Sadly, Mr. Meyer remarked that he does not wish to waste Ms. Aniston’s time, but if it is any consolation to Ms. Aniston (assuming she is in need of consoling), it may be that Mr. Meyer has the dopamine receptor 4 with a seven repeat allele. That would render him almost physiologically incapable of not seeking novelty, regardless of Ms. Aniston’s attributes.
John Mayer: I Didn’t Want to Waste Her Time via TMZ.com
This post is about additional research demonstrating the striking behavioral effect of the 7-repeat allele of dopamine receptor 4, as demonstrated by recent papers on smoking (it’s harder to quit when you have this allele because you enjoy it more), and being irritable (people with this allele are more irritable).
Dopamine receptors seem to always be popping up when you study behavioral genetics of dysfunctional behavior. No wonder – dopamine gives you a rush, and when your dopamine receptors (the places which dopamine sticks to on the cell) are messed up, the dopamine can’t do it’s work. (See the Wikipedia article which explains the dopamine receptors 1-5.) Here are our previous posts relating to dopamine.
Dopamine receptor 4 is sort of the bad boy of dopamine receptors. Variants been correlated with thrill seeking-novelty demanding behavior, ADHD, smoking, drinking and generally carrying on. This has something of an epigenetic twist — yet again, another example where little bits of DNA are within an allele. Where the dopamine receptor gene has extra pieces of DNA the dopamine receptor does not bind dopamine as efficiently (as the receptors who have the plain vanilla gene). Where it takes extra effort to bind dopamine, the person requires more dopamine to feel the rush. So you get in a bad mood, and do something even more foolhardy in order to get the thrill — like, smoke, drink, have loads of sex, be a daredevil, thrill seeking, pick fights — whatever floats your boat in order to get the “dopamine rush.”
Interestingly, the baddest boy allelic variants are found with highest frequency in populations which can be considered the most inquisitive — the earliest migrators. The Dopamine receptor 4 -7 repeat allele is estimated to have arisen prior to the upper Paleolithic era (
40,000–50,000 years ago). So, there was positive selection for novelty seeking — those who were the earliest human explorers, during the ice age. (See the colorful database here, discussed in this post).
And yet again, the 7-repeat allele – the one with 7 extra pieces of DNA in the gene – the one found in the Vikings, Visigoths, Amazonians and various other war-like populations who were probably leaders among the earliest human migrations — makes it tough to quit smoking (see the papers from Perkins et al., here and here) and interact with serotonin related genes to make you extra grumpy, see here.
So, although I don’t know Mr. Meyer (and not to pick on him, he’s just a recent example in the news), he may be totally correct in not wishing to waste Ms. Aniston’s time if she wants someone who will not seek novelty and he has the 7-repeat allele. Perhaps before he gets involved with another person he should have his genome checked and at least give the other person fair warning.
Abstracts cited reproduced below
Am J Hum Genet. 2004 May;74(5):931-44. Epub 2004 Apr 9.
The genetic architecture of selection at the human dopamine receptor D4 (DRD4)
gene locus.
Wang E, Ding YC, Flodman P, Kidd JR, Kidd KK, Grady DL, Ryder OA, Spence MA,
Swanson JM, Moyzis RK.
Department of Biological Chemistry, University of California at Irvine, Irvine,
CA 92697, USA.
Associations of the seven-repeat (7R) allele of the human dopamine receptor D4
(DRD4) gene with both the personality trait of novelty seeking and attention
deficit/hyperactivity disorder have been reported. Recently, on the basis of the
unusual DNA sequence organization of the DRD4 7R 48-bp tandem repeat (VNTR), we
proposed that the 7R allele originated as a rare mutational event that increased
to high frequency by positive selection. We now have resequenced the entire DRD4
locus from 103 individuals homozygous for 2R, 4R, or 7R variants of the VNTR, a
method developed to directly estimate haplotype diversity. DNA from individuals
of African, European, Asian, North and South American, and Pacific Island
ancestry were used. 4R/4R homozygotes exhibit little linkage disequilibrium (LD)
over the region examined, with more polymorphisms observed in DNA samples from
African individuals. In contrast, the evidence for strong LD surrounding the 7R
allele is dramatic, with all 7R/7R individuals (including those from Africa)
exhibiting the same alleles at most polymorphic sites. By intra-allelic
comparison at 18 high-heterozygosity sites spanning the locus, we estimate that
the 7R allele arose prior to the upper Paleolithic era (approximately 40000-50000
years ago). Further, the pattern of recombination at these polymorphic sites is
the pattern expected for selection acting at the 7R VNTR itself, rather than at
an adjacent site. We propose a model for selection at the DRD4 locus consistent
with these observed LD patterns and with the known biochemical and physiological
differences between receptor variants.
