, respectively) injecting into the BLA, the enhancing effect of clenbuterol on PS was reduced. Moreover, the population excitatory post-synaptic potential also decreased in the SB-clenbuterol and TCS- clenbuterol experimental groups. However, the PS amplitude was also decreased in the group treated only by SB or TCS relative to the clenbuterol treated group. The PS amplitude or EPSP slope in the groups treated by both application of orexin receptors' antagonists and clenbuterol was considerably lower relative to the groups treated only by orexin receptors' antagonists. It is concluded that the BLA orexinergic system modulates hippocampal plasticity in relation with the adrenergic system.

The modulation of the spatial reference memory by the orexinergic system of the dorsal raphe nucleus.

The dorsal raphe nucleus (DRN) is a brainstem nucleus involved in the pathophysiology of the depression, through its serotoninergic innervation. Furthermore, depressive symptoms in patients are also associated with some memory and sleep complaints. Anatomical evidence confirmed the presence of projections from the lateral hypothalamus to serotonergic neurons of the dorsal raphe nucleus (DRN). These projection fibers release orexin neuropeptides which play roles in the spatial memory. Both of the orexinergic receptors are widely distributed in dorsal raphe nucleus. Therefore, the present work was aimed to assess the probable roles of orexin 1 and 2 receptors using an orexin 1 receptor antagonist, SB-334867-A, and an orexin 2 receptor antagonist, TCS-OX2-29 in the DRN on the retrieval, and consolidation phases of spatial reference memory in the Morris water maze (MWM) task. The results demonstrated that blocking orexin 1 receptors in the DRN impairs the process of memory consolidation in the spatial MWM via increasing in the time of the escape latency of the probe day. Blocking these receptors did not affect the retrieval phase of MWM learning. Furthermore, blocking of the orexin 2 receptors in this area did not affect neither consolidation nor retrieval phases of the memory. In conclusion, orexin 1 receptors in the DRN play major roles in the consolidation of the spatial reference memory in rats.

The Effect of Orexin Receptor Antagonism on Quinpirole-Induced Compulsive-Like Checking Behavior in Rats.

The orexinergic system supposedly plays a role in stress circuits for arousing behaviors during anxiety, suggesting that it may play a role also in neural circuits mediating the compulsive behavior characteristic of obsessive-compulsive disorder (OCD). This study aims to investigate the roles of the orexinergic system in the development of OCD behaviors, using as preparation the induction of compulsive checking by chronic treatment with the D2/D3 agonist, quinpirole. Repeated injections of quinpirole (0.5 mg/kg, twice per week for a total of 10 injections) were used to induce compulsive checking. In separate groups of rats, OX1R (SB334867-A; 10 µg i.c.v) and OX2R (TCS-OX2-29; 10 µg i.c.v) receptor antagonists were co-administered together with quinpirole. Checking behavior in a large open field was measured after the first, fifth, and tenth injections of the drugs. SB334867-A attenuated checking behavior and the level of anxiety. TCS-OX2-29 administration ameliorated anxiety but did not block the development of compulsive checking. Orexin 1 receptors seem to play a more critical role than orexin 2 receptors in the induction of compulsive checking. Considering that the quinpirole sensitization model of OCD involves activation of dopamine systems and sensitization to quinpirole, it is suggested that neural interaction between orexigenic and dopamine systems may be important in the pathogenesis of OCD.

Modulation of long-term and short-term plasticity in the dentate gyrus granule cells by activating the ß-adrenergic receptors of the basolateral amygdala.

The beta-adrenergic receptors of the basolateral amygdala (BLA) are involved in modulating emotional memory formation in the hippocampus. The molecular mechanisms of this involvement are still unclear. In this study, we investigate the effects of the beta-adrenergic receptors of the BLA involvements during the major cellular mechanisms that underlie memory formation in hippocampal sub-regions. Wistar rats were injected with the selective beta receptor agonist, clenbuterol (15 ng/0.5 µl) bilaterally into the BLA. Then, the long-term potentiation (LTP) and the paired-pulse responses were recorded. Control rats were injected by saline at the same volume. Our data indicated that the injection of clenbuterol into the BLA area enhanced the amplitude of the population spike (PS) but not the slope of the excitatory postsynaptic potential (EPSP). In addition, short-term plasticity in the dentate gyrus (DG) region was significantly changed at 500 ms inter-pulse interval. These results suggest that the activation of the beta-adrenergic receptors of the BLA can improve LTP induction, which depends on the short-term plasticity with a mechanism related to the GABAergic transmission. Thus, it can be concluded that the adrenergic system of the BLA engages with long-term and short-term plasticity.

Orexin 1 and orexin 2 receptor antagonism in the basolateral amygdala modulate long-term potentiation of the population spike in the perforant path-dentate gyrus-evoked field potential in rats.

Involvement of amygdalo-hippocampal substructures in patients with narcolepsy due to deficiencies in the orexinergic system, and the presence of hippocampus-dependent memory impairments in this disorder, have led us to investigate the effects of orexin 1 and 2 receptor antagonism in the basolateral amygdala (BLA) on long-term potentiation (LTP) of dentate gyrus (DG) granular cells. We used a 200-Hz high-frequency stimulation protocol in anesthetized rats. We studied the long-term synaptic plasticity of perforant path-dentate gyrus granule cells following the inactivation of orexin receptors before and after tetanic stimulation. LTP of the DG population spike was attenuated in the presence of orexin 1 and 2 receptor antagonism (treatment with SB-334867-A and TCS-OX2-29, respectively) in the BLA when compared to that observed following treatment with dimethyl sulfoxide (DMSO). However, the population excitatory post-synaptic potentials were not affected. Moreover, when orexin 1 and 2 receptors in the BLA were blocked after LTP induction, there were no differences between the DMSO and treatment groups. Our findings suggest that the orexinergic system of the BLA plays a modulatory role in the regulation of hippocampal plasticity in rats.

The effect of orexin 1 and orexin 2 receptors antagonisms in the basolateral amygdala on memory processing in a passive avoidance task.

There is an extensive evidence concerning basolateral amygdala (BLA) function to hippocampal memory processing. However, few researches have addressed the orexinergic system roles in this modulation. Then, the present study aims at investigating the action of orexin 1 and 2 receptors in BLA on passive avoidance (PA) learning. Wistar male rats (n=79) were trained to avoid foot shock in one type of PA task. The rats were injected bilaterally into BLA, a selective orexin 1 receptor antagonist, SB-334867-A (3, 6, 12µg/0.5µl), and an orexin 2 receptor antagonist, TCS-OX2-29 (2.5, 5, 10µg/0.5µl), after training or before retrieval of the inhibitory avoidance task. Control rats received dimethyl sulfoxide at the same volume. The amount of learning was assessed 24h later. The time of the first entrance to the dark compartment and the total time spending in the light compartment were measured as criteria for the avoidance memory. The results showed that consolidation and retrieval were significantly impaired by SB-334867-A administration into BLA in 3, 6 and 12µg/0.5µl. However, TCS-OX2-29 in 2.5µg/0.5µl could not influence neither consolidation nor retrieval. The TCS-OX2-29 administration into BLA impaired memory retrieval in 5 and 10µg/0/5µl but not the consolidation. It gives the impression that orexinergic system of the BLA plays an important role in regulation of memory processing and learning in the rats.