Medications for the Treatment of Addiction – A Neurobiological Perspective

Individual Differences and Medication Development

Widespread attempts are being made to identify genetic markers that may be involved in addiction. However, a more exciting possibility is that single-nucleotide polymorphisms in certain genes in the human population may predict a vulnerability to certain subtypes of excessive drinking syndromes and predict responsiveness to the use of medications in the treatment of alcoholism. Animal and human studies are beginning to exploit this tremendous opportunity.

Genetic association studies have focused on two pathways: one that represents the reward side of addiction (μ opioid peptide system) and one that represents the “dark side” of addiction (CRF brain stress system). The human μ opioid receptor is encoded by the OPRM1 gene and is a candidate for the pharmacogenetic variability of the clinical effects of opioid drugs and clinical effects in addiction of anti-opioid receptor drugs. Mutations in the OPRM1 gene have been found in the promoter, coding regions and intron of the gene. One mutation that has received considerable attention is the 118A>G single-nucleotide polymorphism, which causes an amino acid substitution at position 40 of the μ opioid receptor protein where asparagine is substituted with aspartate (termed Asp40 or the G allele). Normal human subjects with this variant allele have been shown to require almost twice as high a plasma level of morphine to achieve the same analgesic response as subjects with the non-mutated allele. In addition, human subjects with this variant allele may respond more robustly to naltrexone treatment than carriers of the more common 118A allele. Subjects with alcoholism and the 118G allele have been termed those with “endorphin-dependent alcoholism,” and subjects with this allele are represented in one-third of subjects of European ancestry with alcoholism (for further reading, see Heilig et al., 2011).

An association was also found between two single-nucleotide polymorphisms of the CRF1 receptor gene (crhr1) and binge drinking in adolescent and alcohol-dependent adults. Homozygosity at one of these polymorphisms (rs1876831, C allele) was associated with heavy drinking in relation to stressful life events in adolescents. rs1876831 is located on an intron that can potentially influence the transcription of the CRF1 receptor gene (Table 9.5; for further reading, see Blomeyer et al., 2008).

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