RESUMEN
Endocannabinoids are released 'on-demand' on the basis of physiological need, and can be pharmacologically augmented by inhibiting their catabolic degradation. The endocannabinoid anandamide is degraded by the catabolic enzyme fatty acid amide hydrolase (FAAH). Anandamide is implicated in the mediation of fear behaviors, including fear extinction, suggesting that selectively elevating brain anandamide could modulate plastic changes in fear. Here we first tested this hypothesis with preclinical experiments employing a novel, potent and selective FAAH inhibitor, AM3506 (5-(4-hydroxyphenyl)pentanesulfonyl fluoride). Systemic AM3506 administration before extinction decreased fear during a retrieval test in a mouse model of impaired extinction. AM3506 had no effects on fear in the absence of extinction training, or on various non-fear-related measures. Anandamide levels in the basolateral amygdala were increased by extinction training and augmented by systemic AM3506, whereas application of AM3506 to amygdala slices promoted long-term depression of inhibitory transmission, a form of synaptic plasticity linked to extinction. Further supporting the amygdala as effect-locus, the fear-reducing effects of systemic AM3506 were blocked by intra-amygdala infusion of a CB1 receptor antagonist and were fully recapitulated by intra-amygdala infusion of AM3506. On the basis of these preclinical findings, we hypothesized that variation in the human FAAH gene would predict individual differences in amygdala threat-processing and stress-coping traits. Consistent with this, carriers of a low-expressing FAAH variant (385A allele; rs324420) exhibited quicker habituation of amygdala reactivity to threat, and had lower scores on the personality trait of stress-reactivity. Our findings show that augmenting amygdala anandamide enables extinction-driven reductions in fear in mouse and may promote stress-coping in humans.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Amígdala del Cerebelo/fisiología , Ácidos Araquidónicos/fisiología , Endocannabinoides/fisiología , Extinción Psicológica/fisiología , Miedo/fisiología , Adaptación Psicológica/fisiología , Adulto , Alcanosulfonatos/administración & dosificación , Alcanosulfonatos/farmacología , Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/genética , Amígdala del Cerebelo/efectos de los fármacos , Animales , Ácidos Araquidónicos/metabolismo , Antagonistas de Receptores de Cannabinoides/administración & dosificación , Antagonistas de Receptores de Cannabinoides/farmacología , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Endocannabinoides/metabolismo , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Miedo/efectos de los fármacos , Miedo/psicología , Femenino , Neuroimagen Funcional , Estudios de Asociación Genética , Habituación Psicofisiológica/efectos de los fármacos , Habituación Psicofisiológica/fisiología , Humanos , Masculino , Ratones , Microinyecciones , Persona de Mediana Edad , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Personalidad/genética , Personalidad/fisiología , Fenoles/administración & dosificación , Fenoles/farmacología , Piperidinas/administración & dosificación , Piperidinas/farmacología , Polimorfismo de Nucleótido Simple , Alcamidas Poliinsaturadas/metabolismo , Pirazoles/administración & dosificación , Pirazoles/farmacología , RimonabantRESUMEN
While a large body of literature documents the impairing effect of anxiety on cognition, performing a demanding task was shown to be effective in reducing anxiety. Here we explored the mechanisms of this anxiolytic effect by examining how a pharmacological challenge designed to improve attentional processes influences the interplay between the neural networks engaged during anxiety and cognition. Using a double-blind between-subject design, we pharmacologically manipulated working memory (WM) using a single oral dose of 20 mg methylphenidate (MPH, cognitive enhancer) or placebo. Fifty healthy adults (25/drug group) performed two runs of a WM N-back task in a 3 T magnetic resonance imaging scanner. This task comprised a low (1-Back) and high (3-Back) WM load, which were performed in two contexts, safety or threat of shocks (induced-anxiety). Analyses revealed that (1) WM accuracy was overall improved by MPH and (2) MPH (vs. placebo) strengthened the engagement of regions within the fronto-parietal control network (FPCN) and reduced the default mode network (DMN) deactivation. These MPH effects predominated in the most difficult context, i.e., threat condition, first run (novelty of the task), and 3-Back task. The facilitation of neural activation can be interpreted as an expansion of cognitive resources, which could foster both the representation and integration of anxiety-provoking stimuli as well as the top-down regulatory processes to protect against the detrimental effect of anxiety. This mechanism might establish an optimal balance between FPCN (cognitive processing) and DMN (emotion regulation) recruitment.