title: Peripheral biomarkers of cognitive response to dopamine receptor agonist treatment.
abstract: BACKGROUND
  Using biological markers to objectively measure addiction severity or to identify individuals who might benefit most from pro-cognitive treatment could potentially revolutionize neuropsychopharmacology. We investigated the use of dopamine receptor mRNA levels in circulating blood cells as predictors of cognitive response following dopamine agonist treatment, and as biomarkers of the severity of stimulant drug dependence.
  
  
  METHODS
  We employed a double-blind, placebo-controlled cross-over design, administering a single dose of the selective dopamine D(2/3) receptor agonist pramipexole (0.5 mg) to increase dopamine transmission in one session and a placebo treatment in another session in 36 volunteers. Half the volunteers had a formal diagnosis of stimulant dependence, while half had no psychiatric history. Participants performed neurocognitive tests from the CANTAB battery on both occasions, and stimulant-dependent individuals rated drug craving using visual analog scales. Whole-blood mRNA levels were measured for three dopamine-related genes: DRD3 and DRD4 (dopamine receptors), and catechol-O-methyltransferase (COMT; a dopamine catabolic enzyme).
  
  
  RESULTS
  Stimulant users performed worse than healthy volunteers on the cognitive tests. The variation in peripheral dopamine D(3) receptor mRNA expression explained over one quarter of the variation in response to pramipexole on the spatial working memory test across all participants. The severity of stimulant dependence was also significantly associated with peripheral COMT mRNA expression in stimulant users.
  
  
  CONCLUSIONS
  Peripheral expression of dopamine-related genes may be useful as a biomarker of cognitive response to dopamine agonist drugs and of severity of addiction to dopamine-releasing stimulant drugs.
authors.affiliation: Department of Psychiatry, University of Cambridge, Herchel Smith Building for Brain and Mind Sciences, Cambridge Biomedical Campus, Cambridge, CB2 0SZ, UK. ke220@cam.ac.uk
authors.forename: Karen D
authors.initials: KD
authors.lastname: Ersche
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Roiser
authors.forename: Mark
authors.initials: M
authors.lastname: Lucas
authors.forename: Enrico
authors.initials: E
authors.lastname: Domenici
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Robbins
authors.forename: Edward T
authors.initials: ET
authors.lastname: Bullmore
mesh_terms: D000328:Adult; D019969:Amphetamine-Related Disorders / Q000097:blood*; D052160:Benzothiazoles / Q000097:blood / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood*; D002394:Catechol O-Methyltransferase / Q000235:genetics; D019970:Cocaine-Related Disorders / Q000097:blood*; D003071:Cognition / Q000187:drug effects*; D018592:Cross-Over Studies; D018491:Dopamine Agonists / Q000097:blood / Q000494:pharmacology*; D004311:Double-Blind Method; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D009483:Neuropsychological Tests; D000077487:Pramipexole; D011237:Predictive Value of Tests; D011388:Prolactin / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors / Q000235:genetics; D050638:Receptors, Dopamine D4 / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D052160:Benzothiazoles; D015415:Biomarkers; C493593:DRD3 protein, human; C493599:DRD4 protein, human; D018491:Dopamine Agonists; D012333:RNA, Messenger; D050637:Receptors, Dopamine D3; D050638:Receptors, Dopamine D4; D000077487:Pramipexole; D011388:Prolactin; D002394:Catechol O-Methyltransferase