Kreek MJ, Bart G, Lilly C, LaForge KS, Nielsen DA. Pharmacogenetics and human molecular genetics of opiate and cocaine addictions and their treatments. Pharmacol Rev 57: 1-26

The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, Box 171, 1230 York Avenue, New York, New York 10021, USA.
Pharmacological Reviews (Impact Factor: 17.1). 04/2005; 57(1):1-26. DOI: 10.1124/pr.57.1.1
Source: PubMed

ABSTRACT Opiate and cocaine addictions are major social and medical problems that impose a significant burden on society. Despite the size and scope of these problems, there are few effective treatments for these addictions. Methadone maintenance is an effective and most widely used treatment for opiate addiction, allowing normalization of many physiological abnormalities caused by chronic use of short-acting opiates. There are no pharmacological treatments for cocaine addiction. Epidemiological, linkage, and association studies have demonstrated a significant contribution of genetic factors to the addictive diseases. This article reviews the molecular genetics and pharmacogenetics of opiate and cocaine addictions, focusing primarily on genes of the opioid and monoaminergic systems that have been associated with or have evidence for linkage to opiate or cocaine addiction. This evidence has been marshalled either through identification of variant alleles that lead to functional alterations of gene products, altered gene expression, or findings of linkage or association studies. Studies of polymorphisms in the mu opioid receptor gene, which encodes the receptor target of some endogenous opioids, heroin, morphine, and synthetic opioids, have contributed substantially to knowledge of genetic influences on opiate and cocaine addiction. Other genes of the endogenous opioid and monoaminergic systems, particularly genes encoding dopamine beta-hydroxylase, and the dopamine, serotonin, and norepinephrine transporters have also been implicated. Variants in genes encoding proteins involved in metabolism or biotransformation of drugs of abuse and also of treatment agents are reviewed.

