Dopamine and opioid gene variants are associated with increased smoking reward and reinforcement owing to negative mood

Behav Pharmacol. 2008 Sep;19(5-6):641-9. doi: 10.1097/FBP.0b013e32830c367c.


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 2x2 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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Affect / drug effects*
  • Alleles
  • Dopamine Plasma Membrane Transport Proteins / genetics*
  • Dose-Response Relationship, Drug
  • Female
  • Genotype
  • Humans
  • Male
  • Minisatellite Repeats / genetics
  • Nicotine / pharmacology*
  • Polymorphism, Single Nucleotide / genetics
  • Protein Serine-Threonine Kinases / genetics*
  • Receptors, Dopamine D3 / genetics*
  • Receptors, Dopamine D4 / genetics*
  • Receptors, Opioid, mu / genetics*
  • Reinforcement, Psychology*
  • Reward*
  • Serotonin Plasma Membrane Transport Proteins / genetics*
  • Set, Psychology
  • Smoking / genetics*
  • Smoking / psychology
  • Taq Polymerase / genetics*
  • Tobacco Use Disorder / genetics*
  • Tobacco Use Disorder / psychology
  • Young Adult


  • DRD3 protein, human
  • DRD4 protein, human
  • Dopamine Plasma Membrane Transport Proteins
  • OPRM1 protein, human
  • Receptors, Dopamine D3
  • Receptors, Opioid, mu
  • SLC6A3 protein, human
  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins
  • Receptors, Dopamine D4
  • Nicotine
  • ANKK1 protein, human
  • Protein Serine-Threonine Kinases
  • Taq Polymerase