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Glutamatergic dysfunction leads to a hyper-dopaminergic phenotype through deficits in short-term habituation: a mechanism for aberrant salience.
Panayi, Marios C; Boerner, Thomas; Jahans-Price, Thomas; Huber, Anna; Sprengel, Rolf; Gilmour, Gary; Sanderson, David J; Harrison, Paul J; Walton, Mark E; Bannerman, David M.
Afiliación
  • Panayi MC; Department of Experimental Psychology, University of Oxford, Tinsley Building, Mansfield Road, Oxford, OX1 3SR, UK. marios.panayi@nih.gov.
  • Boerner T; Wellcome Centre for Integrative Neuroimaging, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK. marios.panayi@nih.gov.
  • Jahans-Price T; National Institute on Drug Abuse Intramural Research Program, 251 Bayview Blvd., Baltimore, MD, 21224, USA. marios.panayi@nih.gov.
  • Huber A; Department of Experimental Psychology, University of Oxford, Tinsley Building, Mansfield Road, Oxford, OX1 3SR, UK.
  • Sprengel R; Department of Experimental Psychology, University of Oxford, Tinsley Building, Mansfield Road, Oxford, OX1 3SR, UK.
  • Gilmour G; Wellcome Centre for Integrative Neuroimaging, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
  • Sanderson DJ; Department of Psychiatry, University of Oxford, Oxford, OX3 7JX, UK.
  • Harrison PJ; Max Planck Institute for Medical Research, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany.
  • Walton ME; Lilly Centre for Cognitive Neuroscience, Discovery Biology, Lilly Research Centre, Lilly UK, Windlesham, Surrey, UK.
  • Bannerman DM; Department of Psychology, Durham University, Durham, UK.
Mol Psychiatry ; 28(2): 579-587, 2023 02.
Article en En | MEDLINE | ID: mdl-36460723
ABSTRACT
Psychosis in disorders like schizophrenia is commonly associated with aberrant salience and elevated striatal dopamine. However, the underlying cause(s) of this hyper-dopaminergic state remain elusive. Various lines of evidence point to glutamatergic dysfunction and impairments in synaptic plasticity in the etiology of schizophrenia, including deficits associated with the GluA1 AMPAR subunit. GluA1 knockout (Gria1-/-) mice provide a model of impaired synaptic plasticity in schizophrenia and exhibit a selective deficit in a form of short-term memory which underlies short-term habituation. As such, these mice are unable to reduce attention to recently presented stimuli. In this study we used fast-scan cyclic voltammetry to measure phasic dopamine responses in the nucleus accumbens of Gria1-/- mice to determine whether this behavioral phenotype might be a key driver of a hyper-dopaminergic state. There was no effect of GluA1 deletion on electrically-evoked dopamine responses in anaesthetized mice, demonstrating normal endogenous release properties of dopamine neurons in Gria1-/- mice. Furthermore, dopamine signals were initially similar in Gria1-/- mice compared to controls in response to both sucrose rewards and neutral light stimuli. They were also equally sensitive to changes in the magnitude of delivered rewards. In contrast, however, these stimulus-evoked dopamine signals failed to habituate with repeated presentations in Gria1-/- mice, resulting in a task-relevant, hyper-dopaminergic phenotype. Thus, here we show that GluA1 dysfunction, resulting in impaired short-term habituation, is a key driver of enhanced striatal dopamine responses, which may be an important contributor to aberrant salience and psychosis in psychiatric disorders like schizophrenia.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Dopamina / Habituación Psicofisiológica Límite: Animals Idioma: En Revista: Mol Psychiatry Asunto de la revista: BIOLOGIA MOLECULAR / PSIQUIATRIA Año: 2023 Tipo del documento: Article País de afiliación: Reino Unido

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Dopamina / Habituación Psicofisiológica Límite: Animals Idioma: En Revista: Mol Psychiatry Asunto de la revista: BIOLOGIA MOLECULAR / PSIQUIATRIA Año: 2023 Tipo del documento: Article País de afiliación: Reino Unido