SUMMARY OF THE RESEARCH PROJECT

Diseases related to anxiety, specifically phobias, panic disorders, and posttraumatic stress disorder (PTSD) are characterised by resistance to fear extinction, or an inadequate response against various aversive situations. The current prevalence of anxiety disorders varies between 14% and 31% among developed countries, constituting together with mood alterations, the most frequent psychiatric pathologies. There is an evident need to develop more effective and safe new pharmacological tools to treat anxiety disorders.

The orexinergic/hypocretinergic system is composed of two neuropeptides, orexins A and B (also known as hypocretins 1 and 2), and their G-protein coupled receptors (OX1R y OX2R). Neurons expressing orexin represent a small population located exclusively in the lateral hypothalamus. However, these neurons have extensive projections throughout the brain. It is because of this, that orexins are involved in a wide range of physiological processes such as wake-sleep cycle regulation, food intake, reinforcement and stress processes. In addition, it has been recently suggested that orexins are involved in the regulation of emotional memories as per the dense projection of these neurons to different areas of the limbic system.

In the last few years, our research group has studied the role of these neuropeptides in the regulation of addictive processes and emotional memory. In doing so, we have demonstrated that orexins participate in the additive properties of nicotine and cannabinoids. Moreover, the orexinergic system modulates regulation to fear. The antagonism of this system facilitates fear extinction, while the administration of orexin-A induces the opposite effect, resistance to extinction. Therefore, different ligands with antagonistic properties to orexinergic receptors could potentially be used to treat addiction and anxiety disorders.

PROJECTS over the last 7 years:

Research project funded by the Ministry of Economy, Industry and Competitiveness (Ministerio de Economia, Industria y Competitividad – MINECO) (SAF2017-85299-R) entitled: “Orexins/Hypocretins and aversive memory: neurobiological mechanisms and potential use in animal models of resistance to fear extinction” (2018-2020).

Research project funded by the Government Delegation for the National Plan on Drugs (Delegacion del Gobierno para el Plan Nacional sobre Drogas) (2014I019) entitled: “Exposure to cannabinoids during adolescence and its influence in regulation of aversive memories and associative reinforcement: role of the hypocretinergic system” (2015-2018).

Research project funded by Healthcare Research funds (Fondo de Investigaciones Sanitarias – FIS) (13/00042) entitled: “Role of hypocretins/orexins in the consolidation and extinction of aversive memories” (2014-2016).

PUBLICATIONS over the last 7 years:

Saravia R, Ten-Blanco M, Julià-Hernández M, Gagliano H, Andero R, Armario A, Maldonado R, Berrendero F Concomitant THC and stress adolescent exposure induces impaired fear extinction and related neurobiological changes in adulthood Neuropharmacology 144: 345-357 (2019).

Saravia R, Ten-Blanco M, Grande MT, Maldonado R, Berrendero F. Anti-inflammatory agents for smoking cessation? Focus on cognitive deficits associated with nicotine withdrawal in male mice. Brain, Behavior, and Immunity 75: 228-239 (2019).

Berrendero F, Flores Á, Robledo P. When orexins meet cannabinoids: bidirectional functional interactions. Biochemical Pharmacology 157: 43-50 (2018).

Flores Á, Herry C, Maldonado R, Berrendero F. Facilitation of contextual fear extinction by orexin-1 receptor antagonism is associated with the activation of specific amygdala cell subpopulations. International Journal of Neuropsychopharmacology 20: 654-659 (2017).

Saravia R, Flores A, Plaza-Zabala A, Busquets-García A, Pastor A, de la Torre R, Di Marzo V, Marsicano G, Ozaita A, Maldonado R., Berrendero F. CB1 cannabinoid receptors mediate cognitive deficits and structural plasticity changes during nicotine withdrawal. Biological Psychiatry 81: 625-634 (2017).

Flores A, Maldonado R, Berrendero F. Hypocretins/orexins and addiction: role in cannabis dependence, en: The Handbook of Cannabis and Related Pathologies: Biology, Diagnosis, Treatment, and Pharmacology. Edited by Victor R. Preedy. Academic Press (533-542) (2017).

Flores A, Julià-Hernández M, Maldonado R, Berrendero F. Involvement of the orexin/hypocretin system in the pharmacological effects induced by D9-tetrahydrocannabinol. British Journal of Pharmacology 173: 1381-1392 (2016).

Flores A., Saravia R., Maldonado R., Berrendero F. Orexins and fear: implications for the treatment of anxiety disorders. Trends in Neurosciences 38: 550-559 (2015).

Flores A., Maldonado R., Berrendero F. The hypocretin/orexin receptor-1 as a novel target to modulate cannabinoid reward. Biological Psychiatry 75: 499-507 (2014).

Flores A, Valls-Comamala V, Costa G, Saravia R, Maldonado R, Berrendero F. The hypocretin/orexin system mediates the extinction of fear memories. Neuropsychopharmacology 39: 2732-2741 (2014).

Maldonado R, Robledo P, Berrendero F. Endocannabinoid system and drug addiction: new insights from mutant mice approaches. Current Opinion in Neurobiology 23: 480-486 (2013).

Plaza-Zabala A., Flores A., Martín-García E., Saravia R., Maldonado R., Berrendero F. A role for hypocretin/orexin receptor-1 in cue-induced reinstatement of nicotine-seeking behavior. Neuropsychopharmacology 38: 1724-1736 (2013).

Flores A., Maldonado R., Berrendero F. Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far. Frontiers in Neuroscience 7: 256 (2013).

Plaza-Zabala A, Li X, Milovanovic M, Loweth JA, Maldonado R, Berrendero F, Wolf ME. An investigation of interactions between hypocretin/orexin signaling and glutamate receptor surface expression in the rat nucleus accumbens under basal conditions and after cocaine exposure. Neurosciences Letters 557 Pt B: 101-106 (2013).