Anxiety disorders are often associated with an inability to extinguish learned fear responses. The hypocretin/orexin system is involved in the regulation of emotional states and could also participate in the consolidation and extinction of aversive memories. Using hypocretin receptor-1 and hypocretin receptor-2 antagonists, hypocretin-1 and hypocretin-2 peptides, and hypocretin receptor-1 knockout mice, we investigated the role of the hypocretin system in cue- and context-dependent fear conditioning and extinction. Hypocretins were crucial for the consolidation of fear conditioning, and this effect was mainly observed in memories with a high emotional component. Notably, after the acquisition of fear memory, hypocretin receptor-1 blockade facilitated fear extinction, whereas hypocretin-1 administration impaired this extinction process. The extinction-facilitating effects of the hypocretin receptor-1 antagonist SB334867 were associated with increased expression of cFos in the basolateral amygdala and the infralimbic cortex. Intra-amygdala, but neither intra-infralimbic prefrontal cortex nor intra-dorsohippocampal infusion of SB334867 enhanced fear extinction. These results reveal a key role for hypocretins in the extinction of aversive memories and suggest that hypocretin receptor-1 blockade could represent a novel therapeutic target for the treatment of diseases associated with inappropriate retention of fear, such as post-traumatic stress disorder and phobias.

An understanding of the neurobiological mechanisms involved in the regulation of fear is essential for the development of new treatments for anxiety disorders, such as phobias, panic, and post-traumatic stress disorders (PTSD). Orexins, also known as hypocretins, are neuropeptides located exclusively in hypothalamic neurons that have extensive projections throughout the central nervous system. Although this system was initially believed to be primarily involved in the regulation of feeding behavior, recent studies have shown that orexins also modulate neural circuits implicated in the expression and extinction of fear memories. Here, we discuss recent findings involving orexins in anxiety disorders and current clinical trials using orexin ligands that could be applied to identify new therapies for diseases characterized by pathological fear.

These data demonstrate that hypocretin signaling acting on Hcrtr-1 in the PVN plays a crucial role in the expression of nicotine withdrawal.

Hypocretin/orexin signaling is critically involved in relapse to drug-seeking behaviors. In this study, we investigated the involvement of the hypocretin system in the reinstatement of nicotine-seeking behavior induced by nicotine-associated cues. Pretreatment with the hypocretin receptor-1 antagonist SB334867, but not with the hypocretin receptor-2 antagonist TCSOX229, attenuated cue-induced reinstatement of nicotine-seeking, which was associated with an activation of hypocretin neurons of the lateral and perifornical hypothalamic areas. In addition, relapse to nicotine-seeking increased the phosphorylation levels of GluR2-Ser880, NR1-Ser890, and p38 MAPK in the nucleus accumbens (NAc), but not in the prefrontal cortex. Notably, phosphorylation levels of NR1-Ser890 and p38 MAPK, but not GluR2-Ser880, were dependent on hypocretin receptor-1 activation. The intra-accumbens infusion of the protein kinase C (PKC) inhibitor NPC-15437 reduced nicotine-seeking behavior elicited by drug-paired cues consistent with the PKC-dependent phosphorylations of GluR2-Ser880 and NR1-Ser890. SB334867 failed to modify cue-induced reinstatement of food-seeking, which did not produce any biochemical changes in the NAc. These data identify hypocretin receptor-1 and PKC signaling as potential targets for the treatment of relapse to nicotine-seeking induced by nicotine-associated cues.

Nicotine exerts its psychopharmacological effects by activating the nicotinic acetylcholine receptor (nAChR), composed of alpha and/or beta subunits, giving rise to a diverse population of receptors with a distinct pharmacology. β4-containing (β4*) nAChRs are located almost exclusively in the habenulo-interpeduncular pathway. We examined the role of β4* nAChRs in the medial habenula (MHb) and the interpeduncular nucleus (IPN) in nicotine reinforcement using behavioral, electrophysiological, and molecular techniques in transgenic mice. Nicotine intravenous self-administration (IVSA) was lower in constitutive β4 knockout (KO) mice at all doses tested (7.5, 15, 30, and 60 μg/kg/infusion) compared with wild-type (WT) mice. In vivo microdialysis showed that β4KO mice have higher extracellular dopamine (DA) levels in the nucleus accumbens than in WT mice, and exhibit a differential sensitivity to nicotine-induced DA outflow. Furthermore, electrophysiological recordings in the ventral tegmental area (VTA) demonstrated that DA neurons of β4KO mice are more sensitive to lower doses of nicotine than that of WT mice. Re-expression of β4* nAChRs in IPN neurons fully restored nicotine IVSA, and attenuated the increased sensitivity of VTA DA neurons to nicotine. These findings suggest that β4* nAChRs in the IPN have a role in maintaining nicotine IVSA.

