A haplotype at the DBH locus, associated with low plasma dopamine β-hydroxylase activity, also associates with cocaine-induced paranoia

Cubells, Joseph F.; Kranzler, Henry R.; McCance‐Katz, Elinore F.; Anderson, George M.; Malison, Robert T.; Price, Lawrence H.; Gelernter, Joel

doi:10.1038/sj.mp.4000657

Cited by 172 publications

(151 citation statements)

References 43 publications

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“…DBH activity is genetically controlled and highly variable in humans (Weinshilboum, 1978;Zabetian et al, 2001). The haplotype associated with low DBH activity in humans is also associated with more cocaine-induced paranoia (Cubells et al, 2000;Kalayarisi et al, 2007). This increase in one of the aversive properties of cocaine may underlie the effectiveness of DBH inhibition via disulfiram in curbing cocaine intake.…”

Section: Discussionmentioning

confidence: 99%

Effects of disulfiram and dopamine beta-hydroxylase knockout on cocaine-induced seizures

Gaval-Cruz

Schroeder

Liles

et al. 2008

Pharmacology Biochemistry and Behavior

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The antialcoholism drug disulfiram has shown recent promise as a pharmacotherapy for treating cocaine dependence, probably via inhibition of dopamine β-hydroxylase (DBH), the enzyme that catalyzes the conversion of dopamine (DA) to norepinephrine (NE). We previously showed that DBH knockout (Dbh -/-) mice, which lack NE, are susceptible to seizures and are hypersensitive to the psychomotor, rewarding, and aversive effects of cocaine, suggesting that disulfiram might exacerbate cocaine-induced seizures (CIS) by inhibiting DBH. To test this, we examined CIS in wild-type and Dbh -/-mice following administration of disulfiram or the selective DBH inhibitor nepicastat. We found that Dbh genotype had no effect on CIS probability or frequency, whereas disulfiram, but not nepicastat, increased the probability of having CIS in both wild-type and Dbh -/-mice. Both disulfiram and nepicastat increased CIS frequency in wild-type but not Dbh -/-mice. There were no genotype or treatment effects on serum cocaine levels, except for an increase in disulfiram-treated Dbh -/-mice at the highest dose of cocaine. These results suggest that disulfiram enhances CIS via two distinct mechanisms: it both increases CIS frequency by inhibiting DBH and increases CIS frequency in a DBH-independent manner.

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Section: Discussionmentioning

confidence: 99%

Effects of disulfiram and dopamine beta-hydroxylase knockout on cocaine-induced seizures

Gaval-Cruz

Schroeder

Liles

et al. 2008

Pharmacology Biochemistry and Behavior

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“…CT heterozygotes have levels about 50% lower than those found in CC homozygotes, whereas TT homozygotes have very low DBH activity (B10% of CC). Also of note, individuals receiving disulfiram treatment have reported a higher incidence of paranoia associated with cocaine use than those not receiving disulfiram (Hameedi et al, 1995;McCance-Katz et al, 1998a, b), and individuals with genetically low DBH activity appear to be particularly susceptible to cocaine-induced paranoia (Cubells et al, 2000;R Malison, personal communication).…”

Section: Disulfiram and Cocaine Dependencementioning

confidence: 99%

“…The effects of disulfiram and DBH mutations on catecholamine levels are additive in mice (Bourdelat-Parks et al, 2005), and individuals with low DBH activity are more susceptible to some aversive side effects of disulfiram, including psychosis (Heath et al, 1965;Ewing et al, 1977;Major et al, 1979) and sedation (Ewing et al, 1978). In a recent genotype-controlled pilot study, disulfiram effectively reduced cocaine intake only in individuals carrying at least one low-activity DBH allele (Cubells et al, 2000). Together, these combined results suggest the existence of a second aversive 'Antabuse reaction' that promotes cocaine abstinence and that is mediated by inhibition of DBH, not aldehyde dehydrogenase.…”