PMCID: PMC1181986
PMID: 15077199 [PubMed - indexed for MEDLINE]
Related Links
Evidence of positive selection acting at the human dopamine receptor D4 gene
locus. [Proc Natl Acad Sci U S A. 2002] PMID:11756666
High prevalence of rare dopamine receptor D4 alleles in children diagnosed with
attention-deficit hyperactivity disorder. [Mol Psychiatry. 2003] PMID:12808433
Novelty seeking and the dopamine D4 receptor gene (DRD4) revisited in Asians:
haplotype characterization and relevance of the 2-repeat allele. [Am J Med Genet
B Neuropsychiatr Genet. 2007] PMID:17474081
D4 dopamine-receptor (DRD4) alleles and novelty seeking in substance-dependent,
personality-disorder, and control subjects. [Am J Hum Genet. 1997] PMID:9345090
Dopamine receptor D4 (DRD4) gene in Han Chinese children with
attention-deficit/hyperactivity disorder (ADHD): increased prevalence of the
2-repeat allele. [Am J Med Genet B Neuropsychiatr Genet. 2005] PMID:15578612
The association of 5-HTTLPR and DRD4 VNTR polymorphisms with affective temperamental traits in healthy volunteers
J Affect Disord. 2008 Jul;109(1-2):157-63. Epub 2008 Jan 8.
The association of 5-HTTLPR and DRD4 VNTR polymorphisms with affective
temperamental traits in healthy volunteers.
Kang JI, Namkoong K, Kim SJ.
Department of Psychiatry and Institute of Behavioral Science in Medicine, Yonsei
University College of Medicine, Seoul, Republic of Korea.
BACKGROUND: There has been growing evidence that temperamental traits, including
affective temperaments, are heritable and associated with genetic polymorphisms.
The purpose of the present study was to investigate the possible relationship
between affective temperaments and the triallelic serotonin transporter
gene-linked polymorphic region (5-HTTLPR) and dopamine receptor D4 (DRD4)
polymorphisms in healthy Korean subjects. METHODS: Three hundred thirty-five
healthy college students were recruited, and 290 participants with a complete
data set (172 males, 118 females) were included in the data analysis. The DNA of
the subjects was isolated from whole blood cells, and the 5-HTTLPR and DRD4
variable number of tandem repeats polymorphisms were genotyped using polymerase
chain reaction. Participants performed the 110-item version of the Temperament
Evaluation of Memphis, Pisa, Paris, and San Diego auto-questionnaire (TEMPS-A)
measuring five affective temperamental traits. RESULTS: A significant association
was found between the DRD4 polymorphism and the cyclothymic and irritable
temperaments in male subjects. No significant association was shown between the
5-HTTLPR gene polymorphisms and affective temperaments. LIMITATION: Our data were
collected from a specific group of college students and cannot be generalized
easily to other non-clinical populations. In addition, Korean version of the
TEMPS-A used in this study has not yet been validated in Korean population.
CONCLUSIONS: This study showed a possible association between the DRD4
polymorphism and certain affective temperaments in the Korean male population.
The clarification of the biological basis of predisposing temperaments such as
cyclothymic temperament might help to understand the pathophysiology and
mechanisms of mood disorders.
PMID: 18191458 [PubMed - in process]
Related Links
Association of DRD4 and COMT polymorphisms with anger and forgiveness traits in
healthy volunteers. [Neurosci Lett. 2008] PMID:18063308
TEMPS-A: progress towards validation of a self-rated clinical version of the
Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego
Autoquestionnaire. [J Affect Disord. 2005] PMID:15780671
Towards a genetically validated new affective temperament scale: A delineation of
the temperament ‘phenotype’ of 5-HTTLPR using the TEMPS-A. [J Affect Disord.
2008] PMID:18455241
TEMPS-A (Rome): psychometric validation of affective temperaments in clinically
well subjects in mid- and south Italy. [J Affect Disord. 2008] PMID:17884175
TEMPS-A: validation of a short version of a self-rated instrument designed to
measure variations in temperament. [J Affect Disord. 2005] PMID:15780675
Behav Pharmacol. 2008 Sep;19(5-6):641-649.
Dopamine and opioid gene variants are associated with increased smoking reward
and reinforcement owing to negative mood.
Perkins KA, Lerman C, Grottenthaler A, Ciccocioppo MM, Milanak M, Conklin CA,
Bergen AW, Benowitz NL.
aDepartment of Psychiatry, University of Pittsburgh, Pittsburgh bDepartment of
Psychiatry and Abramson Cancer Center, University of Pennsylvania, Philadelphia,
Pennsylvania cSRI International, Menlo Park dDepartment of Medicine and
Biopharmaceutical Sciences, University of California, San Francisco, California,
USA.
Negative mood increases smoking reinforcement and risk of relapse. We explored
associations of gene variants in the dopamine, opioid, and serotonin pathways
with smoking reward (‘liking’) and reinforcement (latency to first puff and total
puffs) as a function of negative mood and expected versus actual nicotine content
of the cigarette. Smokers of European ancestry (n=72) were randomized to one of
four groups in a 2×2 balanced placebo design, corresponding with manipulation of
actual (0.6 vs. 0.05 mg) and expected (told nicotine and told denicotinized)
nicotine ‘dose’ in cigarettes during each of two sessions (negative vs. positive
mood induction). Following mood induction and expectancy instructions, they
sampled and rated the assigned cigarette, and then smoked additional cigarettes
ad lib during continued mood induction. The increase in smoking amount owing to
negative mood was associated with: dopamine D2 receptor (DRD2) C957T (CC>TT or
CT), SLC6A3 (presence of 9 repeat>absence of 9), and among those given a nicotine
cigarette, DRD4 (presence of 7 repeat>absence of 7) and DRD2/ANKK1 TaqIA (TT or
CT>CC). SLC6A3, and DRD2/ANKK1 TaqIA were also associated with smoking reward and
smoking latency. OPRM1 (AA>AG or GG) was associated with smoking reward, but
SLC6A4 variable number tandem repeat was unrelated to any of these measures.
