TY - JOUR
T1 - Dopamine D4 receptors modulate brain metabolic activity in the prefrontal cortex and cerebellum at rest and in response to methylphenidate
AU - Michaelides, Michael
AU - Pascau, Javier
AU - Gispert, Juan Domingo
AU - Delis, Foteini
AU - Grandy, David K.
AU - Wang, Gene Jack
AU - Desco, Manuel
AU - Rubinstein, Marcelo
AU - Volkow, Nora D.
AU - Thanos, Panayotis K.
PY - 2010/8
Y1 - 2010/8
N2 - 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 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, D 4-/- 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.
AB - 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 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, D 4-/- 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.
KW - 2-[F]-fluoro-2-deoxy-d-glucose
KW - Attention deficit hyperactivity disorder
KW - Mice
KW - Micro-positron emission tomography
KW - Positron emission tomography
UR - http://www.scopus.com/inward/record.url?scp=77955753194&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77955753194&partnerID=8YFLogxK
U2 - 10.1111/j.1460-9568.2010.07319.x
DO - 10.1111/j.1460-9568.2010.07319.x
M3 - Article
C2 - 20646063
AN - SCOPUS:77955753194
SN - 0953-816X
VL - 32
SP - 668
EP - 676
JO - European Journal of Neuroscience
JF - European Journal of Neuroscience
IS - 4
ER -