Neuroendocrinological and neuropsychological correlates of dopaminergic function in nicotine dependence

136

The catechol-O-methyltransferase (COMT) gene plays a prominent role in dopaminergic circuits central to drug reward. Allelic variants within the COMT gene are therefore potential candidates for examining interindividual differences in vulnerability to nicotine dependence (ND). We analyzed five single nucleotide polymorphisms (SNPs), including the Val/Met variant (rs4680), which results in a three-to fourfold difference in enzyme activity within COMT, for association with the three ND measures, SQ, HSI, and FTND, in 602 nuclear families of African-American (AA) or European-American (EA) origin. The Val/Met variant showed a significant association with the three ND measures in the pooled and EA samples and with FTND in the AA sample. Haplotype analysis revealed a major protective A-G-T haplotype (frequency 23.6%) for rs740603-rs4680-rs174699 in the AA sample (minimum Z ¼ À3.35; P ¼ 0.0005 for FTND), a major protective T-G-T haplotype (frequency 15.2%; minimum Z ¼ À2.92; P ¼ 0.003 for FTND) in the EA sample, and a high-risk C-A-T haplotype (frequency 16.9%; minimum Z ¼ 3.16; P ¼ 0.002 for SQ) in the AA sample for rs933271-rs4680-rs174699. Furthermore, we found that the significant haplotypes within COMT were gender-specific and the significantly associated A-G-T is protective in AA females only, whereas T-G-T is protective in EA males only. Moreover, we found a major high-risk T-A-T haplotype (frequency 56.7%) that showed significant association with the three ND measures in EA males. Further examination of two protective haplotypes, A-G-T in AAs and T-G-T in EAs, indicated that the low COMT enzyme activity Met allele is protective to become nicotine dependent. In summary, our results provide evidence for a role of COMT in the susceptibility to ND and further confirm that its effect is ethnic and gender specific.

Section: Discussionsupporting

confidence: 92%

Significant Association of Catechol-O-Methyltransferase (COMT) Haplotypes with Nicotine Dependence in Male and Female Smokers of Two Ethnic Populations

Beuten

Payne

Jennie

et al. 2005

136

“…In particular, smoking withdrawal seems to be associated with a hypo-dopaminergic state in humans (Smolka et al, 2004) and animals (Fung et al, 1996;Epping-Jordan et al, 1998), which could lead to abnormal neural activity in areas implicated in cue-reactivity, in particular the DLPFC, ACC, and striatum.…”

Section: Introductionmentioning

confidence: 99%

Effects of Expectancy and Abstinence on the Neural Response to Smoking Cues in Cigarette Smokers: an fMRI Study

McBride

Barrett

Kelly

et al. 2006

295

240

Cues associated with drug taking can trigger relapse, drug seeking, and craving in addicted individuals. Behavioral studies suggest that drug availability and withdrawal can affect the individual response to drug cues. Moreover, the importance of subjective craving in cue-induced relapse has been questioned and an alternative model put forward according to which drug cues trigger habitual drug-seeking behaviors independently of craving. We used functional magnetic resonance imaging to compare the brain response to smoking and control videotapes in 20 healthy smokers, while varying their expectancy to smoke and abstinence levels. The neural response to cigarette cues was strongly modulated by expectancy and, to a lesser extent, abstinence. In people expecting to smoke immediately after the scan, smoking cues activated brain areas implicated in arousal, attention, and cognitive control. However, when subjects knew they would not be allowed to smoke for 4 h, there was almost no brain activation in response to smoking cues, despite equivalent reported levels of craving. In the dorsolateral prefrontal cortex, the neural response was a function of both craving and expectancy. Thalamo-cingulate connectivity, thought to be an index of arousal, was greater during expectancy than nonexpectancy. Our findings confirm the importance of expectancy in the neural response to drug cues, and lend support to the theory that these cues act on brain areas involved in arousal and attention.

“…Acute nicotine produces both rewarding and aversive stimulus properties (Laviolette and van der Kooy, 2004;Sellings et al, 2008;Wilkinson and Bevins, 2008). Dopaminergic signaling is involved in acute nicotine aversion (Laviolette and van der Kooy, 2003;Tan et al, 2009) and chronic nicotine motivation (Bruijnzeel and Markou, 2005;Kenny and Markou, 2001;Laviolette et al, 2008;Smolka et al, 2004); however, little is known regarding the role of dopaminergic signaling in the opponent motivational processes of acute and chronic nicotine.…”

Section: Introductionmentioning

confidence: 99%

Dopaminergic Signaling Mediates the Motivational Response Underlying the Opponent Process to Chronic but Not Acute Nicotine

Grieder

Sellings

Vargas‐Perez

et al. 2009

The mesolimbic dopamine (DA) system is implicated in the processing of the positive reinforcing effect of all drugs of abuse, including nicotine. It has been suggested that the dopaminergic system is also involved in the aversive motivational response to drug withdrawal, particularly for opiates, however, the role for dopaminergic signaling in the processing of the negative motivational properties of nicotine withdrawal is largely unknown. We hypothesized that signaling at dopaminergic receptors mediates chronic nicotine withdrawal aversions and that dopaminergic signaling would differentially mediate acute vs dependent nicotine motivation. We report that nicotine-dependent rats and mice showed conditioned place aversions to an environment paired with abstinence from chronic nicotine that were blocked by the DA receptor antagonist a-flupenthixol (a-flu) and in DA D 2 receptor knockout mice. Conversely, a-flu pretreatment had no effect on preferences for an environment paired with abstinence from acute nicotine. Taken together, these results suggest that dopaminergic signaling is necessary for the opponent motivational response to nicotine in dependent, but not non-dependent, rodents. Further, signaling at the DA D 2 receptor is critical in mediating withdrawal aversions in nicotine-dependent animals. We suggest that the alleviation of nicotine withdrawal primarily may be driving nicotine motivation in dependent animals. Neuropsychopharmacology (2010) 35, 943-954;