These results warrant replication but provide the first evidence for genetic
associations with the acute increase in smoking reward and reinforcement owing to
negative mood.
PMID: 18690118 [PubMed - as supplied by publisher]
Related Links
Gene and gene by sex associations with initial sensitivity to nicotine in
nonsmokers. [Behav Pharmacol. 2008] PMID:18690117
Sex differences in the influence of nicotine dose instructions on the reinforcing
and self-reported rewarding effects of smoking. [Psychopharmacology (Berl). 2006]
PMID:16075290
Mood influences on acute smoking responses are independent of nicotine intake and
dose expectancy. [J Abnorm Psychol. 2008] PMID:18266487
The influence of instructions and nicotine dose on the subjective and reinforcing
effects of smoking. [Exp Clin Psychopharmacol. 2004] PMID:15122953
Instructions about nicotine dose influence acute responses to nasal spray.
[Nicotine Tob Res. 2004] PMID:15801579
Behav Pharmacol. 2008 Sep;19(5-6):630-640.
Gene and gene by sex associations with initial sensitivity to nicotine in
nonsmokers.
Perkins KA, Lerman C, Coddington S, Jetton C, Karelitz JL, Wilson A, Jennings JR,
Ferrell R, Bergen AW, Benowitz NL.
aDepartment of Psychiatry bDepartment of Environmental and Occupational Health,
Salk Hall cDepartment of Human Genetics, Graduate School of Public Health,
University of Pittsburgh, Pittsburgh dDepartment of Psychiatry, University of
Pennsylvania, Philadelphia PA eDepartment of Psychology, University of
California, Los Angeles fDepartment of Medicine and Biopharmaceutical Sciences,
University of California, San Francisco gSRI International, Menlo Park,
California, USA.
Genetic variation may influence initial sensitivity to nicotine (i.e. during
early tobacco exposure), perhaps helping to explain differential vulnerability to
nicotine dependence. This study explored associations of functional candidate
gene polymorphisms with initial sensitivity to nicotine in 101 young adult
nonsmokers of European ancestry. Nicotine (0, 5, 10 mug/kg) was administered
through nasal spray followed by mood, nicotine reward (e.g. ‘liking’) and
perception (e.g. ‘feel effects’) measures, physiological responses, sensory
processing (prepulse inhibition of startle), and performance tasks. Nicotine
reinforcement was assessed in a separate session using a nicotine versus placebo
spray choice procedure. For the dopamine D4 receptor [DRD4 variable number of
tandem repeats (VNTR)], presence of the 7-repeat allele was associated with
greater aversive responses to nicotine (decreases in ‘vigor’, positive affect,
and rapid information processing; increased cortisol) and reduced nicotine
choice. Individuals with at least one DRD4 7-repeat allele also reported
increased ‘feel effects’ and greater startle response, but in men only. Other
genetic associations were also observed in men but not women, such as greater
‘feel effects’ and anger, and reduced fatigue, in the dopamine D2 receptor (DRD2
C957T single nucleotide polymorphism) TT versus CT or CC genotypes. Very few or
no significant associations were seen for the DRD2/ANKK1 TaqIA polymorphism, the
serotonin transporter promoter VNTR or 5HTTLPR (SLC6A4), the dopamine transporter
3′ VNTR (SLC6A3), and the mu opioid receptor A118G single nucleotide polymorphism
(mu opioid receptor polymorphism 1). Although these results are preliminary, this
study is the first to suggest that genetic polymorphisms related to function in
the dopamine D4, and perhaps D2, receptor may modulate initial sensitivity to
nicotine before the onset of dependence and may do so differentially between men
and women.
PMID: 18690117 [PubMed - as supplied by publisher]
Related Links
Dopamine and opioid gene variants are associated with increased smoking reward
and reinforcement owing to negative mood. [Behav Pharmacol. 2008] PMID:18690118
Initial nicotine sensitivity in humans as a function of impulsivity.
[Psychopharmacology (Berl). 2008] PMID:18604520
Genetic variation in the dopamine D4 receptor (DRD4) gene and smoking cessation:
follow-up of a randomised clinical trial of transdermal nicotine patch.
[Pharmacogenomics J. 2008] PMID:17387332
Association of retrospective early smoking experiences with prospective
sensitivity to nicotine via nasal spray in nonsmokers. [Nicotine Tob Res. 2008]
PMID:18686181
Antipsychotic-induced extrapyramidal symptoms in patients with schizophrenia:
associations with dopamine and serotonin receptor and transporter polymorphisms.
[Eur J Clin Pharmacol. 2007] PMID:17225991
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