In vivo imaging of cerebral dopamine D3 receptors in alcoholism.
Animal studies support the role of the dopamine D3 receptor (DRD3) in alcohol reinforcement or liking. Sustained voluntary alcohol drinking in rats has been associated with an upregulation of striatal DRD3 gene expression and selective blockade of DRD3 reduces ethanol preference, consumption, and cue-induced reinstatement. In vivo measurement of DRD3 in the living human brain has not been possible until recently owing to a lack of suitable tools. In this study, DRD3 status was assessed for the first time in human alcohol addiction. Brain DRD3 availability was compared between 16 male abstinent alcohol-dependent patients and 13 healthy non-dependent age-matched males using the DRD3-preferring agonist positron emission tomography (PET) radioligand [(11)C]PHNO with and without blockade with a selective DRD3 antagonist (GSK598809 60 mg p.o.). In striatal regions of interest, where the [(11)C]PHNO PET signal represents primarily DRD2 binding, no differences were seen in [(11)C]PHNO binding between the groups at baseline. However, baseline [(11)C]PHNO binding was higher in alcohol-dependent patients in hypothalamus (VT: 16.5 ± 4 vs 13.7 ± 2.9, p = 0.040), a region in which the [(11)C]PHNO signal almost entirely reflects DRD3 availability. The reductions in regional receptor binding (VT) following a single oral dose of GSK598809 (60 mg) were consistent with those observed in previous studies across all regions. There were no differences in regional changes in VT following DRD3 blockade between the two groups, indicating that the regional fractions of DRD3 are similar in the two groups, and the increased [(11)C]PHNO binding in the hypothalamus in alcohol-dependent patients is explained by elevated DRD3 in this group. Although we found no difference between alcohol-dependent patients and controls in striatal DRD3 levels, increased DRD3 binding in the hypothalamus of alcohol-dependent patients was observed. This may be relevant to the development of future therapeutic strategies to treat alcohol abuse.
Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK.
David
D
Erritzoe
1] Clinical Imaging Centre, GlaxoSmithKline, London, UK [2] FMRIB Centre, Department of Clinical Neurology, University of Oxford, Oxford, UK.
Andri
A
Tziortzi
Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK.
David
D
Bargiela
1] Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK [2] Clinical Imaging Centre, GlaxoSmithKline, London, UK.
Alessandro
A
Colasanti
Clinical Imaging Centre, GlaxoSmithKline, London, UK.
Graham E
GE
Searle
1] Clinical Imaging Centre, GlaxoSmithKline, London, UK [2] Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
Roger N
RN
Gunn
Clinical Imaging Centre, GlaxoSmithKline, London, UK.
John D
JD
Beaver
Department of Imaging, Charing Cross Hospital, London, UK.
Adam
A
Waldman
Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK.
David J
DJ
Nutt
CEDD for Neurosciences, GlaxoSmithKline, Verona, Italy.
Massimo
M
Bani
CEDD for Neurosciences, GlaxoSmithKline, Verona, Italy.
Emilio
E
Merlo-Pich
Clinical Imaging Centre, GlaxoSmithKline, London, UK.
Eugenii A
EA
Rabiner
Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK.
Anne
A
Lingford-Hughes
D000328:Adult; D000367:Age Factors; D000437:Alcoholism / Q000097:blood / Q000000981:diagnostic imaging / Q000473:pathology*; D053961:Azabicyclo Compounds / Q000494:pharmacology; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000097:blood / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010080:Oxazoles / Q000494:pharmacology; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D011569:Psychiatric Status Rating Scales; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012907:Smoking; D055815:Young Adult
D053961:Azabicyclo Compounds; D018492:Dopamine Antagonists; C000594007:GSK598809; D010078:Oxazines; D010080:Oxazoles; D050637:Receptors, Dopamine D3; C042631:naxagolide