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1.  Maternal cannabis use alters ventral striatal dopamine D2 gene regulation in the offspring 
Biological psychiatry  2011;70(8):763-769.
Prenatal cannabis exposure has been linked to addiction vulnerability, but the neurobiology underlying this risk is unknown.
Striatal dopamine and opioid-related genes were studied in human fetal subjects exposed to cannabis (as well as cigarettes and alcohol). Cannabis-related gene disturbances observed in the human fetus were subsequently characterized using an animal model of prenatal delta-9-tetrahydrocannabinol (THC; 0.15 mg/kg) exposure.
Prenatal cannabis exposure decreased dopamine receptor D2 (DRD2) mRNA expression in the human ventral striatum (nucleus accumbens; NAc), a key brain reward region. No significant alterations were observed for the other genes in cannabis-exposed subjects. Maternal cigarette use was associated with reduced NAc prodynorphin mRNA expression and alcohol exposure induced broad alterations primarily in the dorsal striatum of most genes. To explore the mechanisms underlying the cannabis-associated disturbances, we exposed pregnant rats to THC and examined the epigenetic regulation of the NAc Drd2 gene in their offspring at postnatal day 2, comparable to the human fetal period studied, and in adulthood. Chromatin immunoprecipitation of the adult NAc revealed increased 2meH3K9 repressive mark and decreased 3meH3K4 and RNA polymerase II at the Drd2 gene locus in the THC-exposed offspring. Decreased Drd2 expression was accompanied by reduced D2R binding sites and increased sensitivity to opiate reward in adulthood.
These data suggest that maternal cannabis use alters developmental regulation of mesolimbic D2R in offspring through epigenetic mechanisms that regulate histone lysine methylation, and the ensuing reduction of D2R may contribute to addiction vulnerability later in life.
PMCID: PMC3186868  PMID: 21820648
THC; addiction; development; enkephalin; dynorphin; D1 receptor
2.  Evaluation of Genetic Variability in the Dopamine Receptor D2 in Relation to Behavioral Inhibition and Impulsivity/Sensation Seeking: An Exploratory Study With d-Amphetamine in Healthy Participants 
The dopamine D2 receptor (DRD2) appears to be involved in impulsive behaviors, and particularly in behavioral inhibition. We sought to determine whether inhibition and impulsivity were related to genetic polymorphisms in the DRD2 gene (DRD2) in healthy volunteers (N = 93). Participants received placebo or d-amphetamine in random order. They performed the stop task, measuring behavioral inhibition, and rated their mood states on each session. They also completed the Zuckerman–Kuhlman Personality Questionnaire, including an Impulsivity subscale. We investigated the association between 12 single nucleotide polymorphisms (SNPs) and haplotypes in DRD2 and stop task performance in the nondrug (i.e., placebo) session and on the personality measure of impulsivity. We secondarily evaluated the DRD2 SNPs in relation to response to d-amphetamine on stop task performance and mood ratings. Mood was not related to genotypes in either the drug free condition or in response to drug. However, 2 SNPs, rs4648317 and rs12364283, and a haplotype block consisting of those SNPs, were associated with better performance on the stop task in the drug free condition and lower scores on the Impulsivity subscale. We also found that rs12364283 was associated with effects of d-amphetamine on stop task performance: d-amphetamine decreased stop reaction time (RT) in the A/A group but increased stop RT in the combined A/G + G/G genotype. Of the SNPs we evaluated, rs12364283, which has been associated with DRD2 expression, was the most significantly associated with inhibition and impulsivity. The significant relationship between DRD2 genotype and both behavioral inhibition and impulsivity suggests a possible common genetic influence on behavioral and self-report measures of impulsivity.
PMCID: PMC2879583  PMID: 19968402
DRD2; inhibition; impulsivity; amphetamine; Stop Task
3.  Motives for cannabis use in high-risk adolescent users 
The present investigation examined the relationships between motives for cannabis use and negative consequences associated with cannabis use following a brief intervention. The sample consisted of 205 adolescent cannabis users (66.3% male), who were recruited in high schools and randomly assigned to a brief two-session motivational enhancement therapy (MET) or an educational feedback control (EFC). Results supported the hypothesis that using cannabis to cope with negative affect would predict the number of problems and dependence symptoms related to cannabis use, after controlling for age, gender, years and frequency of cannabis use, and internalizing and externalizing behavior problems. Significant interactions between internalizing behavior problems and the coping motive showed that using to cope was associated with a higher number of cannabis dependence symptoms among adolescents reporting lower levels internalizing behavior problems. Findings support the potential utility of conducting further research to explore the coping motive as an important indicator of problematic cannabis use.
PMCID: PMC3211084  PMID: 21688873
cannabis; marijuana; adolescents; cannabis use motives; internalizing behavior problems
4.  The Interplay between Parental Monitoring and the Dopamine D4 Receptor Gene in Adolescent Cannabis Use 
PLoS ONE  2012;7(11):e49432.
