Peripheral biomarkers of cognitive response to dopamine receptor agonist treatment

Abstract

Rationale: 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.

Methodology: 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.

Fig. 1

Relationships between peripheral biomarkers and cognitive/clinical measures. a Associations between peripheral DRD3 mRNA levels in blood cells and pramipexole-induced changes in accuracy in working memory; b Association between peripheral COMT mRNA levels in blood cells and severity of stimulant dependence, as reflected by the number of DSM-IV criteria satisfied for the diagnosis of dependence on stimulant drugs. Levels of mRNA were not detectable in five blood samples (two stimulant users, three controls)