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Aiding and Abetting Anhedonia: Impact of Inflammation on the Brain and Pharmacological Implications.
Lucido, Michael J; Bekhbat, Mandy; Goldsmith, David R; Treadway, Michael T; Haroon, Ebrahim; Felger, Jennifer C; Miller, Andrew H.
Afiliación
  • Lucido MJ; Emory Behavioral Immunology Program, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia (M.J.L., M.B., D.R.G., E.H., J.C.F., A.H.M.); and Department of Psychology, Emory University, Atlanta, Georgia (M.T.T.).
  • Bekhbat M; Emory Behavioral Immunology Program, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia (M.J.L., M.B., D.R.G., E.H., J.C.F., A.H.M.); and Department of Psychology, Emory University, Atlanta, Georgia (M.T.T.).
  • Goldsmith DR; Emory Behavioral Immunology Program, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia (M.J.L., M.B., D.R.G., E.H., J.C.F., A.H.M.); and Department of Psychology, Emory University, Atlanta, Georgia (M.T.T.).
  • Treadway MT; Emory Behavioral Immunology Program, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia (M.J.L., M.B., D.R.G., E.H., J.C.F., A.H.M.); and Department of Psychology, Emory University, Atlanta, Georgia (M.T.T.).
  • Haroon E; Emory Behavioral Immunology Program, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia (M.J.L., M.B., D.R.G., E.H., J.C.F., A.H.M.); and Department of Psychology, Emory University, Atlanta, Georgia (M.T.T.).
  • Felger JC; Emory Behavioral Immunology Program, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia (M.J.L., M.B., D.R.G., E.H., J.C.F., A.H.M.); and Department of Psychology, Emory University, Atlanta, Georgia (M.T.T.).
  • Miller AH; Emory Behavioral Immunology Program, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia (M.J.L., M.B., D.R.G., E.H., J.C.F., A.H.M.); and Department of Psychology, Emory University, Atlanta, Georgia (M.T.T.) amill02@emory.edu.
Pharmacol Rev ; 73(3): 1084-1117, 2021 07.
Article en En | MEDLINE | ID: mdl-34285088
Exogenous administration of inflammatory stimuli to humans and laboratory animals and chronic endogenous inflammatory states lead to motivational deficits and ultimately anhedonia, a core and disabling symptom of depression present in multiple other psychiatric disorders. Inflammation impacts neurotransmitter systems and neurocircuits in subcortical brain regions including the ventral striatum, which serves as an integration point for reward processing and motivational decision-making. Many mechanisms contribute to these effects of inflammation, including decreased synthesis, release and reuptake of dopamine, increased synaptic and extrasynaptic glutamate, and activation of kynurenine pathway metabolites including quinolinic acid. Neuroimaging data indicate that these inflammation-induced neurotransmitter effects manifest as decreased activation of ventral striatum and decreased functional connectivity in reward circuitry involving ventral striatum and ventromedial prefrontal cortex. Neurocircuitry changes in turn mediate nuanced effects on motivation that include decreased willingness to expend effort for reward while maintaining the ability to experience reward. Taken together, the data reveal an inflammation-induced pathophysiologic phenotype that is agnostic to diagnosis. Given the many mechanisms involved, this phenotype represents an opportunity for development of novel and/or repurposed pharmacological strategies that target inflammation and associated cellular and systemic immunometabolic changes and their downstream effects on the brain. To date, clinical trials have failed to capitalize on the unique nature of this transdiagnostic phenotype, leaving the field bereft of interpretable data for meaningful clinical application. However, novel trial designs incorporating established targets in the brain and/or periphery using relevant outcome variables (e.g., anhedonia) are the future of targeted therapy in psychiatry. SIGNIFICANCE STATEMENT: Emerging understanding of mechanisms by which peripheral inflammation can affect the brain and behavior has created unprecedented opportunities for development of pharmacological strategies to treat deficits in motivation including anhedonia, a core and disabling symptom of depression well represented in multiple psychiatric disorders. Mechanisms include inflammation and cellular and systemic immunometabolism and alterations in dopamine, glutamate, and kynurenine metabolites, revealing a target-rich environment that nevertheless has yet to be fully exploited by current clinical trial designs and drugs employed.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Anhedonia Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Pharmacol Rev Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Anhedonia Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Pharmacol Rev Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos