When Orexins Meet Cannabinoids: Bidirectional Functional Interactions.

A growing body of evidence suggests the existence of biochemical and functional interactions between the endocannabinoid and orexin systems. Cannabinoid and orexin receptors have been shown to form heterodimers in agreement with the overlapping distribution of both receptors in several brain areas, and the activation of common intracellular signaling pathways, such as the MAP kinase cascade. The activation of orexin receptors induces the synthesis of the endocannabinoid 2-arachidonoyl glycerol suggesting that the endocannabinoid system participates in some physiological functions of orexins. Indeed, functional interactions between these two systems have been demonstrated in several behavioral responses including nociception, reward and food intake. The present review is focused on the latest developments in cannabinoid-orexin cross-modulation and the implications of this interesting interaction.pre-print455 K

THC exposure during adolescence does not modify nicotine reinforcing effects and relapse in adult male mice.

Rationale: Cannabis use is typically initiated during adolescence, and different studies suggest that adolescent cannabinoid exposure may increase the risk for drug addiction in adulthood. Objectives: This study investigated the effects of adolescent exposure to the main psychoactive component of cannabis, Δ9-tetrahydrocannabinol (THC), in the reinforcing properties of nicotine in adult male mice. Possible alterations in relapse to nicotine-seeking behaviour in adult animals due to THC adolescent exposure were also evaluated. Methods: Adolescent mice were exposed to escalating doses of THC from PND35 to PND49. When mice reached adulthood (PND70), surgical procedures were applied for further behavioural evaluation. Nicotine self-administration sessions were conducted consecutively for 10 days. Following extinction, mice were tested for cue- and stress-induced reinstatement of nicotine-seeking behaviour. Results: Adolescent THC treatment did not modify acquisition and extinction of nicotine self-administration in adulthood. Moreover, THC exposure did not alter relapse to nicotine seeking induced by stress or nicotine-associated cues. Conclusions: These results suggest that a history of exposure to THC during adolescence under these particular conditions does not modify the reinforcing effects and seeking behaviour of nicotine in the adult period.pre-print256 K

Facilitation of Contextual Fear Extinction by Orexin-1 Receptor Antagonism Is Associated with the Activation of Specific Amygdala Cell Subpopulations.

Background: Orexins are hypothalamic neuropeptides recently involved in the regulation of emotional memory. The basolateral amygdala, an area orchestrating fear memory processes, appears to be modulated by orexin transmission during fear extinction. However, the neuronal types within the basolateral amygdala involved in this modulation remain to be elucidated. Methods: We used retrograde tracing combined with immunofluorescence techniques in mice to identify basolateral amygdala projection neurons and cell subpopulations in this brain region influenced by orexin transmission during contextual fear extinction consolidation. Results: Treatment with the orexin-1 receptor antagonist SB334867 increased the activity of basolateral amygdala neurons projecting to infralimbic medial prefrontal cortex during fear extinction. GABAergic interneurons expressing calbindin, but not parvalbumin, were also activated by orexin-1 receptor antagonism in the basolateral amygdala. Conclusions: These data identify neuronal circuits and cell populations of the amygdala associated with the facilitation of fear extinction consolidation induced by the orexin-1 receptor antagonist SB334867.post-print1256 K

Targeting the orexin/hypocretin system for the treatment of neuropsychiatric and neurodegenerative diseases: from animal to clinical studies

Orexins (also known as hypocretins) are neuropeptides located exclusively in hypothalamic neurons that have extensive projections throughout the central nervous system and bind two different G protein-coupled receptors (OX1R and OX2R). Since its discovery in 1998, the orexin system has gained the interest of the scientific community as a potential therapeutic target for the treatment of different pathological conditions. Considering previous basic science research, a dual orexin receptor antagonist, suvorexant, was the first orexin agent to be approved by the US Food and Drug Administration to treat insomnia. In this review, we discuss and update the main preclinical and human studies involving the orexin system with several psychiatric and neurodegenerative diseases. This system constitutes a nice example of how basic scientific research driven by curiosity can be the best route to the generation of new and powerful pharmacological treatments

When Spinal Neuromodulation Meets Sensorimotor Rehabilitation: Lessons Learned From Animal Models to Regain Manual Dexterity After a Spinal Cord Injury