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    • "Importantly, dynorphin-like peptides and κ-opioid receptors are expressed and localized, among others, in mesolimbic-mesocortical systems (i.e., ventral tegmental area, nucleus accumbens, and prefrontal areas (Shippenberg, 2009)) and are assumed to exert tonic inhibitory control over striatal dopamine release (Bruijnzeel, 2009; Kreek et al., 2002; Lutz and Kieffer, 2013; Margolis et al., 2006; Steiner and Gerfen, 1998). In particular, dynorphin peptides lower basal, but also drug-induced dopamine levels in these systems (Kreek, et al., 2005). Dopamine neurons of the ventral tegmental area (the starting point of the mesolimbic dopamine system) receive input from neurons innervated by dynorphin and also express κ-opioid receptors. "
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    ABSTRACT: Recent research suggests that not only the dopamine neurotransmitter system but also the endogenous opioid system is involved in performance monitoring and the generation of prediction error signals. Therefore, the current study investigated the potential link between the functional opioid peptide prodynorphin (PDYN) 68bp VNTR genetic polymorphism and neuronal correlates of performance monitoring. To this end, forty-seven healthy participants genotyped for this polymorphism, related to high-, intermediate-, and low-expression levels of PDYN, performed a choice-reaction task while their electroencephalogram (EEG) was recorded. On the ehavioural level, no differences between the three PDYN groups could be observed. EEG data, however, showed significant differences. High PDYN expression individuals showed heightened neural error processing indicated by higher ERN amplitudes, compared to intermediate and low expression individuals. Later stages of error processing, indexed by late Pe amplitudes, and stimulus-driven conflict processing, indexed by N2 amplitudes, were not affected by PDYN genotype. The current results corroborate the notion of an indirect effect of endogenous opioids on performance monitoring, probably mediated by the mesencephalic dopamine system. Overall, enhanced ERN amplitudes suggest a hyper-active performance monitoring system in high PDYN expression individuals, and this might also be an indicator of a higher risk for internalizing disorders. Copyright © 2015. Published by Elsevier Ltd.
    Neuropsychologia 09/2015; DOI:10.1016/j.neuropsychologia.2015.08.028 · 3.30 Impact Factor
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    • "The GG mice have a four-fold greater vStr/NAcc DA release to alcohol than the former (Ramchandani et al., 2011). Also this gene is involved in opiate and cocaine addiction and treatment (Kreek et al., 2005). Recently Zhang et al. (2015) found that GG mice self-administrated more heroin and had more brain dopamine release in response to heroin than AA mice. "
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    ABSTRACT: To determine if overnight tobacco abstinent carriers of the AG or GG (*G) vs. the AA variant of the human mu opioid receptor (OPRM1) A118G polymorphism (rs1799971) differ in [(11)C]carfentanil binding after tobacco smoking. Twenty healthy American male smokers who abstained from tobacco overnight were genotyped and completed positron emission tomography (PET) scans with the mu opioid receptor agonist, [(11)C]carfentanil. They smoked deniconized (denic) and average nicotine (avnic) cigarettes during the PET scans. Smoking avnic cigarette decreased the binding potential (BPND) of [(11)C]carfentanil in the right medial prefrontal cortex (mPfc; 6,56,18), left anterior medial prefrontal cortex (amPfc; -2,46,44), right ventral striatum (vStr; 16, 3, -10), left insula (Ins; -42,10,-12), right hippocampus (Hippo; 18,-6,-14) and left cerebellum (Cbl; -10,-88,-34), and increased the BPND in left amygdala (Amy; -20,0,-22), left putamen (Put; -22, 10,-6) and left nucleus accumbens (NAcc; -10,12,-8). In the AA allele carriers, avnic cigarette smoking significantly changed the BPND compared to after denic smoking in most brain areas listed above. However in the *G carriers the significant BPND changes were confirmed in only amPfc and vStr. Free mu opioid receptor availability was significantly less in the *G than the AA carriers in the Amy and NAcc. The present study demonstrates BPND changes induced by avnic smoking in OPRM1 *G carriers were blunted compared to the AA carriers. Also *G smokers had less free mu opioid receptor availability in Amy and NAcc. Copyright © 2015. Published by Elsevier Inc.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 01/2015; 59. DOI:10.1016/j.pnpbp.2015.01.007 · 3.69 Impact Factor
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    • "Overall, cocaine appears to primarily act by inhibiting presynaptic dopamine transporters, but also hinders serotonin and norepinephrine transporters (Sora et al., 2001; Hall et al., 2004; Kreek et al., 2005; Hall et al., 2009), and may also secondarily dysregulate inhibitory GABAergic function (Cameron & Williams, 1994). Cocaine also modulates the endogenous opioid system, especially MOR, κ opioid receptors (KOR), and preprodynorphin (Kreek et al., 2005). "
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    ABSTRACT: Considerable insight has been gained into the comorbid, interactive effects of HIV and drug abuse in the brain using experimental models. This review, which considers opiates, methamphetamine, and cocaine, emphasizes the importance of host genetics and glial plasticity in driving the pathogenic neuron remodeling underlying neuro-acquired immunodeficiency syndrome and drug abuse comorbidity. Clinical findings are less concordant than experimental work, and the response of individuals to HIV and to drug abuse can vary tremendously. Host-genetic variability is important in determining viral tropism, neuropathogenesis, drug responses, and addictive behavior. However, genetic differences alone cannot account for individual variability in the brain "connectome." Environment and experience are critical determinants in the evolution of synaptic circuitry throughout life. Neurons and glia both exercise control over determinants of synaptic plasticity that are disrupted by HIV and drug abuse. Perivascular macrophages, microglia, and to a lesser extent astroglia can harbor the infection. Uninfected bystanders, especially astroglia, propagate and amplify inflammatory signals. Drug abuse by itself derails neuronal and glial function, and the outcome of chronic exposure is maladaptive plasticity. The negative consequences of coexposure to HIV and drug abuse are determined by numerous factors including genetics, sex, age, and multidrug exposure. Glia and some neurons are generated throughout life, and their progenitors appear to be targets of HIV and opiates/psychostimulants. The chronic nature of HIV and drug abuse appears to result in sustained alterations in the maturation and fate of neural progenitors, which may affect the balance of glial populations within multiple brain regions.
    International Review of Neurobiology 09/2014; 118C:231-313. DOI:10.1016/B978-0-12-801284-0.00009-9 · 1.92 Impact Factor
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