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Controlled Clinical Trial
. 2016 Dec;10(4):1254-1263.
doi: 10.1007/s11682-015-9488-z.

Cannabis and cocaine decrease cognitive impulse control and functional corticostriatal connectivity in drug users with low activity DBH genotypes

J G Ramaekers  1 , J H van Wel  2 , D Spronk  3 , B Franke  3   4 , G Kenis  5 , S W Toennes  6 , K P C Kuypers  2 , E L Theunissen  2 , P Stiers  2 , R J Verkes  3   7
Affiliations
Controlled Clinical Trial

Cannabis and cocaine decrease cognitive impulse control and functional corticostriatal connectivity in drug users with low activity DBH genotypes

J G Ramaekers et al. Brain Imaging Behav. 2016 Dec.

Abstract

The dopamine β-hydroxylase (DβH) enzyme transforms dopamine into noradrenaline. We hypothesized that individuals with low activity DBH genotypes (rs1611115 CT/TT) are more sensitive to the influence of cannabis and cocaine on cognitive impulse control and functional connectivity in the limbic 'reward' circuit because they experience a drug induced hyperdopaminergic state compared to individuals with high activity DBH genotypes (rs1611115 CC). Regular drug users (N = 122) received acute doses of cannabis (450 μg/kg THC), cocaine HCl 300 mg and placebo. Cognitive impulse control was assessed by means of the Matching Familiar Figures Test (MFFT). Resting state fMRI was measured in a subset of participants to determine functional connectivity between the nucleus accumbens (NAc) and (sub)cortical areas. The influence of cannabis and cocaine on impulsivity and functional connectivity significantly interacted with DBH genotype. Both drugs increased cognitive impulsivity in participants with CT/TT genotypes but not in CC participants. Both drugs also reduced functional connectivity between the NAc and the limbic lobe, prefrontal cortex, striatum and thalamus and primarily in individuals with CT/TT genotypes. Correlational analysis indicated a significant negative association between cognitive impulsivity and functional connectivity in subcortical areas of the brain. It is concluded that interference of cannabis and cocaine with cognitive impulse control and functional corticostriatal connectivity depends on DBH genotype. The present data provide a neural substrate and behavioral mechanism by which drug users can progress to drug seeking and may also offer a rationale for targeted pharmacotherapy in chronic drug users with high risk DBH genotypes.

Keywords: Cannabis; Cocaine; DBH genotype; Fuctional connectivity; Impulse control.

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Conflict of interest statement

The authors report no financial interests or potential conflicts of interest. Informed consent All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, and the applicable revisions at the time of the investigation. Informed consent was obtained from all patients for being included in the study.

Figures

Fig. 1
Fig. 1
Mean (se) performance in the MFFT during drug and placebo challenges averaged over DBH groups and for carriers of CC and CT/TT genotypes separately (CAN = cannabis, COC = cocaine, PLA = placebo); * = p < 0.05 (drug-placebo contrasts across genotypes); + = p < 0.05 (drug x DBH genotype interaction)
Fig. 2
Fig. 2
NAc related functional connectivity decrements following cannabis and cocaine in the left and right hemisphere, relative to placebo. Shown are thresholded (t = 2.34) Z-score maps of functional connectivity (a) averaged over DBH genotypes and (b) for individuals with CC and CT/TT genotypes separately (CAN = cannabis, COC = cocaine; left = left; planes are made at MNI seed position)
Fig. 3
Fig. 3
NAc related functional connectivity decrements as a function of cannabis x DBH and cocaine x DBH interactions in the left (LH) and right hemisphere (RH), (CAN = cannabis, COC = cocaine; left = left; planes are made at MNI seed position)
Fig. 4
Fig. 4
Significant correlations in the striatum and the thalamus between functional connectivity and the MFFT measure of impulsivity in each treatment condition (CAN = cannabis, COC = cocaine, PLA = placebo), across DBH genotypes
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