Section: Disulfiram and Cocaine Dependencementioning

confidence: 99%

There and Back Again: A Tale of Norepinephrine and Drug Addiction

Weinshenker

Schroeder

2006

Neuropsychopharmacol

322

277

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Fueled by anatomical, electrophysiological, and pharmacological analyses of endogenous brain reward systems, norepinephrine (NE) was identified as a key mediator of both natural and drug-induced reward in the late 1960s and early 1970s. However, reward experiments from the mid-1970s that could distinguish between the noradrenergic and dopaminergic systems resulted in the prevailing view that dopamine (DA) was the primary 'reward transmitter' (a belief holding some sway still today), thereby pushing NE into the background. Most damaging to the NE hypothesis of reward were studies demonstrating that NE receptor antagonists and NE reuptake inhibitors failed to impact drug self-administration. In recent years new tools, such as genetically engineered mice, and new experimental paradigms, such as reinstatement of drug seeking following withdrawal, have propelled NE back into the awareness of addiction researchers. Of particular interest is disulfiram, an inhibitor of the NE biosynthetic enzyme dopamine b-hydroxylase, which has demonstrated promising efficacy in the treatment of cocaine dependence in preliminary clinical trials. The purpose of this review is to synthesize the new data linking NE to critical aspects of DA signaling and drug addiction, with a focus on psychostimulants (eg, cocaine), opiates (eg, morphine), and alcohol.

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“…19 The primers were: 5 0 -CTGTATTTG GAACTTGGCATC-3 0 (forward) and 5 0 -AGG CATTTTACTACCCAGAGG-3 0 (reverse). Methods for genotyping the other SNPs have been published previously 7,9,11 and are available from the corresponding author (JFC).…”

Section: Samplesmentioning

confidence: 99%

“…7 -14 These polymorphisms include an insertion/deletion polymorphism located approximately 3 kb 5 0 to the DBH transcriptional start site. 7 Another polymorphism is À1021C-T (rs1611115), a single-nucleotide polymorphism (SNP) located approximately 1 kb upstream of the transcriptional initiation codon of DBH that accounts for 31 -52% of the variance in pDbH in populations from diverse geographic origins. 11,15 In European Americans (EAs) and ethnic Germans, rs1611115 resides within a haplotype block (defined as described by Zabetian et al 11 ) extending from approximately -2200 bp through intron 4 (B9.9 kb), but the boundaries of the block remain imprecisely mapped.…”

Section: Introductionmentioning

confidence: 99%

Genotypic and haplotypic associations of the DBH gene with plasma dopamine β-hydroxylase activity in African Americans

et al. 2007

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Several variants at DBH are significantly associated with plasma DbH activity (pDbH). However, the overwhelming majority of data on this genotype -phenotype relationship has been gathered in samples from Europeans and European Americans (EAs). In this study, we examined the relationship between DBH polymorphisms and pDbH in samples from African-American (AA) subjects. Genotypes were determined at a 19-bp insertion/deletion polymorphism (ins/del) and four single-nucleotide polymorphisms (SNPs) at DBH in 109 samples. Analyses were performed using analyses of variance (ANOVAs) (for individual SNPs) and regression procedures (to assess the joint effects and the specific SNP-based haplotypes). We found:(1) single-variant analysis of all polymorphisms revealed apparent associations to pDbH, with rs1611115 accounting for the largest proportion of the variance in pDbH (28.7%) and ins/del the smallest (6.5%); (2) modest but significant linkage disequilibrium (LD) existed between ins/del and rs1611115; (3) LD between all other pairs of variants was not observed; (3) stepwise regression showed that a model containing rs1611115, rs2519152 and rs6271 accounted for 37.6% of the variance in pDbH, with rs6271 showing additional 7.6% above the effect of rs1611115, and rs2519152 showing additional 2% above rs1611115 and rs6271; (4) two common haplotypes, C-T-C and T-C-C at rs1611115-rs2519152-rs6271 were significantly associated with pDbH (P ¼ 0.0025 and 0.0036, respectively). The data support the validity of prior reported associations and underscore the importance of analyzing multiple SNPs across DBH in future association studies examining disease and biochemical phenotypes.

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A haplotype at the DBH locus, associated with low plasma dopamine β-hydroxylase activity, also associates with cocaine-induced paranoia

Cited by 172 publications

References 43 publications

Effects of disulfiram and dopamine beta-hydroxylase knockout on cocaine-induced seizures

Effects of disulfiram and dopamine beta-hydroxylase knockout on cocaine-induced seizures

There and Back Again: A Tale of Norepinephrine and Drug Addiction

Genotypic and haplotypic associations of the DBH gene with plasma dopamine β-hydroxylase activity in African Americans

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