Dr. Fernando Berrendero Díaz   fernando.berrendero@ufv.es

Cristina Izquierdo Luengo
María Ponce Renilla

RESEARCH LINES
Neurobiological mechanisms involved in fear regulation
Neurobiology of nicotine and cannabinoid addiction
Physiological functions of orexins/hypocretins
Effects of adolescent exposure to synthetic cannabinoids in Spice/k2

Anxiety-related diseases, especially phobias, panic disorders, and post-traumatic stress syndrome (PTSD), are characterized by resistance to fear extinction, or by inadequate responses to aversive situations. The current prevalence of anxiety disorders varies between 14% and 31% in developed countries, constituting, together with mood disorders, the most abundant psychiatric pathologies. At present, there is a clear need for the development of new, more effective and safer pharmacological tools for the treatment of anxiety disorders.

The orexinergic/hypocretinergic system is constituted by two neuropeptides, orexins A and B (also called hypocretins 1 and 2), and their G protein-coupled receptors (OX1R and OX2R). Orexin-expressing neurons represent a small population located exclusively in the lateral hypothalamus. However, these neurons have extensive projections throughout the brain. Thus, orexins are involved in a wide variety of physiological processes such as the regulation of wake/sleep cycles, feeding, reinforcement processes and stress. In addition, it has recently been suggested that orexins are involved in the regulation of emotional memory according to a dense projection of these neurons to different areas of the limbic system.

Our research group has studied during the last years the role of these neuropeptides in the regulation of addictive processes and emotional memory. Thus, we have demonstrated that orexins are involved in the addictive properties of nicotine and cannabinoids. Moreover, the orexinergic system modulates fear regulation. Antagonism of this system facilitates fear extinction, whereas administration of orexin-A induces the opposite effect, i.e. resistance to extinction. Therefore, different ligands with orexinergic receptor antagonist properties could have potential utility for the treatment of addiction and anxiety disorders.

Izquierdo-Luengo C, Ten-Blanco M, Ponce-Renilla M, Perezzan R, Pereda-Pérez I, Berrendero F
Adolescent exposure to the Spice/K2 cannabinoid JWH-018 impairs sensorimotor gating and alters cortical perineuronal nets in a sex-dependent manner
Translational Psychiatry 13: 176 (2023)

Ten-Blanco M, Flores Á, Cristino L, Pereda-Pérez I, Berrendero F
Targeting the orexin/hypocretin system for the treatment of neuropsychiatric and neurodegenerative diseases: From animal to clinical studies.
Frontiers in Neuroendocrinology 69: 101066 (2023)

Ten-Blanco M, Pereda-Pérez I, Izquierdo-Luengo C, Berrendero F. “CB2 cannabinoid receptor expression is increased in 129S1/SvImJ mice: behavioral consequences”. Frontiers in Pharmacology 13: 975020 (2022).

Ten-Blanco M, Flores Á, Pereda-Pérez I, Piscitelli F, Izquierdo-Luengo C, Cristino L, Romero J, Hillard CJ, Maldonado R, Di Marzo V, Berrendero F Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1 Biomedicine & Pharmacotherapy 149: 112925 (2022)

Saravia R, Ten-Blanco M, Pereda-Pérez I, Berrendero F. New insights in the involvement of the endocannabinoid system and natural cannabinoids in nicotine dependence. International Journal of Molecular Sciences 22(24): 13316 (2021)

Flores A, Maldonado R, Berrendero F. THC exposure during adolescence does not modify nicotine reinforcing effects and relapse in adult male mice. Psychopharmacology 237: 801-809 (2020).

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, in: 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).