Both environmental risk and genetic variation is believed to play a role in substance use. A candidate environmental variable is parenting. Recent studies have found support for the idea that the dopamine system affects the susceptibility to environmental influences. In the present study we will examine the interplay between effects of parental monitoring and the presence of the DRD4 7-repeat allele in adolescent lifetime cannabis use and the developmental course of cannabis use.
A total of 311 adolescents participated in a five-wave longitudinal design. First, we conducted logistic regression analyses to examine the prospective associations between parental monitoring, the DRD4 polymorphism, their interaction and lifetime cannabis use. Second, individual growth parameters were calculated for frequency of cannabis use. Linear regression was used to assess the relationship between parental monitoring, the DRD4 polymorphism, their interaction, and the frequency of cannabis use.
There were no significant main effects of parental monitoring or the DRD4 polymorphism. However, both analyses showed that over a period of four years, a) when experiencing low levels of parental monitoring, individuals with the 7-repeat allele were more likely to show lifetime cannabis use and a stronger increase in frequency of cannabis use than individuals without this allele; b) when experiencing high levels of parental monitoring, individuals with the 7-repeat allele were less likely to show lifetime cannabis use and they showed a smaller increase in frequency of cannabis use than individuals without the 7-repeat allele.
This study shows that carriers of the DRD4 7-repeat allele are disproportionally affected by the negative and positive effects of parental monitoring such that carriers of the DRD4 7-repeat allele, as compared to non-carriers, are more likely to use cannabis when levels of parental monitoring are low, and less likely to use cannabis when parental monitoring levels are high.
PMCID: PMC3509099  PMID: 23209577
5.  Lack of Association between Polymorphisms of the Dopamine Receptor D4 and Dopamine Transporter Genes and Personality Traits in a Korean Population 
Yonsei Medical Journal  2006;47(6):787-792.
Human personality traits have a considerable genetic component. Cloninger et al. were the first to postulate that certain personality traits, such as novelty seeking, are related to the dopamine neurotransmitter system. In this study, we investigated the associations between dopamine receptor D4 (DRD4) exon III and dopamine transporter (DAT1) polymorphisms and personality traits. The DRD4 and DAT1 gene polymorphisms were genotyped in 214 healthy Korean subjects, whose personality traits were assessed with the Temperament and Character Inventory (TCI). There were no significant differences between scores of TCI temperament dimensions (novelty seeking, harm avoidance, reward dependence, and persistence) and DRD4 gene polymorphism. The DAT1 gene polymorphisms also showed no significant association with any of the temperament subscales of the TCI. These data suggest that DRD4 and DAT1 gene polymorphism may not associated with personality traits in a Korean population.
PMCID: PMC2687817  PMID: 17191306
Dopamine receptor D4; dopamine transporter gene; polymorphism; personality traits; temperament and character inventory; Korean
6.  A Genomewide Association Study of DSM-IV Cannabis Dependence 
Addiction biology  2010;16(3):514-518.
Despite twin studies showing that 50–70% of variation in DSM-IV cannabis dependence is attributable to heritable influences, little is known of specific genotypes that influence vulnerability to cannabis dependence. We conducted a genomewide association study of DSM-IV cannabis dependence. Association analyses of 708 DSM-IV cannabis dependent cases with 2,346 cannabis exposed nondependent controls was conducted using logistic regression in PLINK. None of the 948,142 SNPs met genomewide significance (p < E−8). The lowest p-values were obtained for polymorphisms on chromosome 17 (rs1019238 and rs1431318, p-values at E−7) in the ANKFN1 gene. While replication is required, this study represents an important first step towards clarifying the biological underpinnings of cannabis dependence.
PMCID: PMC3117436  PMID: 21668797
7.  Associations between Cannabinoid Receptor-1 (CNR1) Variation and Hippocampus and Amygdala Volumes in Heavy Cannabis Users 
Neuropsychopharmacology  2012;37(11):2368-2376.
Heavy cannabis users display smaller amygdalae and hippocampi than controls, and genetic variation accounts for a large proportion of variance in liability to cannabis dependence (CD). A single nucleotide polymorphism in the cannabis receptor-1 gene (CNR1), rs2023239, has been associated with CD diagnosis and intermediate phenotypes, including abstinence-induced withdrawal, cue-elicited craving, and parahippocampal activation to cannabis cues. This study compared hippocampal and amygdalar volumes (potential CD intermediate phenotypes) between heavy cannabis users and healthy controls, and analyzed interactions between group, rs2023239 variation, and the volumes of these structures. Ninety-four heavy cannabis users participated, of whom 37 (14 men, 23 women; mean age=27.8) were matched to 37 healthy controls (14 men, 23 women; mean age=27.3) for case-control analyses. Controlling for total intracranial volume and other confounding variables, matched cannabis users had smaller bilateral hippocampi (left, p=0.002; right, p=0.001) and left amygdalae (p=0.01) than controls. When genotype was considered in the case-control analyses, there was a group by genotype interaction, such that the rs2023239 G allele predicted lower volume of bilateral hippocampi among cannabis users relative to controls (both p<0.001). This interaction persisted when all 94 cannabis users were compared to controls. There were no group by genotype interactions on amygdalar volume. These data replicate previous findings of reduced hippocampal and amygdalar volume among heavy cannabis users, and suggest that CNR1 rs2023239 variation may predispose smaller hippocampal volume after heavy cannabis use. This association should be tested in future studies of brain volume differences in CD.
