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

• Published in: International journal of molecular sciences Vol. 24; no. 6; p. 5926
• Main Authors: Battaglia, Simone, Di Fazio, Chiara, Vicario, Carmelo M, Avenanti, Alessio
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21.03.2023; MDPI
• Subjects: Adjuvants; Adrenergic receptors; Aspartate; brain plasticity; Brain research; Cannabinoid receptors; Conditioning (learning); Endangered & extinct species; Endocannabinoid system; Endocannabinoids - physiology; enzyme fatty acid amide hydrolase (FAAH); Enzymes; Extinction, Psychological - physiology; Fatty acids; Fatty-acid amide hydrolase; Fear; Fear & phobias; Fear - physiology; Fear conditioning; Glutamate receptors; glutamatergic receptor N-methyl-D-aspartate (NMDA); Glutamatergic transmission; Glutamic acid receptors (ionotropic); Humans; Learning; Memory; Methyl aspartate; N-Methyl-D-aspartic acid receptors; N-Methylaspartate; Nervous system; Neural plasticity; Neurobiology; Neuromodulation; neuropharmacology; Noradrenaline; noradrenaline (NA); Norepinephrine; Phenols; Physiology; Plastic properties; Recall; Receptors, N-Methyl-D-Aspartate - metabolism; Review; Synaptic plasticity; synaptic receptors; Synaptic transmission; Synaptic Transmission - physiology; noradrenaline (NA); threat learning; fear extinction learning; fear learning; neuropharmacology; synaptic receptors; enzyme fatty acid amide hydrolase (FAAH); glutamatergic receptor N-methyl-D-aspartate (NMDA); brain plasticity
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24065926

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.