Acute effects of cocaine and cannabis on reversal learning as a function of COMT and DRD2 genotype

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Abstract

Rationale

Long-term cannabis and cocaine use has been associated with impairments in reversal learning. However, how acute cannabis and cocaine administration affect reversal learning in humans is not known.

Objective

In this study, we aimed to establish the acute effects of administration of cannabis and cocaine on valence-dependent reversal learning as a function of DRD2 Taq1A (rs1800497) and COMT Val108/158Met (rs4680) genotype.

Methods

A double-blind placebo-controlled randomized 3-way crossover design was used. Sixty-one regular poly-drug users completed a deterministic reversal learning task under the influence of cocaine, cannabis, and placebo that enabled assessment of both reward- and punishment-based reversal learning.

Results

Proportion correct on the reversal learning task was increased by cocaine, but decreased by cannabis. Effects of cocaine depended on the DRD2 genotype, as increases in proportion correct were seen only in the A1 carriers, and not in the A2/A2 homozygotes. COMT genotype did not modulate drug-induced effects on reversal learning.

Conclusions

These data indicate that acute administration of cannabis and cocaine has opposite effects on reversal learning. The effects of cocaine, but not cannabis, depend on interindividual genetic differences in the dopamine D2 receptor gene.

Electronic supplementary material

The online version of this article (doi:10.1007/s00213-015-4141-5) contains supplementary material, which is available to authorized users.

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Most cited references 84

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Specific impairments of planning.

T Shallice (1982)

An information-processing model is outlined that predicts that performance on non-routine tasks can be impaired independently of performance on routine tasks. The model is related to views on frontal lobe functions, particularly those of Luria. Two methods of obtaining more rigorous tests of the model are discussed. One makes use of ideas from artificial intelligence to derive a task heavily loaded on planning abilities. A group of patients with left anterior lesions has a specific deficit on the task. Subsidiary investigations support the inference that this is a planning impairment.

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Pharmacokinetics and pharmacodynamics of cannabinoids.

Franjo Grotenhermen (2003)

Delta(9)-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for non-receptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15-30 minutes, and taper off within 2-3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30-90 minutes, reach their maximum after 2-3 hours and last for about 4-12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial. They are reported to be low in humans and do not preclude legitimate therapeutic use of cannabis-based drugs. Properties of cannabis that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, sedation, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and induction of apoptosis in cancer cells.

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Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain.

Jingshan Chen, Barbara K. Lipska, Nader Halim … (2004)

Catechol-O-methyltransferase (COMT) is a key enzyme in the elimination of dopamine in the prefrontal cortex of the human brain. Genetic variation in the COMT gene (MIM 116790) has been associated with altered prefrontal cortex function and higher risk for schizophrenia, but the specific alleles and their functional implications have been controversial. We analyzed the effects of several single-nucleotide polymorphisms (SNPs) within COMT on mRNA expression levels (using reverse-transcriptase polymerase chain reaction analysis), protein levels (using Western blot analysis), and enzyme activity (using catechol methylation) in a large sample (n = 108) of postmortem human prefrontal cortex tissue, which predominantly expresses the -membrane-bound isoform. A common coding SNP, Val158Met (rs4680), significantly affected protein abundance and enzyme activity but not mRNA expression levels, suggesting that differences in protein integrity account for the difference in enzyme activity between alleles. A SNP in intron 1 (rs737865) and a SNP in the 3' flanking region (rs165599)--both of which have been reported to contribute to allelic expression differences and to be associated with schizophrenia as part of a haplotype with Val--had no effect on mRNA expression levels, protein immunoreactivity, or enzyme activity. In lymphocytes from 47 subjects, we confirmed a similar effect on enzyme activity in samples with the Val/Met genotype but no effect in samples with the intron 1 or 3' SNPs. Separate analyses revealed that the subject's sex, as well as the presence of a SNP in the P2 promoter region (rs2097603), had small effects on COMT enzyme activity. Using site-directed mutagenesis of mouse COMT cDNA, followed by in vitro translation, we found that the conversion of Leu at the homologous position into Met or Val progressively and significantly diminished enzyme activity. Thus, although we cannot exclude a more complex genetic basis for functional effects of COMT, Val is a predominant factor that determines higher COMT activity in the prefrontal cortex, which presumably leads to lower synaptic dopamine levels and relatively deleterious prefrontal function.

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Author and article information

Contributors

Desirée B. Spronk: desireespronk@gmail.com

Journal

Journal ID (nlm-ta): Psychopharmacology (Berl)

Journal ID (iso-abbrev): Psychopharmacology (Berl.)

Title: Psychopharmacology

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0033-3158

ISSN (Electronic): 1432-2072

Publication date (Electronic): 17 November 2015

Publication date PMC-release: 17 November 2015

Publication date (Print): 2016

Volume: 233

Pages: 199-211

Affiliations

[ ]Department of Psychiatry, Radboud university medical center, Nijmegen, The Netherlands

[ ]Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands

[ ]Expert Center for Chronic Fatigue, Radboud university medical center, Nijmegen, The Netherlands

[ ]Department of Clinical Psychology, Leiden Institute for Brain and Cognition, Leiden University, Leiden, The Netherlands

[ ]Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands

[ ]Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands

[ ]Pompestichting for Forensic Psychiatry, Nijmegen, The Netherlands

[ ]Department of Criminal Law and Criminology, Radboud University, Nijmegen, The Netherlands

Article

Publisher ID: 4141

DOI: 10.1007/s00213-015-4141-5

PMC ID: 4700084

PubMed ID: 26572896

SO-VID: ecf781c0-08f2-4ce8-b561-6f259c29e79a

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 20 March 2015

Date accepted : 20 September 2015

Custom metadata

ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: cocaine,cannabis,thc,reversal learning,comt val108/158met,drd2 taq1a,polymorphism,individual differences,human

Data availability:

ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: cocaine, cannabis, thc, reversal learning, comt val108/158met, drd2 taq1a, polymorphism, individual differences, human

Acute effects of cocaine and cannabis on reversal learning as a function of COMT and DRD2 genotype

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Abstract

Rationale

Objective

Methods

Results

Conclusions

Electronic supplementary material

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RNA drug delivery

Most cited references 84

Specific impairments of planning.

Pharmacokinetics and pharmacodynamics of cannabinoids.

Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain.

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