PMCID: PMC3442352  PMID: 22669173
marijuana; genetics; endocannabinoid; hippocampus; amygdala; addiction & substance abuse; amygdala; endocannabinoid; genetics; hippocampus; imaging; clinical or preclinical; marijuana; neuroanatomy; neurogenetics
8.  The Influence of Inhibitory Control and Episodic Memory on the Risky Sexual Behavior of Young Adult Cannabis Users 
Cannabis use is associated with risky sexual behavior (RSB) and sex-related negative health consequences. This investigation examined the role of inhibitory control and episodic memory in predicting RSB and sex-related negative consequences among current cannabis users. Findings indicated that the relationships between cannabis, neurocognition and sexual-risk varied according to the dimension of neurocognition and the parameter of RSB in question. Specifically, more risk-taking was associated with more RSB. Furthermore, amount of recent cannabis use was associated with more RSB and sex-related negative consequences, but only among those with worse performances on a measure of decision-making and of risk-taking. Contrary to hypotheses, worse episodic memory also significantly predicted higher overall sexual-risk and decreased safe-sex practices. Results indicate that worse neurocognitive performance in the areas of risk-taking, decision-making, and episodic memory may influence the degree to which cannabis users engage in RSB and experience negative health consequences as a result.
PMCID: PMC3677559  PMID: 22676889
Cannabis; Risky Sex; Young Adults; Cognition; Inhibitory Control; Episodic Memory
9.  Cannabis Receptor Haplotype Associated With Fewer Cannabis Dependence Symptoms In Adolescents 
Cannabis is a major substance of abuse, and the gene encoding for the central cannabinoid receptor (CNR1) is a logical candidate gene for vulnerability toward developing symptoms of cannabis dependence. We studied four single-nucleotide polymorphisms (SNPs) in the CNR1 gene for association with having one or more symptoms of cannabis dependence in 541 adolescent subjects who had all tried cannabis five or more times. Cases (327) were defined as those who had tried marijuana and developed one or more symptoms, and controls (214) as those who had tried marijuana but developed no dependence symptoms. Cannabis dependence symptoms were assessed in these youth when they were 17 or older with the Composite International Diagnostic Interview- Substance Abuse Module. Univariate (single-marker) association tests demonstrated that SNP rs806380, located in intron 2 of the CNR1 gene, was significantly associated with developing one or more cannabis dependence symptoms, with the G allele having a protective effect (p < 0.02). This was consistent with the results of the global haplotype test (p < 0.01). One of the common haplotypes examined (present in 21% of the subjects) was significantly associated with a lower rate of having one or more cannabis dependence symptoms. Our findings provide evidence suggesting that a common CNR1 haplotype is associated with developing fewer cannabis dependence symptoms among adolescents who have experimented with cannabis.
PMCID: PMC2564870  PMID: 16917946
Cannabis; Adolescence; Genetics; CNR1
10.  Evidence for association between polymorphisms in the Cannabinoid Receptor 1 (CNR1) gene and cannabis dependence 
Genomic studies of cannabis use disorders have been limited. The cannabinoid receptor 1 gene (CNR1) on chromosome 6q14–15 is an excellent candidate gene for cannabis dependence due to the important role of the G-protein coupled receptor encoded by this gene in the rewarding effects of Δ9-tetrahydrocannabinol. Previous studies have found equivocal evidence for an association between SNPs in CNR1 and a general vulnerability to substance use disorders. We investigate the association between 9 SNPs spanning CNR1 and cannabis dependence in 1,923 individuals. Two SNPs that were previously associated with cannabis dependence in other studies were also significant with this phenotype in our analyses [rs806368 (p = 0.05) and rs806380 (p = 0.009)]. Haplotype analyses revealed the association to be largely driven by the SNP rs806380. These results suggest a role for the cannabinoid receptor 1 gene in cannabis dependence.
