2006 - 2007 Publications > Genetics of Opioid Addiction

Genetics of Opioid Addiction

Gelernter et al, 2006 identified a locus on chromosome 17 at 103 cM for heavy opioid user for both African American and European Americans with combined LOD of 3.06. For this map position a LOD of 1.76 was observed for DSM-IV opioid dependence.  Thus Gelernter was able to identify a subgroup that is less heterogeneous than the one defined by DSM-IV diagnosis.  This is the first step to identify gene variants that confer vulnerability to addiction to opiates Am J Hum Genet. 2006 May;78(5):759-69.     

Glatt et al 2006 identified preliminary evidence for suggestive linkage for heroin dependence on chromosomal region 4q31.21 at 143.3 cM and on at 53.4 cM on chromosomal region 17q11.2 in Han Chinese.  The loci on chr 17 is within 25 cM of Gelernter et al (2006) finding of linkage for non-opioid dependent subjects.  Am J Med Genet B Neuropsychiatr Genet. 2006 Sep 5;141(6):648-52  

In a post morten study of heroin addicts in Sweden Drakenberg et al (2006) found a significant association of the A118G mu opioid receptor with heroin addiction.  Marked reduction of prokenphalin and prodynorphin transcription was observed in the shell of the nucleus accumbens of heroin addicts with A118G alleles that was accompanied by increased levels of enkephalin and dynorphin.  Drakenberg et al (2006) suggest that low levels  of HERC1 an E3 ubiquitin–protein ligase  regulating protein degredation may explain the increase levels of enkephalin and dynorphin in the striatum of heroin addicts with the A118G allele. Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3908-13

Zachariou et al, 2006 reports that overexpression of deltaFosB in the nucleus accumbens increases the rewarding effects of morphine, intensifies the symptoms of morphine withdrawal, and increase the rate of analgesic tolerance to morphine.  At the same time the analgesic of morphine are attenuated.  Zachariou suggests that these effects are mediated by deltaFosB increasing the expression of the opioid peptide dynorphin. Nat Neurosci. 2006 Feb;9(2):205-11

Li et al 2006 showed Mice lacking calmodulin-stimulate adenylyl cyclase (AC1 and AC8) show normal antinoceptive responses but morphine tolerance, naloxone precipitated withdrawal, morphine hyperlocomotion and morphine conditioned place preference are significantly attenuated in the double knockout mice.  CREB phosphorylation was also blocked in the double knockout mice suggesting that CREB activation requires the activation of AC1 and AC8 (Mol Pharmacol. 2006 Nov;70(5):1742-9)

Kim et al (2006) show that the behavioral effects of morphine, including locomotor activation, analgesia, tolerance, reward, and physical dependence and withdrawal symptoms, are attenuated in mice lacking adenylyl cyclase type 5 (AC5), a form of adenylyl cyclase that is highly enriched in striatum. Furthermore, the behavioral effects of selective mu or delta opioid receptor agonists are lost in AC5-/- mice, whereas the behavioral effects of selective kappa opioid receptor agonists are unaffected Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3908-13  

CXBK mice, recombinant inbred mice derived from C57BL/6By and BALB/cBy progenitors, display reduced morphine-induced analgesia that is associated with reduced levels of the MOR-1 transcript.  The MOR-1 transcript of the CXBK contains an abnormally long 3’ untranslated region that contains an intracisternal A-particle element insertion.  Han et al 2006 suggest that MOR-1 3’ untranslated region produces the reduced morphine responses in CXBK mice as compared to BALB/cBy mice.  These result may suggest the mechanism underlying the differences in sensitivity to opiates in humans.  Pharmacogenet Genomics. 2006 Jun;16(6):451-60 

Bart et al, 2006 reports that healthy subjects with at least one copy of the A118G allele in exon 1 of the Mu opioid receptor gene show elevated basal cortisol levels. Neuropsychopharmacology. 2006 Oct;31(10):2313-7

Proudnikov et al 2006 reports a point-wise nominally significant association of allele 1180G with a protective effect from heroin addiction in people of European ancestry Pharmacogenet Genomics. 2006 Jan;16(1):25-36.