The human serotonin (5-hydroxytryptamine) transporter, encoded by the SLC6A4 gene on chromosome 17q11.1-q12, is the cellular reuptake site for serotonin and a site of action for several drugs with central nervous system effects, including both therapeutic agents (e.g. antidepressants) and drugs of abuse (e.g. cocaine).
Consequently, we examined how serotonin transporter (5-HTTLPR) polymorphisms, monoamine oxidase-A (MAO-A) variants, and childhood abuse measured with the Childhood Trauma Questionnaire relate to dimensions of psychopathy in a forensic sample of 237 men with elevated levels of environmental adversity.
Imaging gene-substance interactions: the effect of the DRD2 TaqIA polymorphism and the dopamine agonist bromocriptine on the brain activation during the anticipation of reward.
Future studies with ICSS could help (a) to clarify mechanisms that increase MOR agonist abuse potential during early opioid exposure or during chronic exposure leading to dependence, (b) to evaluate novel opioids either developed as candidate analgesics with reduced abuse potential or identified as designer opioids being synthesized and distributed for illicit use, and (c) to test candidate pharmacotherapies for treatment of opioid abuse in non-dependent and dependent subjects.
With severity of abuse accounted for in the model, genetic effects of the DRD2 and DRD4 polymorphisms were still significant (DRD2 TaqIB: p = 0.001, DRD2 TaqIA: p = 0.008, DRD4 -616 C/G: p = 0.002).
To deal successfully with the opioid crisis, we need to discover novel analgesics whose mechanisms do not involve the mu opioid receptor but that have high analgesic potency and low risk of adverse effects, particularly no abuse liability.The question is how to achieve this.
The DRD2 genotype may pose an increased risk for alcohol use and abuse, depending on the presence of environmental risk factors, such as alcohol-specific parenting.
The dopamine D2 receptor gene (DRD2) appears to be one of these genes since variants at this locus are significantly increased in frequency in TS, ADHD, conduct disorder and drug abuse.
Sensation Seeking was elevated in carriers of the low-function allele of the DRD2 Taq1A polymorphism who also reported childhood sexual abuse, relative to that in individuals showing other combinations of alleles and abuse exposures.
Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators.
Our data are consistent with the hypothesis that DRD2 gene variants marked by these polymorphisms may work, probably in concert with other genetic and environmental factors, to enhance vulnerability to psychostimulant abuse.
The SS genotype of the serotonin transporter gene (5-HTTLPR) was associated with high levels of impulsivity when the subjects reported emotional abuse [odds ratio (OR) 5.55, 95% confidence interval (CI) 1.75-17.5] or physical abuse (OR 5.03, 95% CI 1.50-16.9) in their childhood.
The relationship of various dimensions of temperament, measured by the Tridimensional Personality Questionnaire (TPQ), to polymorphisms of the D2 dopamine receptor (DRD2) and D4 dopamine receptor (DRD4) genes was determined in 119 healthy Caucasian boys who had not yet begun to consume alcohol and other drugs of abuse.
Our results point to a gene-gene-environment interaction that relevantly impacts on the role of the s/s genotype of the 5-HTTLPR in childhood abuse: Depending on the BDNF background (Val/Val versus Met allele) the s/s genotype showed either protective or risk properties with regard to depressive symptoms.
For the four MDD outcome measures, we examined the direct effects of 5-HTTLPR/rs25531-haplotypes, five environmental factors (lifetime and recent stressful life-events, sexual abuse, low educational attainment, and childhood trauma) and their interaction in logistic regression models.
However, under an additive model there was also an interaction between sexual and physical abuse considered independently and 5-HTTLPR, and no interaction with traumatic life events.
The recently shown efficacy of these analgesics combined with a possible lower abuse potential and side effect burden than mu opioid receptor agonists makes delta and peripherally restricted kappa opioid receptor agonists promising targets for treating pain.
Similarly, women with a BSD who reported a history of childhood sexual abuse showed a trend-level elevation of DRD2 methylation compared to our NED group.
The combination of MOR agonists with non-MOR agonists may increase the analgesic potency of MOR agonists, reduce the development of tolerance and dependence, reduce the diversion and abuse, overdose, and reduce other clinically significant side effects associated with prolonged opioid use such as constipation.