PMCID: PMC2703788  PMID: 19016476
CNR1; cannabis dependence; COGA; pedigree disequilibrium test; association
11.  Implicit Associations and Explicit Expectancies toward Cannabis in Heavy Cannabis Users and Controls 
Cognitive biases, including implicit memory associations are thought to play an important role in the development of addictive behaviors. The aim of the present study was to investigate implicit affective memory associations in heavy cannabis users. Implicit positive-arousal, sedation, and negative associations toward cannabis were measured with three Single Category Implicit Association Tests (SC-IAT’s) and compared between 59 heavy cannabis users and 89 controls. Moreover, we investigated the relationship between these implicit affective associations and explicit expectancies, subjective craving, cannabis use, and cannabis related problems. Results show that heavy cannabis users had stronger implicit positive-arousal associations but weaker implicit negative associations toward cannabis compared to controls. Moreover, heavy cannabis users had stronger sedation but weaker negative explicit expectancies toward cannabis compared to controls. Within heavy cannabis users, more cannabis use was associated with stronger implicit negative associations whereas more cannabis use related problems was associated with stronger explicit negative expectancies, decreasing the overall difference on negative associations between cannabis users and controls. No other associations were observed between implicit associations, explicit expectancies, measures of cannabis use, cannabis use related problems, or subjective craving. These findings indicate that, in contrast to other substances of abuse like alcohol and tobacco, the relationship between implicit associations and cannabis use appears to be weak in heavy cannabis users.
PMCID: PMC3689035  PMID: 23801968
cannabis; implicit association test; cannabis use disorder; craving; affective associations
12.  Cannabis users differ from non-users on measures of personality and schizotypy 
Psychiatry research  2011;186(1):46-52.
Accumulating evidence indicates that cannabis use may be a risk factor for schizophrenia (SZ), and chronic cannabis users score higher than non-users on measures of schizotypal personality traits. The purpose of the present study was to investigate the relations between normal personality, schizotypy, and cannabis use. Sixty-two chronic cannabis users and 45 cannabis-naïve controls completed a measure of normal personality, the NEO-Five Factor Inventory (NEO-FFI), and two measures of schizotypy, the Schizotypal Personality Questionnaire (SPQ) and Perceptual Aberration Scale (PAS). Substance use was assessed using the SCID I alcohol/drug module and a locally developed drug use questionnaire. On the NEO-FFI, users scored higher than controls on Openness, but lower on Agreeableness and Conscientiousness, and endorsed greater schizotypy on the SPQ and PAS. Higher Neuroticism predicted greater schizotypy in both groups, and, higher Extraversion predicted lower negative-syndrome schizotypy among users. Finally, duration of cannabis use was positively correlated with scores on the SPQ and PAS among users, suggesting a relation between overall cannabis use chronicity and schizotypy. These data show that cannabis users differ from non-users on dimensions of normal personality and schizotypy, and provide further evidence that cannabis use is associated with increased levels of psychosis-related personality traits.
PMCID: PMC3036782  PMID: 20813412
Five-factor model; marijuana; Schizotypal Personality Questionnaire; Perceptual Aberration Scale; schizophrenia
13.  Functional variation of the dopamine D2 receptor gene is associated with emotional control as well as brain activity and connectivity during emotion processing in humans 
Personality traits related to emotion processing are, at least in part, heritable and genetically determined. Dopamine D2 receptor signaling is involved in modulation of emotional behavior and activity of associated brain regions such as the amygdala and the prefrontal cortex. An intronic single nucleotide polymorphism within the D2 receptor gene (DRD2, rs1076560, guanine>thymine - G>T) shifts splicing of the two protein isoforms (D2 short, D2S, mainly presynaptic, and D2 long, D2L) and has been associated with modulation of memory performance and brain activity. Here, our aim was to investigate the association of DRD2 rs1076560 genotype with personality traits of emotional stability and with brain physiology during processing of emotionally relevant stimuli. DRD2 genotype and Big Five Questionnaire scores were evaluated in 134 healthy subjects demonstrating that GG subjects have reduced ‘emotion control’ compared with GT subjects. fMRI in a sample of 24 individuals indicated greater amygdala activity during implicit processing and greater dorsolateral prefrontal cortex (DLPFC) response during explicit processing of facial emotional stimuli in GG subjects compared with GT. Other results also demonstrate an interaction between DRD2 genotype and facial emotional expression on functional connectivity of both amygdala and dorsolateral prefrontal regions with overlapping medial prefrontal areas. Moreover, rs1076560 genotype is associated with differential relationships between amygdala/DLPFC functional connectivity and emotion control scores. These results suggest that genetically determined D2 signaling may explain part of personality traits related to emotion processing and individual variability in specific brain responses to emotionally relevant inputs.
PMCID: PMC2834475  PMID: 19940176
amygdala; DRD2; dopamine; emotion; fMRI; prefrontal cortex
14.  Multivariate Analysis of Dopaminergic Gene Variants as Risk Factors of Heroin Dependence 
PLoS ONE  2013;8(6):e66592.
Heroin dependence is a debilitating psychiatric disorder with complex inheritance. Since the dopaminergic system has a key role in rewarding mechanism of the brain, which is directly or indirectly targeted by most drugs of abuse, we focus on the effects and interactions among dopaminergic gene variants.
