If a person carries a gene predisposing them to becoming a substance abuser, is it inevitable that they eventually will?
While the relationship between genes and addiction is a complicated one, there is a clear link between genetics and addiction. Only after taking many college courses in subjects such as psychology, and psychopharmacology, did I decide that bringing children into this world, with my genetic history, could be ok if I provide a wholesome environment and teach them to value this information. From my position, I have to be diligent if I want my children to live healthy lifestyles (particularly in adolescence and early adulthood when they are more susceptible to risky, impulsive behavior—the prefrontal cortex, which is associated with decision making, is not fully myelinated, or “online”, until the mid-to-late 20’s). The environment in which I raise my daughter is crucially integral to her success, as she is vulnerable to substance abuse and bipolar disorder. Genetic predisposition to substance abuse does not mean that one will become an addict. For instance, addiction and genes (follow the link for more information on addiction and genes), indicate that an allele of the dopamine receptor gene, called DRD2, is commonly found in individuals addicted to opioids, cocaine and alcohol. Dopamine, a neurotransmitter, and the reward pathway are essential to appetitive and addictive behaviors, so the A1 allele is likely related to increased sensitivity of the reward pathway to those substances. An allele is simply a version of a gene. For example, the gene that determines eye color has a blue eye color allele. In the instance of the A1 allele of the DRD2*2 gene, we can infer that one person may enjoy certain drugs more than another person, this also highlights the importance of environment. We may consider the evolutionary need for these appetitive behaviors and why the reward pathway exists; It is not inherently negative, but actually necessary to survival in many ways.
Clues are present in the following pedigree that suggest a genetic component to substance abuse:
A pedigree is a common way to examine genetic links without having to actually examine genes. Circles represent females and squares represent males. The filled in squares and circle show phenotypical signs of a trait or disorder. When there is a line between the shapes it indicates marriage, or a similar type of relationship and a downward line indicates offspring. When examining the pedigree above, the first and second generations provide little evidence of a genetic component to substance abuse. If we look at the third generation, we see that there may be a recessive or pseudodominant genetic component. It appears as though substance abuse potential was inherited and because there were no phenotypical signs in the second generation, we may assume the trait is recessive (but is it really recessive?). In genetics, the phenotype is the visible trait–like brown eyes–and the genotype is based on the genes we have. Substance abuse disorders and the related genes can be tricky to analyze because of the masking ability of environment, the multivariable risk-factors, and the complexity of the genes involved. For instance, if one never uses nicotine, they will not know they have increased potential of addiction to the substance. Some may smoke a few cigarettes and strongly dislike them while others may some a few cigarettes and love them. Further, a person who does not have increased potential to addiction, can still become addicted to a substance, though it is less likely because of the harmful side-effects. This is one reason non-human animal models are so helpful; we can precisely control their environment, insert genes, remove genes, and give them addictive substances.
In the pedigree, it appears as though substance abuse is recessive pseudodominant. From what we understand about the difference between epigenetics and mutations we can see that it is important to analyze the conditions in which each family member is living. Epigenetic changes are not changes to the DNA code itself, just reversible modification; A mutation is an actual change to the genetic code. Both can be passed from generation to generation in different ways. For the most part, mutations are considered permanent without intervention, and epigenetic changes are maliable to environmental influence. We may discover that there is epigenetic inheritance because of environmental changes and continued exposure to that environment, like a child raised around alcoholism, who grows up and abuses alcohol around her own children. In the case that the individual was adopted and exhibits the trait (alcoholism) outside of the toxic environment, we may entertain the idea that a mutation is responsible. In these cases, it is difficult decipher precisely how much each gene influences the trait of interest. The best way to discover if it is a mutation or a heritable epigenetic change is by examining a gene and discovering methylation, either methylation of a C or sometimes a methyl of acetyl group may influence histones. In fact, there are at least 5 different ways that histones can be chemically modified to bring about epigenetic changes. There are many genes involved so it is not an easy task to sort out such scenarios. Histones are proteins that are tightly wrapped in DNA. In order for a gene to be expressed, the DNA must loosen, exposing the area of the gene that must be copied. So, histones along with methyl and acetyl groups mediate which genes are expressed, or exhibited.
Which gene variant(s) predispose individuals to abuse alcohol more frequently and/or readily? What is known, if anything, about the biological process involved?
An allele (A1) of the DRD2 dopamine receptor gene is common in alcoholics, opioid addicts and also cocaine addicts. As mentioned above, this is thought to be associated with how drugs affect the reward system/reward processing. Reward processing is a product of the limbic system, which include the mesolimbic and meso-cortical pathways. Both dopaminergic axonal pathways that induce or suppress appetitive, hedonic behavior. The mesolimbic pathway is associated with reward seeking, whereas the meso-cortical pathway is associated with inhibitory signals from the prefrontal cortex saying, “well that sounds fun but it is a terrible idea”. Some consider the prefrontal cortex an honorary member of the limbic system because of its importance in inhibition and decision making. Weighting and processing of reward, or risk assessment is often skewed in addicts. Mice, and many other animals have similar systems, especially regarding the mesolimbic pathway, their prefrontal cortex is not quite as advanced as ours, but they make wonderful test subjects. Studies show that mice with variations in the Per1 and Per2 genes drink much more alcohol than normal, especially when anxious. Adolescents and adults have similarly patterned behavior, according to the website. Further, an allele ALDH2*2 (alcohol dehydrogenase 2) causes a person to have issues processing alcohol, making them more likely to become nauseated after drinking. Other symptoms that may accompany include, increased heartrate, headache and facial flushing. This allele contributes to alcohol aversion.
Are results obtained in model systems such as Drosophila and mice are applicable to what we might expect in humans?
Absolutely! As I mentioned above, as detrimental as it can be, the reward pathway is actually essential in many ways, so it is evolutionarily ancient. The limbic system is responsible for instinctive behaviors such as feeding, aggression, sex, and the stress-response. While it is not the only neurotransmitter involved, dopamine is the key player in hyper hedonic activity. Influx of dopamine can be caused by drugs themselves, or other activities that we enjoy. It is said that to be considered pathologically addicted, an individual must experience an influx of dopamine brought on by a substance or activity. This neurotransmitter, and the limbic system structures are present in many nonhuman animal species, making it easy to use these animal models for research purposes. Ethology has been immensely important in many scientific discoveries of human behavior. Scientists find the nonhuman model that most lends itself to studying the phenomena in question by examining differences and similarities between humans and animal counterparts. Animal studies, lesion studies, fMRI, and natural damage from war—famine—disease—natural disaster, all contribute to the body of knowledge we have on human physiology and neural structure. Historically, there were fewer regulations, and some pretty heinous things were done on humans (like the frontal lobotomy), but now there are more regulations and nonhuman animal models are common in invasive studies. It is worth mentioning, there are also regulations prohibiting animal cruelty in science, they are just much less limiting than those regarding research on humans (Kalat, 2019).