Emerging findings suggest the existence of a cross-talk between hypocretinergic and endocannabinoid systems. Although few studies have examined this relationship, the apparent overlap observed in the neuroanatomical distribution of both systems as well as their putative functions strongly point to the existence of such cross-modulation. In agreement, biochemical and functional studies have revealed the existence of heterodimers between CB1 cannabinoid receptor and hypocretin receptor-1, which modulates the cellular localization and downstream signaling of both receptors. Moreover, the activation of hypocretin receptor-1 stimulates the synthesis of 2-arachidonoyl glycerol culminating in the retrograde inhibition of neighboring cells and suggesting that endocannabinoids could contribute to some hypocretin effects. Pharmacological data indicate that endocannabinoids and hypocretins might have common physiological functions in the regulation of appetite, reward and analgesia. In contrast, these neuromodulatory systems seem to play antagonistic roles in the regulation of sleep/wake cycle and anxiety-like responses. The present review attempts to piece together what is known about this interesting interaction and describes its potential therapeutic implications.

Electrical enabling motor control (eEmc) through transcutaneous spinal cord stimulation is a non-invasive method that can modify the functional state of the sensory-motor system. We hypothesize that eEmc delivery, together with hand training, improves hand function in healthy subjects more than either intervention alone by inducing plastic changes at spinal and cortical levels. Ten voluntary participants were included in the following three interventions: (i) hand grip training, (ii) eEmc, and (iii) eEmc with hand training. Functional evaluation included the box and blocks test (BBT) and hand grip maximum voluntary contraction (MVC), spinal and cortical motor evoked potential (sMEP and cMEP), and resting motor thresholds (RMT), short interval intracortical inhibition (SICI), and F wave in the abductor pollicis brevis muscle. eEmc combined with hand training retained MVC and increased F wave amplitude and persistency, reduced cortical RMT and facilitated cMEP amplitude. In contrast, eEmc alone only increased F wave amplitude, whereas hand training alone reduced MVC and increased cortical RMT and SICI. In conclusion, eEmc combined with hand grip training enhanced hand motor output and induced plastic changes at spinal and cortical level in healthy subjects when compared to either intervention alone. These data suggest that electrical neuromodulation changes spinal and, perhaps, supraspinal networks to a more malleable state, while a concomitant use-dependent mechanism drives these networks to a higher functional state.

Study design: One of the problems that arise in spinal cord injury (SCI) is alteration in trunk control. Despite the need for standardized scales, these do not exist for evaluating trunk control in SCI. Objective: To propose and validate a trunk control test in individuals with SCI. Setting: National Institute of Rehabilitation, Mexico. Methods: The test was developed and later evaluated for reliability and criteria, content, and construct validity. Results: We carried out 531 tests on 177 patients and found high inter-and intra-rater reliability. In terms of criterion validity, analysis of variance demonstrated a statistically significant difference in the test score of patients with adequate or inadequate trunk control according to the assessment of a group of experts. A receiver operating characteristic curve was plotted for optimizing the instrument's cutoff point, which was determined at 13 points, with a sensitivity of 98% and a specificity of 92.2%. With regard to construct validity, the correlation between the proposed test and the spinal cord independence measure (SCIM) was 0.873 (P ¼ 0.001) and that with the evolution time was 0.437 (P ¼ 0.001). For testing the hypothesis with qualitative variables, the Kruskal-Wallis test was performed, which resulted in a statistically significant difference between the scores in the proposed scale of each group defined by these variables. Conclusion: It was proven experimentally that the proposed trunk control test is valid and reliable. Furthermore, the test can be used for all patients with SCI despite the type and level of injury.