To study the potential association between allelic variants of dopamine D2 receptor (DRD2), ANKK1 (ankyrin repeat and kinase domain containing 1), dopamine D4 receptor (DRD4), catechol-O-methyl transferase (COMT) and dopamine transporter (SLC6A3) genes and heroin dependence in Hungarian patients.
303 heroin dependent subjects and 555 healthy controls were genotyped for 7 single nucleotide polymorphisms (SNPs) rs4680 of the COMT gene; rs1079597 and rs1800498 of the DRD2 gene; rs1800497 of the ANKK1 gene; rs1800955, rs936462 and rs747302 of the DRD4 gene. Four variable number of tandem repeats (VNTRs) were also genotyped: 120 bp duplication and 48 bp VNTR in exon 3 of DRD4 and 40 bp VNTR and intron 8 VNTR of SLC6A3. We also perform a multivariate analysis of associations using Bayesian networks in Bayesian multilevel analysis (BN-BMLA).
Findings and conclusions
In single marker analysis the TaqIA (rs1800497) and TaqIB (rs1079597) variants were associated with heroin dependence. Moreover, –521 C/T SNP (rs1800955) of the DRD4 gene showed nominal association with a possible protective effect of the C allele. After applying the Bonferroni correction TaqIB was still significant suggesting that the minor (A) allele of the TaqIB SNP is a risk component in the genetic background of heroin dependence. The findings of the additional multiple marker analysis are consistent with the results of the single marker analysis, but this method was able to reveal an indirect effect of a promoter polymorphism (rs936462) of the DRD4 gene and this effect is mediated through the –521 C/T (rs1800955) polymorphism in the promoter.
PMCID: PMC3696122  PMID: 23840506
15.  Stress-Related Factors in Cannabis Use and Misuse: Implications for Prevention and Treatment 
We examined the role of stress as a risk factor and motivation for cannabis use/misuse. A systematic review of studies gathered from PsychINFO and MEDLINE databases was conducted. Findings suggest that cannabis is commonly used as a stress-coping strategy. Negative life events, trauma, and maladaptive coping were all related to consumption. Cannabis use for stress-coping purposes was most evident when examining chronic as compared with experimental use. While many individuals may be able to use cannabis without consequences, there appears to be a subset of individuals who experience greater life stress and who may be more likely to use for stress-coping purposes. These individuals may be at greatest risk for addiction. Chronic use may potentiate stress-related motivation to use/abuse cannabis and is associated with decision making deficits and alterations in brain-stress pathways that may exacerbate compulsive drug-seeking and sensitize individuals to stress-related drug use. Overall, stress-coping interventions and harm reduction focused on reducing the amount ingested may facilitate prevention and recovery efforts.
PMCID: PMC2696937  PMID: 19004601
cannabis; marijuana; motives; stress; life events; coping; emotion regulation; trauma; traumatic stress; HPA; decision-making
16.  Individual differences in reward–prediction–error: extraversion and feedback-related negativity 
Medial frontal scalp-recorded negativity occurring ∼200–300 ms post-stimulus [known as feedback-related negativity (FRN)] is attenuated following unpredicted reward and potentiated following unpredicted non-reward. This encourages the view that FRN may partly reflect dopaminergic ‘reward–prediction–error’ signalling. We examined the influence of a putatively dopamine-based personality trait, extraversion (N = 30), and a dopamine-related gene polymorphism, DRD2/ANKK1 (N = 24), on FRN during an associative reward-learning paradigm. FRN was most negative following unpredicted non-reward and least-negative following unpredicted reward. A difference wave contrasting these conditions was significantly more pronounced for extraverted participants than for introverts, with a similar but non-significant trend for participants carrying at least one copy of the A1 allele of the DRD2/ANKK1 gene compared with those without the allele. Extraversion was also significantly higher in A1 allele carriers. Results have broad relevance to neuroscience and personality research concerning reward processing and dopamine function.
PMCID: PMC3190205  PMID: 20855297
feedback-related negativity; reward–prediction–error; extraversion; dopamine; DRD2/ANKK1
17.  Linkage analyses of cannabis dependence, craving, and withdrawal in the San Francisco Family Study 
Cannabis is the most widely used illicit drug in the United States. There is ample evidence that cannabis use has a heritable component, yet the genes underlying cannabis use disorders are yet to be completely identified. This study's aims were to map susceptibility loci for cannabis use and dependence and two narrower cannabis-related phenotypes of “craving” and “withdrawal” using a family study design. Participants were 2524 adults participating in the University of California San Francisco (UCSF) Family Alcoholism Study. DSM-IV diagnoses of cannabis dependence, as well as indices of cannabis craving and withdrawal, were obtained using a modified version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). Genotypes were determined for a panel of 791 microsatellite polymorphisms. Multipoint variance component LOD scores were obtained using SOLAR. Genome-wide significance for linkage (LOD > 3.0) was not found for the DSM-IV cannabis dependence diagnosis, however, linkage analyses of cannabis “craving” and the cannabis withdrawal symptom of “nervous, tense, restless or irritable” revealed five sites with LOD scores over 3.0 on chromosomes 1, 3, 6, 7, 9. These results identify new regions of the genome associated with cannabis use phenotypes as well as corroborate the importance of several chromosome regions highlighted in previous linkage analyses for other substance dependence phenotypes.
