INGEBI   02650
INSTITUTO DE INVESTIGACIONES EN INGENIERIA GENETICA Y BIOLOGIA MOLECULAR "DR. HECTOR N TORRES"
Unidad Ejecutora - UE
artículos
Título:
Dopamine D4 receptors modulate brain metabolic activity in the prefrontal cortex and cerebellum at rest and in response to methylphenidate
Autor/es:
MICHAELIDES M; PAASCAU J; GISPERT JD; FONTEINI D; GRANDY DK; WANG GJ; DESCO M; RUBINSTEIN M; VOLKOW ND; THANOS PK
Revista:
EUROPEAN JOURNAL OF NEUROSCIENCE
Editorial:
WILEY-BLACKWELL PUBLISHING, INC
Referencias:
Año: 2010 vol. 32 p. 668 - 676
ISSN:
0953-816X
Resumen:
Methylphenidate (MP) is widely used to treat attention deficit hyperactivity disorder (ADHD). Variable number of tandem repeats
polymorphisms in the dopamine D4 receptor (D4) gene have been implicated in vulnerability to ADHD and the response to MP. Here
we examined the contribution of dopamine D4 receptors (D4Rs) to baseline brain glucose metabolism and to the regional metabolic
responses to MP. We compared brain glucose metabolism (measured with micro-positron emission tomography and [18F]2-fluoro-
2-deoxy-d-glucose) at baseline and after MP (10 mg ⁄ kg, i.p.) administration in mice with genetic deletion of the D4. Images were
analyzed using a novel automated image registration procedure. Baseline D44) gene have been implicated in vulnerability to ADHD and the response to MP. Here
we examined the contribution of dopamine D4 receptors (D4Rs) to baseline brain glucose metabolism and to the regional metabolic
responses to MP. We compared brain glucose metabolism (measured with micro-positron emission tomography and [18F]2-fluoro-
2-deoxy-d-glucose) at baseline and after MP (10 mg ⁄ kg, i.p.) administration in mice with genetic deletion of the D4. Images were
analyzed using a novel automated image registration procedure. Baseline D418F]2-fluoro-
2-deoxy-d-glucose) at baseline and after MP (10 mg ⁄ kg, i.p.) administration in mice with genetic deletion of the D4. Images were
analyzed using a novel automated image registration procedure. Baseline D4d-glucose) at baseline and after MP (10 mg ⁄ kg, i.p.) administration in mice with genetic deletion of the D4. Images were
analyzed using a novel automated image registration procedure. Baseline D44
) ⁄ ) mice had lower metabolism in the prefrontal cortex
(PFC) and greater metabolism in the cerebellar vermis (CBV) than D4
+ ⁄ + and D4
+ ⁄ ) mice; when given MP, D4⁄ ) mice had lower metabolism in the prefrontal cortex
(PFC) and greater metabolism in the cerebellar vermis (CBV) than D4
+ ⁄ + and D4
+ ⁄ ) mice; when given MP, D44
+ ⁄ + and D4
+ ⁄ ) mice; when given MP, D4⁄ + and D4
+ ⁄ ) mice; when given MP, D4⁄ ) mice; when given MP, D4
) ⁄ ) mice increased
metabolism in the PFC and decreased it in the CBV, whereas in D4
+ ⁄ + and D4
+ ⁄ ) mice, MP decreased metabolism in the PFC and
increased it in the CBV. These findings provide evidence that D4Rs modulate not only the PFC, which may reflect the activation by
dopamine of D4Rs located in this region, but also the CBV, which may reflect an indirect modulation as D4Rs are minimally
expressed in this region. As individuals with ADHD show structural and ⁄ or functional abnormalities in these brain regions, the
association of ADHD with D4Rs may reflect its modulation of these brain regions. The differential response to MP as a function of
genotype could explain differences in brain functional responses to MP between patients with ADHD and healthy controls and
between patients with ADHD with different D4 polymorphisms.⁄ ) mice increased
metabolism in the PFC and decreased it in the CBV, whereas in D4
+ ⁄ + and D4
+ ⁄ ) mice, MP decreased metabolism in the PFC and
increased it in the CBV. These findings provide evidence that D4Rs modulate not only the PFC, which may reflect the activation by
dopamine of D4Rs located in this region, but also the CBV, which may reflect an indirect modulation as D4Rs are minimally
expressed in this region. As individuals with ADHD show structural and ⁄ or functional abnormalities in these brain regions, the
association of ADHD with D4Rs may reflect its modulation of these brain regions. The differential response to MP as a function of
genotype could explain differences in brain functional responses to MP between patients with ADHD and healthy controls and
between patients with ADHD with different D4 polymorphisms.4
+ ⁄ + and D4
+ ⁄ ) mice, MP decreased metabolism in the PFC and
increased it in the CBV. These findings provide evidence that D4Rs modulate not only the PFC, which may reflect the activation by
dopamine of D4Rs located in this region, but also the CBV, which may reflect an indirect modulation as D4Rs are minimally
expressed in this region. As individuals with ADHD show structural and ⁄ or functional abnormalities in these brain regions, the
association of ADHD with D4Rs may reflect its modulation of these brain regions. The differential response to MP as a function of
genotype could explain differences in brain functional responses to MP between patients with ADHD and healthy controls and
between patients with ADHD with different D4 polymorphisms.⁄ + and D4
+ ⁄ ) mice, MP decreased metabolism in the PFC and
increased it in the CBV. These findings provide evidence that D4Rs modulate not only the PFC, which may reflect the activation by
dopamine of D4Rs located in this region, but also the CBV, which may reflect an indirect modulation as D4Rs are minimally
expressed in this region. As individuals with ADHD show structural and ⁄ or functional abnormalities in these brain regions, the
association of ADHD with D4Rs may reflect its modulation of these brain regions. The differential response to MP as a function of
genotype could explain differences in brain functional responses to MP between patients with ADHD and healthy controls and
between patients with ADHD with different D4 polymorphisms.⁄ ) mice, MP decreased metabolism in the PFC and
increased it in the CBV. These findings provide evidence that D4Rs modulate not only the PFC, which may reflect the activation by
dopamine of D4Rs located in this region, but also the CBV, which may reflect an indirect modulation as D4Rs are minimally
expressed in this region. As individuals with ADHD show structural and ⁄ or functional abnormalities in these brain regions, the
association of ADHD with D4Rs may reflect its modulation of these brain regions. The differential response to MP as a function of
genotype could explain differences in brain functional responses to MP between patients with ADHD and healthy controls and
between patients with ADHD with different D4 polymorphisms.⁄ or functional abnormalities in these brain regions, the
association of ADHD with D4Rs may reflect its modulation of these brain regions. The differential response to MP as a function of
genotype could explain differences in brain functional responses to MP between patients with ADHD and healthy controls and
between patients with ADHD with different D4 polymorphisms.4 polymorphisms.