Non-substance-dependent disorders, such as pathologic gambling and compulsive shopping, share many clinical features of addiction. Several lines of arguments suggest that they also share the underlying neurobiologic mechanisms. This conclusion is supported by the clinical observation that, as an adverse effect of dopamine agonist medication, patients with Parkinson’s disease may become pathologic gamblers. Other patients may develop a habit for recreational activities, such as shopping, eating compulsively, or hypersexuality. Although large-scale studies are not yet available, an estimated one in seven parkinsonian patients develops an addiction-like behavior when receiving dopamine agonists (see chapter 28).
Large individual differences exist also in vulnerability to substance-related addiction. Whereas one person may become “hooked” after a few doses, others may be able to use a drug occasionally during their entire lives without ever having difficulty in stopping. Even when dependence is induced with chronic exposure, only a small percentage of dependent users progress to addiction. For example, a retrospective analysis shows that after several decades of cocaine abuse, only 20% become addicted. With cannabis, the fraction is only 10%. A similar percentage for cocaine is also observed in rats and mice that have extended access to the drug. Surprisingly, with dopamine neuron self-stimulation, the fraction of mice that resist punishment is > 50%. Recent studies in rats suggest that impulsivity or excessive anxiety may be crucial traits that represent a risk for addiction. The transition to addiction is determined by a combination of environmental and genetic factors. Heritability of addiction, as determined by comparing monozygotic with dizygotic twins, is relatively modest for cannabinoids but very high for cocaine. It is of interest that the relative risk for addiction (addiction liability) of a drug (Table 32–1) correlates with its heritability, suggesting that the neurobiologic basis of addiction common to all drugs is what is being inherited. Further genomic analysis indicates that numerous, perhaps even hundreds of alleles need to function in combination to produce the phenotype. However, identification of the genes involved remains elusive. Although some substance-specific candidate genes have been identified (eg, alcohol dehydrogenase, nicotinic acetylcholine receptor subunits), future research will also focus on genes implicated in the neurobiologic mechanisms common to all addictive drugs. An appealing idea, now supported by experimental evidence, is the contribution of epigenetics as a determinant of addiction vulnerability. Cocaine regulates posttranslational modifications of histones, DNA methylation, and signaling via non-coding RNAs, which eventually may have an impact on behavior. The cellular mechanism involved and the relationship to synaptic plasticity are currently under investigation.
Synaptic Plasticity, Altered Circuit Function, & Addiction