PMCID: PMC2940710  PMID: 19937978
dependence; genome scan; heritability; marijuana
18.  No association of DRD2, DRD3, and tyrosine hydroxylase gene polymorphisms with personality traits in the Japanese population 
Dopamine D2 receptor (DRD2) and dopamine D3 receptor (DRD3) genes could be candidates for personality-related genes considering their pharmacological profiles or structures. However, a limited number of studies have investigated the association between these genes and personality traits. In the present study, we investigated the DRD2, DRD3, and tyrosine hydroxylase (TH) genes in relation to personality traits in the Japanese population. Epistasis (gene-gene interaction) among the genes was extensively analyzed, in addition to the analysis based on each gene.
The -241A/G, -141C Ins/Del, and Ser311Cys polymorphisms in the DRD2 gene, the Ser9Gly polymorphism of the DRD3 gene, and the Val81Met and PstI site polymorphisms in the TH gene were genotyped in 257 healthy Japanese subjects. Personality traits were evaluated by using the Revised NEO Personality Inventory (NEO PI-R) and the State-Trait Anxiety Inventory (STAI). The associations between gene polymorphisms and the scores for NEO PI-R or Trait Anxiety of STAI were statistically analyzed by one-way analysis of covariance (ANCOVA) adjusting sex and age. Epistasis was assessed using two-way ANCOVA between the polymorphisms of independent two genes.
In the analysis based on each gene, trends for association were observed between State Anxiety and the DRD2 -141C Ins/Del polymorphism (p = 0.031, uncorrected), and between Trait Anxiety and the DRD2 Ser311Cys or TH PstI site polymorphism (p = 0.048 and 0.041, respectively, uncorrected). In epistatic analysis, a trend for interaction was observed on the scores for Neuroticism and Trait Anxiety between the DRD2 -141C Ins/Del and TH Val81Met polymorphisms (p = 0.015 and 0.010, respectively, uncorrected). However, these differences were insignificant after Bonferroni correction.
The present study did not provide evidence for the association between these dopamine-related genes and personality traits in the Japanese population.
PMCID: PMC1601960  PMID: 17018139
19.  12-month follow-up of an exploratory ‘brief intervention’ for high-frequency cannabis users among Canadian university students 
One in three young people use cannabis in Canada. Cannabis use can be associated with a variety of health problems which occur primarily among intensive/frequent users. Availability and effectiveness of conventional treatment for cannabis use is limited. While Brief Interventions (BIs) have been shown to result in short-term reductions of cannabis use risks or problems, few studies have assessed their longer-term effects. The present study examined 12-month follow-up outcomes for BIs in a cohort of young Canadian high-frequency cannabis users where select short-term effects (3 months) had previously been assessed and demonstrated.
N = 134 frequent cannabis users were recruited from among university students in Toronto, randomized to either an oral or a written cannabis BI, or corresponding health controls, and assessed in-person at baseline, 3-months, and 12-months. N = 72 (54 %) of the original sample were retained for follow-up analyses at 12-months where reductions in ‘deep inhalation/breathholding’ (Q = 13.1; p < .05) and ‘driving after cannabis use’ (Q = 9.3; p < .05) were observed in the experimental groups. Reductions for these indicators had been shown at 3-months in the experimental groups; these reductions were maintained over the year. Other indicators assessed remained overall stable in both experimental and control groups.
The results confirm findings from select other studies indicating the potential for longer-term and sustained risk reduction effects of BIs for cannabis use. While further research is needed on the long-term effects of BIs, these may be a valuable – and efficient – intervention tool in a public health approach to high-risk cannabis use.
PMCID: PMC3504513  PMID: 22538183
Cannabis use; Frequent use; Young adults; Brief interventions; Prevention; Canada
20.  Cannabis Withdrawal is Common among Treatment-Seeking Adolescents with Cannabis Dependence and Major Depression, and is Associated with Rapid Relapse to Dependence 
Addictive behaviors  2008;33(11):1500-1505.
