“Addictive personalities”: can your genes get you hooked?

Being a student, I’ve seen for myself: most of us go out, have a good time, have more than a few drinks and maybe the more adventurous (or foolish) dabble in some of the harder substances. All in all, most of us will wake up the next morning, extremely hungover, but not obviously harmed and definitely without overwhelming urges to recover with another pint of wine. However, for a select few people, the tendency to become addicted to elicit substances is considerably higher. These nights, which seem like harmless fun and just part of the package of being young and a student, can lead on to devastating and unforeseen consequences.

The idea of an “addictive personality” is not a new concept and studies have demonstrated that an individual’s genetic material, in combination with environmental factors experienced throughout their life, can directly influence how likely they are to become “hooked”. Here – I’m going to begin to explain how a change of just a few DNA bases out of 3 billion can increase the likelihood of someone developing characteristics of an addict and why these select few have such a high relapse rate in recovery (70-80 % of recovering addicts relapse within a year!)

Synapses in the brain communicate using neurotransmitters such as dopamine

Dopamine, is a neurotransmitter in the brain, which is vital for survival. Not only is it involved in complex circuits which allow us to maintain precise and coordinated control of our physical movements, but it is also the main chemical released in the “rewards pathway” in the brain. Through evolution, it has been necessary for us to be motivated to seek food, water and sex to survive and make sure the population is sustained. This innocent urge to live is has shaped the dopamine pathway which has made us love, crave and seek necessities which are key to flourishing as a species. It stimulates us to seek rewarding substances by creating a feeling of anticipation and then aids in the feeling of pleasure when we have obtained them – that’s why we all eat too much chocolate and why some people have the tendency to look a little like a sexual predator on nights out.

Rats will self-administer drugs to the point of death

The neurones which secrete dopamine originate in midbrain nuclei and have project to a part of the brain called the nucleus accumbens. This is named the mesolimbic pathway and is the dominant one potentiated by addictive substances. By this, I don’t just mean drugs of abuse but all sorts of addictions such as gambling, sugar, nicotine, alcohol, sex – you name it- they all cause a dopamine surge. It has been difficult to study this pathway in humans but since the 1950s it has been known that if you provide rats with a lever which, when pressed, electrically stimulates the mesolimbic pathway, they will continue to press the lever over 6000 times per hour! They become so distracted and involved in self-stimulating that they forget to drink and eat and eventually die from lack of water and food. This reiterates the power of the pathway and helps explain why drug addicts continue to self-administer even when they know that it is causing them severe harm and even when they have the desire to give up. Dopamine-containing neurones also project to the cortex- the region of the brain used for strategic planning and voluntary actions. If you think about how many movements and stages need to be carried out in order to obtain drugs – calling the dealer, waiting in artic conditions to meet him, hurrying a mile down the road to get cash out – it is no surprise that higher regions of the brain are involved.

There are 100 trillion synapses (connections) in the human brain, which can have one or more different neurotransmitter signals. This makes the brain the most complex structure known to man

In the brain of an addict, the carefully designed and regulated neurocircuits are not in balance. Over time, connections between neurones can be strengthened – a process known as long term potentiation and this is how we form memories. The strengthening of certain connections means that an addict has a more powerful drive to complete the actions needed to be done to obtain the rewarding substance. Additionally, the associated memories are strong – meaning certain seemingly innocent cues can prompt neuronal firing and “cravings”. If you show a cocaine addict an image of someone else snorting a line and image their brain, there is significantly more hyperactivity observed in the brain regions involved in the dopamine pathway than in a healthy control. This activity is thought to initiate cravings and a desire to complete the task themselves. In addition to this, the reward value of other, naturally rewarding activities, such as spending time with family and friends, are decreased. Rationality goes out the window as the input descending from the prefrontal cortex, which is normally the main source of self-control and the reason why most people would say no, is diminished.

So how do mutations in certain genes, coupled with environmental factors, lead to disruptions and discrepancies in this dopamine pathway?

How can these cause some people to become addicts and go through endless cycles of recovery and relapse? Most people who have used elicit substances are lucky enough to be able to leave it all behind them and go on to obtain successful careers, get married, have kids, go on package holidays and pay off their mortgage. What is it, in the genetic make up, which helps code for these differences? The answer, in part, is down to a protein which codes for a subtype of dopamine receptor: DRD2. These are expressed in the membranes of neurones throughout the brain. When dopamine binds to DRD2 it acts as an inhibitory signal, dampening down activity of these neurones via complex cascades of signalling proteins and chemicals.