Electrical neuromodulation has strongly hit the foundations of spinal cord injury and repair. Clinical and experimental studies have demonstrated the ability to neuromodulate and engage spinal cord circuits to recover volitional motor functions lost after the injury. Although the science and technology behind electrical neuromodulation has attracted much of the attention, it cannot be obviated that electrical stimulation must be applied concomitantly to sensorimotor rehabilitation, and one would be very difficult to understand without the other, as both need to be finely tuned to efficiently execute movements. The present review explores the difficulties faced by experimental and clinical neuroscientists when attempting to neuromodulate and rehabilitate manual dexterity in spinal cord injured subjects. From a translational point of view, we will describe the major rehabilitation interventions employed in animal research to promote recovery of forelimb motor function. On the other hand, we will outline some of the state-of-the-art findings when applying electrical neuromodulation to the spinal cord in animal models and human patients, highlighting how evidences from lumbar stimulation are paving the path to cervical neuromodulation

Cervical Electrical Neuromodulation Effectively Enhances Hand Motor Output in Healthy Subjects by Engaging a Use-Dependent Intervention

Altres ajuts: Fundació La Marató de TV3 2017 (201713.31) to G.G.-A.; Premi Beca "Mike Lane" 2019-Castellers de la Vila de Gràcia to H.K.; and National Institutes of Health Grant 1R01 NS102920-01A1 to Y.G.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

Transcutaneous electrical neuromodulation of the cervical spinal cord depends both on the stimulation intensity and the degree of voluntary activity for training. A pilot study

Electrical enabling motor control (eEmc) through transcutaneous spinal cord stimulation offers promise in improving hand function. However, it is still unknown which stimulus intensity or which muscle force level could be better for this improvement. Nine healthy individuals received the following interventions: (i) eEmc intensities at 80%, 90% and 110% of abductor pollicis brevis motor threshold combined with hand training consisting in 100% handgrip strength; (ii) hand training consisting in 100% and 50% of maximal handgrip strength combined with 90% eEmc intensity. The evaluations included box and blocks test (BBT), maximal voluntary contraction (MVC), F wave persistency, F/M ratio, spinal and cortical motor evoked potentials (MEP), recruitment curves of spinal MEP and cortical MEP and short-interval intracortical inhibition. The results showed that: (i) 90% eEmc intensity increased BBT, MVC, F wave persistency, F/M ratio and cortical MEP recruitment curve; 110% eEmc intensity increased BBT, F wave persistency and cortical MEP and recruitment curve of cortical MEP; (ii) 100% handgrip strength training significantly modulated MVC, F wave persistency, F/M wave and cortical MEP recruitment curve in comparison to 50% handgrip strength. In conclusion, eEmc intensity and muscle strength during training both influence the results for neuromodulation at the cervical level

Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1.

Anxiety and stress disorders are often characterized by an inability to extinguish learned fear responses. Orexins/ hypocretins are involved in the modulation of aversive memories, and dysregulation of this system may contribute to the aetiology of anxiety disorders characterized by pathological fear. The mechanisms by which orexins regulate fear are unknown. Here we investigated the role of the endogenous cannabinoid system in the impaired fear extinction induced by orexin-A (OXA) in male mice. The selective inhibitor of 2-arachidonoylglycerol (2-AG) biosynthesis O7460 abolished the fear extinction deficits induced by OXA. Accordingly, increased 2- AG levels were observed in the amygdala and hippocampus of mice treated with OXA that do not extinguish fear, suggesting that high levels of this endocannabinoid are related to poor extinction. Impairment of fear extinction induced by OXA was associated with increased expression of CB2 cannabinoid receptor (CB2R) in microglial cells of the basolateral amygdala. Consistently, the intra-amygdala infusion of the CB2R antagonist AM630 completely blocked the impaired extinction promoted by OXA. Microglial and CB2R expression depletion in the amygdala with PLX5622 chow also prevented these extinction deficits. These results show that overactivation of the orexin system leads to impaired fear extinction through 2-AG and amygdalar CB2R. This novel mechanism could be of relevance for the development of novel potential approaches to treat diseases associated with inappropriate retention of fear, such as post-traumatic stress disorder, panic anxiety and phobias.post-print3418 K

Cervical electrical neuromodulation effectively enhances hand motor output in healthy subjects by engaging a use-dependent intervention

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