Recently, reports have suggested that cannabis withdrawal occurs commonly in adults with cannabis dependence, though it is unclear whether this extends to those with comorbid depression or to comorbid adolescents. We hypothesized that cannabis withdrawal would be common among our sample of comorbid adolescents and young adults, and that the presence of cannabis withdrawal symptoms would be associated with a self-reported past history of rapid reinstatement of cannabis dependence symptoms (rapid relapse). The participants in this study included 170 adolescents and young adults, including 104 with cannabis dependence, 32 with cannabis abuse, and 34 with cannabis use without dependence or abuse. All of these subjects demonstrated current depressive symptoms and cannabis use, and most demonstrated current DSM-IV major depressive disorder and current comorbid cannabis dependence. These subjects had presented for treatment for either of two double-blind, placebo-controlled trials involving fluoxetine. Cannabis withdrawal was the most commonly reported cannabis dependence criterion among the 104 subjects in our sample with cannabis dependence, being noted in 92% of subjects, using a two-symptom cutoff for determination of cannabis withdrawal. The most common withdrawal symptoms among those with cannabis dependence were craving (82%), irritability (76%), restlessness (58%), anxiety (55%), and depression (52%). Cannabis withdrawal symptoms (in the N=170 sample) were reported to have been associated with rapid reinstatement of cannabis dependence symptoms (rapid relapse). These findings suggest that cannabis withdrawal should be included as a diagnosis in the upcoming DSM-V, and should be listed in the upcoming criteria list for the DSM-V diagnostic category of cannabis dependence.
PMCID: PMC2565493  PMID: 18313860
21.  Intermediate cannabis dependence phenotypes and the FAAH C385A variant: an exploratory analysis 
Psychopharmacology  2008;203(3):511-517.
Cannabis dependence is a growing problem among individuals who use marijuana frequently, and genetic differences make some users more liable to progress to dependence. The identification of intermediate phenotypes of cannabis dependence may aid candidate genetic analysis. Promising intermediate phenotypes include craving for marijuana, withdrawal symptoms after abstinence, and sensitivity to its acute effects. A single nucleotide polymorphism (SNP) in the gene encoding for fatty acid amide hydrolase (FAAH) has demonstrated association with substance use disorder diagnoses, but has not been studied with respect to these narrower phenotypes. FAAH is an enzyme that inactivates anandamide, an endogenous agonist for CB1 receptors (to which Δ9-tetrahydrocannabinol binds). CB1 binding modulates mesocorticolimbic dopamine release, which underlies many facets of addiction.
The SNP, FAAH C385A (rs324420), was examined to determine whether its variance was associated with changes in craving and withdrawal after marijuana abstinence, craving after cue exposure, or sensitivity to the acute effects of marijuana.
Materials and methods
Forty daily marijuana users abstained for 24 h, were presented with a cue-elicited craving paradigm and smoked a marijuana cigarette in the laboratory.
C385A variance was significantly associated with changes in withdrawal after abstinence, and happiness after smoking marijuana in the predicted directions, was associated with changes in heart rate after smoking in the opposite of the predicted direction, and was not associated with changes in craving or other acute effects.
These data lend support to some previous association studies of C385A, but suggest that further refinement of these intermediate phenotypes is necessary.
PMCID: PMC2863054  PMID: 19002671
Marijuana; Cue-elicited craving; Withdrawal; Acute effects; Gene
22.  Prefrontal Dopaminergic and Enkephalinergic Synaptic Accommodation in HIV-associated Neurocognitive Disorders and Encephalitis 
Changes in synapse structure occur in frontal neocortex with HIV encephalitis (HIVE) and may contribute to HIV-associated neurocognitive disorders (HAND). A postmortem survey was conducted to determine if mRNAs involved in synaptic transmission are perturbed in dorsolateral prefrontal cortex (DLPFC) in subjects with HIVE or HAND. Expression of the opioid neurotransmitter preproenkephalin mRNA (PENK) was significantly decreased in a sampling of 446 brain specimens from HIV-1 infected people compared to 67 HIV negative subjects. Decreased DLPFC PENK was most evident in subjects with HIVE and/or increased expression of interferon regulatory factor 1 mRNA (IRF1). Type 2 dopamine receptor mRNA (DRD2L) was decreased significantly, but not in the same set of subjects with PENK dysregulation. DRD2L downregulation occurred primarily in the subjects without HIVE or neurocognitive impairment. Subjects with neurocognitive impairment often failed to significantly downregulate DRD2L and had abnormally high IRF1 expression. Conclusion: Dysregulation of synaptic preproenkephalin and DRD2L in frontal neocortex can occur with and without neurocognitive impairment in HIV-infected people. Downregulation of DRD2L in the prefrontal cortex was associated with more favorable neuropsychological and neuropathological outcomes; the failure to downregulate DRD2L was significantly less favorable. PENK downregulation was related neuropathologically to HIVE, but was not related to neuropsychological outcome independently. Emulating endogenous synaptic plasticity pharmacodynamically could enhance synaptic accommodation and improve neuropsychological and neuropathological outcomes in HIV/AIDS.