We have 23 pairs of homologous chromosomes, one from each parent, and each carrying a single copy of each gene

DRD2 gene has two variants (alleles): A1 and A2. Each person obtains one allele from each of their parents and so the potential combinations are A1/A1, A1/A2 or A2/A2. Randomised studies performed on Caucasian populations have demonstrated a significant correlation between alcoholics and the A1 allele of the DRD2 gene. Although this linkage has been debated widely for
many years, it has now been suggested that this A1 allele is also implemented in addiction to other substances such as cocaine, nicotine, heroin, marijuana, amphetamines and even carbohydrate cravings. Looking at patients recovering from heroin addiction and dependence – those which held one or two copies of A1 consumed TWICE as much heroin as those patients with two A2 alleles and were 4 times more likely to relapse. But hope is not lost, many people who possess the A1 allele have recovered from alcoholism, lost weight or quit smoking. There are so many other environmental, biochemical and genetic factors at play that this definitely cannot be used as an excuse to keep chugging the cigarettes and eating excessive numbers of chocolate digestives.

So how do these alleles have such influences on behaviour?

PET scans showing decreases DRD2 expression in obese, cocaine addicted and alcoholic individuals compared to a healthy control. Red = DRD2

By labelling DRD2 in the brain radioactively, it has been shown that patients with the A1 allele actually have reduced expression of DRD2. This agreed with results from post-mortems which showed reduced DRD2 in A1 patients, in key brain regions involved in dopamine pathways. It has been shown for years, with brain imaging studies that people addicted to psychostimulatory substances e.g. cocaine, have reduced DRD2 receptor density, but it was heavily debated whether this was a cause or a consequence of their addictive behaviour and actions. More and more evidence is being accumulated that these patients actually started off with fewer DRD2 receptors – they were predisposed to become addicted. Whereas somebody with a healthy density of DRD2 neurones gets a fulfilling amount of hedonic sensations from natural rewards such as palatable foods and good sex, those with fewer DRD2 need to actively seek more potent rewards and reinforce them regularly to get the same effects.

DRD2 receptors become internalised into the cells after chronic drug abuse

The continuous stimulation of the dopamine pathway as they become chronically addicted then causes receptors to be internalised and down-regulated to stop the cell being over-excited to death. This results in even less DRD2 receptors available leading to a never-ending cycle of relapse, addictive behaviour and plummeting DRD2 levels. The role of DRD2 can also help to explain why stressful situations can lead to reinforcement of the addicted behaviour. When you are stressed, the actual numbers and density of DRD2 receptors in the striatum (a region essential for dopamine release) are reduced via other pathways probably induced by prolonged cortisol release. Shockingly, this decrease in DRD2 expression is correlated to social status and poverty.

Although brief, this may give a little insight into why some people are more prone to become addicted. There are real neuroanatomical and neurochemical differences caused by both nature and nurture. The more we find out about the differences, the more likely we are to design drugs and develop therapies to help alleviate the difficulties faced by those suffering from addiction. Moral of the story – don’t be quick to judge those who are “hooked” – stresses, genetics, life style choices and chemicals in the brain are all involved in why they continue to pursue their habits the extent they do.

References

Bressan, Rodrigo A., and Jose A. Crippa. “The role of dopamine in reward and pleasure behaviour– review of data from preclinical research.” Acta Psychiatrica Scandinavica 111.s427 (2005): 14-21.

Clarke, Toni-Kim, et al. “The dopamine receptor D2 (DRD2) SNP rs1076560 is associated with opioid addiction.” Annals of human genetics 78.1 (2014): 33-39.

Compton, Peggy A., et al. “The D2 dopamine receptor gene, addiction, and personality: clinical correlates in cocaine abusers.” Biological psychiatry 39.4 (1996): 302-304.

Comings, D. E., et al. “The dopamine D2 receptor (DRD2) as a major gene in obesity and height.”Biochemical medicine and metabolic biology 50.2 (1993): 176-185.

Fattore, Liana, and Marco Diana. “Drug addiction: an affective-cognitive disorder in need of a cure.” Neuroscience & Biobehavioral Reviews 65 (2016): 341-361.

Fattore, Liana, et al. “Role of opioid receptors in the reinstatement of opioid-seeking behaviour: an overview.” Opioid Receptors. Humana Press, New York, NY (2015): 281-293.

Koob, George F., and Michel Le Moal. “Drug addiction, dysregulation of reward, and allostasis.”Neuropsychopharmacology 24.2 (2001): 97.

National Institute of Drug Abuse, 2014, Drugs and the Brain. Found at: https://www.drugabuse.gov/pubs/teaching/largegifs/slide-9.gif

Shuttershock: Artificial Synapse Bridges the Gap to Brain to Artificial Computers. Found at: https:// singularityhub.com

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