Gene Variants of Brain Dopamine Pathways and Smoking-Induced Dopamine Release in the Ventral Caudate/Nucleus Accumbens

Abstract

Smokers with genes associated with low resting dopamine tone have greater smoking-induced (phasic) dopamine release than those with alternate genotypes. These findings suggest that dopamine system genotype variabilities explain a significant proportion of the interindividual variability in smoking-induced dopamine release and indicate that smoking-induced dopamine release has a genetic predisposition.

Methylphenidate Effects on Brain Activity as a Function of SLC6A3 Genotype and Striatal Dopamine Transporter Availability

“…For example, research on reward sensitivity showed that BOLD during reward anticipation and delivery, as well as during presentation of reward-related stimuli is larger for 9R carriers than 10R hetero-and homozygotes (Dreher et al, 2009;Forbes et al, 2009;Franklin et al, 2009). Direct support of enhanced striatal DA release in 9R carriers was obtained following smoking in a [ 11 C]raclopride PET study (Brody et al, 2006), in agreement with studies suggesting the 9R allele to be associated with enhanced dopaminergic output. Overall, Dreher et al (2009) conclude that '9R carriers, irrespective of the investigated domain, show hyper-responsivity of specific brain networks' (p 620), compatible with our finding of greater BOLD following MPH in 9R carriers than 10/10 homozygotes (however, see Wittmann et al, 2013).…”

Lack of association between dopamine receptor D4 variable numbers of tandem repeats gene polymorphism and smoking

“…After nicotine exposure, inhibitory effects of GABA are reduced and positive effects of glutamatergic and cholinergic projections are increased, resulting in increased dopamine release from VTA [19,27]. Smokers, DRD4 short allele carriers, who have low resting dopamine tone, had greater smoking-induced dopamine release than individuals with other DRD4 genotypes [4,32]. Brody et al [4] reported an association between decreased craving and increased dopamine concentration with smoking.…”

“…Smokers, DRD4 short allele carriers, who have low resting dopamine tone, had greater smoking-induced dopamine release than individuals with other DRD4 genotypes [4,32]. Brody et al [4] reported an association between decreased craving and increased dopamine concentration with smoking. In DRD4 long allele carriers, the ability of dopamine to inhibit cAMP formation is decreased, and these individuals have a greater resting dopaminergic tone, and lower smoking-induced dopamine release than DRD4 short allele carriers [4].…”

“…Brody et al [4] reported an association between decreased craving and increased dopamine concentration with smoking. In DRD4 long allele carriers, the ability of dopamine to inhibit cAMP formation is decreased, and these individuals have a greater resting dopaminergic tone, and lower smoking-induced dopamine release than DRD4 short allele carriers [4]. Therefore, DRD4 long allele carriers are expected to have greater craving for nicotine and higher vulnerability to smoking.…”

Neuroimaging in Psychiatric Pharmacogenetics Research: The Promise and Pitfalls

“…For example, the G allele of the CNR1 variant rs1049353 is associated with poorer antidepressant response and weaker striatal and thalamic response to happy faces (Domschke et al, 2008), whereas a genetic variant conferring reduced expression of NPY (the rs16147 C allele) is associated with greater amygdala reactivity to emotional faces in depressed patients, and with poorer treatment Imaging psychiatric pharmacogenetics M Falcone et al (Brody et al, 2006) Imaging psychiatric pharmacogenetics M Falcone et al response among a subgroup of patients with anxious depression (Domschke et al, 2010). Although limbic reactivity to emotional faces may provide a useful measure to identify likely treatment responders or for early medication screening, important limitations of these studies include the combined analysis of patients taking a range of medications (eg, tricyclics, SSRIs, neuroleptics) and the lack of randomization to medication vs placebo.…”