PMCID: PMC3419353  PMID: 22391864
Dopamine receptor; Enkephalin; HAND; HIVE; HIV encephalitis; HIV-associated neurocognitive disorders; Interferon regulatory factor; Opiate; Opioid; Synaptic plasticity
23.  Adolescent Cannabis Use Increases Risk for Cocaine-Induced Paranoia 
Drug and alcohol dependence  2009;107(2-3):196.
Cannabis can produce and/or exacerbate psychotic symptoms in vulnerable individuals. Early exposure to cannabis, particularly in combination with genetic factors, increases the risk of a subsequent, primary, psychotic disorder. Because paranoia is a common feature of stimulant abuse and cocaine dependent individuals frequently endorse a history of cannabis abuse, we examined whether early cannabis exposure, in conjunction with polymorphic variation in the catechol-O-methyl transferase gene (COMT Val158Met), influences the risk for cocaine-induced paranoia (CIP).
Cannabis-use history was obtained in 1140 cocaine-dependent individuals from a family-based (affected sibling pair) study using the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA). Logistic regression and generalized estimating equations analyses were used to examine the role of adolescent-onset cannabis use (≤ 15 yrs of age) on CIP risk, both controlling for previously implicated CIP risk factors and familial relationships, and considering potential interactions with COMT Val158Met genotype.
Cocaine-dependent individuals who endorsed CIP had significantly higher rates of adolescent-onset cannabis use than those without CIP (62.2% vs. 50.2%; χ2 = 15.2, df = 1, p < 0.0001), a finding that remained after controlling for sibling correlations and other risk factors. There were no effects of COMT genotype or genotype by early cannabis onset interactions. A modest (OR = 1.4) and nearly significant (p = 0.053) effect of CIP status in probands on CIP status in siblings was also noted.
Adolescent-onset cannabis use increases the risk of CIP in cocaine dependent individuals. COMT genotype and its interaction with early cannabis exposure did not emerge as significant predictors of CIP. In addition, trait vulnerability to CIP may also be familial in nature.
PMCID: PMC2821949  PMID: 19944543
cocaine; paranoia; cannabis; adolescent
24.  Negative consequences associated with dependence in daily cannabis users 
Cannabis is the most widely consumed illicit substance in America, with increasing rates of use. Some theorists tend to link frequency of use with cannabis dependence. Nevertheless, fewer than half of daily cannabis users meet DSM-IV-TR criteria for cannabis dependence. This study seeks to determine whether the negative aspects associated with cannabis use can be explained by a proxy measure of dependence instead of by frequency of use.
Over 2500 adult daily cannabis users completed an Internet survey consisting of measures of cannabis and other drug use, in addition to measures of commonly reported negative problems resulting from cannabis use. We compared those who met a proxy measure of DSM-IV-TR criteria for cannabis dependence (N = 1111) to those who did not meet the criteria (N = 1770). Cannabis dependent subjects consumed greater amounts of cannabis, alcohol, and a variety of other drugs. They also had lower levels of motivation, happiness, and satisfaction with life, with higher levels of depression and respiratory symptoms.
Although all of our subjects reported daily use, only those meeting proxy criteria for cannabis dependence reported significant associated problems. Our data suggest that dependence need not arise from daily use, but consuming larger amounts of cannabis and other drugs undoubtedly increases problems.
PMCID: PMC1783648  PMID: 17214886
25.  Attention-deficit-hyperactivity disorder and reward deficiency syndrome 
Molecular genetic studies have identified several genes that may mediate susceptibility to attention deficit hyperactivity disorder (ADHD). A consensus of the literature suggests that when there is a dysfunction in the “brain reward cascade,” especially in the dopamine system, causing a low or hypo-dopaminergic trait, the brain may require dopamine for individuals to avoid unpleasant feelings. This high-risk genetic trait leads to multiple drug-seeking behaviors, because the drugs activate release of dopamine, which can diminish abnormal cravings. Moreover, this genetic trait is due in part to a form of a gene (DRD2 A1 allele) that prevents the expression of the normal laying down of dopamine receptors in brain reward sites. This gene, and others involved in neurophysiological processing of specific neurotransmitters, have been associated with deficient functions and predispose individuals to have a high risk for addictive, impulsive, and compulsive behavioral propensities. It has been proposed that genetic variants of dopaminergic genes and other “reward genes” are important common determinants of reward deficiency syndrome (RDS), which we hypothesize includes ADHD as a behavioral subtype. We further hypothesize that early diagnosis through genetic polymorphic identification in combination with DNA-based customized nutraceutical administration to young children may attenuate behavioral symptoms associated with ADHD. Moreover, it is concluded that dopamine and serotonin releasers might be useful therapeutic adjuncts for the treatment of other RDS behavioral subtypes, including addictions.
PMCID: PMC2626918  PMID: 19183781
attention deficit hyperactivity disorder (ADHD); genes; reward dependence; reward deficiency syndrome; treatment; neuropsychological deficits

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