Neuropharmacological Modulation of N-methyl-D-aspartate, Noradrenaline and Endocannabinoid Receptors in Fear Extinction Learning: Synaptic Transmission and Plasticity

Abstract

Learning to recognize and respond to potential threats is crucial for survival. Pavlovian threat conditioning represents a key paradigm for investigating the neurobiological mechanisms of fear learning. In this review, we address the role of specific neuropharmacological adjuvants that act on neurochemical synaptic transmission, as well as on brain plasticity processes implicated in fear memory. We focus on novel neuropharmacological manipulations targeting glutamatergic, noradrenergic, and endocannabinoid systems, and address how the modulation of these neurobiological systems affects fear extinction learning in humans. We show that the administration of N-methyl-D-aspartate (NMDA) agonists and modulation of the endocannabinoid system by fatty acid amide hydrolase (FAAH) inhibition can boost extinction learning through the stabilization and regulation of the receptor concentration. On the other hand, elevated noradrenaline levels dynamically modulate fear learning, hindering long-term extinction processes. These pharmacological interventions could provide novel targeted treatments and prevention strategies for fear-based and anxiety-related disorders.

Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models

“…In this multidisciplinary endeavor, neuropharmacological research plays a pivotal role. The study of how drugs and compounds interact with the intricate neural networks present in preclinical models provides a deeper understanding of potential therapeutic agents [62][63][64][65][66][67][68][69]. These insights guide the future development of pharmacological interventions that can target the specific molecular pathways implicated in neuropsychiatric conditions.…”

Neurodegeneration in Cognitive Impairment and Mood Disorders for Experimental, Clinical and Translational Neuropsychiatry

“…Hence, there is a requirement for new and inventive methods, such as non-invasive brain stimulation, that can regulate neural activity and plasticity in a secure and reversible manner [ 17 , 18 , 19 , 20 , 21 ]. The field is rapidly evolving, with a focus on identifying new avenues of clinical research, elucidating potential mechanisms for the therapeutic effects of non-invasive brain stimulation (NIBS) and exploring the potential synergy between different stimulation protocols and pharmacological interventions [ 22 , 23 , 24 , 25 , 26 , 27 ].…”

Antidepressant-induced mania in panic disorder: a single-case study of clinical and functional connectivity characteristics

“…To our knowledge, research on the clinical and neurological characteristics of patients with anxiety disorders who develop mania after therapy is lacking. Significant advancements in understanding the pathogenesis, making accurate diagnoses, and investigating novel therapeutics for neuropsychiatric disorders can be achieved through the combined efforts of clinical, experimental, and computational medicine ( 13 , 14 ). There are several findings regarding the clinical characteristics of patients who develop mania during their first depressive episode ( 15 ).…”