ADHD and the DRD4 gene

Genes are specific sequences of nucleotides (building blocks of your DNA) that contain the information required by your cells to produce various kinds of proteins. Each protein changes the way a cell behaves, giving rise to various characteristics of the cell – from eye colour to how your neurons function. This process is influenced by –

  • Genetics: which genes are present
  • Epigenetics: which of the present genes are switched on/off 
  • Cellular health and nutrition: which raw materials required to build proteins are present in the cell

One such gene, the DRD4, codes for proteins that sit on the cell membrane of a neuron and influence how the neuron interacts with dopamine that is released into their synapse (the narrow space between the communicating ends of two neurons) by another neuron or by itself. Such proteins are called dopamine receptors and they can be excitatory (makes the neuron more likely to send out a signal) or inhibitory (the opposite). The DRD4 gene codes for D4 – an inhibitory receptor.

Sidenote: The most common dopamine receptor in the brain is D1, which is excitatory. It is followed by D2, D3 (both inhibitory), D5 (excitatory), and lastly, D4.

 


 

Wait, you might ask, isn’t the whole function of a neuron to transmit signals it receives from other neurons? What’s the point of receiving a signal if it is not going to be transmitted further? Such a question will eventually lead you to a fundamental discovery about neurons:

A neuron’s primary job is not to transmit signals, but to decide if a signal must be transmitted.

There are 2 sources of information (or electrical inputs) a neuron can use to make such a decision:

  1. Real-time stimuli from the outside world, relayed via our sense organs
  2. Stored memories from past experiences

In the simplest version of how a neuron makes this decision, it simply adds up all the signals telling it “fire!” as well as the signals telling it “don’t fire!”. If the resultant signal says “fire!” strongly enough to initiate an outgoing electrical signal, it fires. Else, it doesn’t.

 


 

Now, coming back to the DRD4 gene – it comes in various flavours. Each flavour, called an allele, differs in how many times the specific sequence of nucleotides (that are the signature of DRD4) are repeated within the gene. Most people have the 4R allele in which the sequence repeats 4 times. However, 7R and 2R alleles have also been growing in popularity over the last 40,000 years of human evolution.

Curiously, the 7R allele is twice as common in individuals with ADHD when compared with the overall population, at least amongst white people.

This has led to a lot of attention being given to the role of the 7R allele in explaining the symptoms of ADHD. The 7R allele has also been shown to have a higher prevalence in people with substance abuse issues, novelty-seeking behaviour as well as antisocial personality traits (again, the studies were mostly focused on white people).

Is there any merit to these associations or are they just a case of correlation being confused with causation? Let’s try to predict how the 7R allele might affect a person’s day-to-day life so that we can come to our own conclusions on this matter.

Sidenote: Interestingly, while 48% of Americans have DRD4-7R, only 2% of Asians have this allele.

 


 

The 7R allele, by virtue of a small change in the spatial geometry of the D4 receptors it produces, happens to be less efficient in its task of inhibiting a neuron than the 4R allele (only half as efficient in lab conditions). Let’s first look at how it affects the individual neurons carrying the D4 receptors.

Normally, when the D4 receptor binds with dopamine released in its vicinity, it ends up inhibiting the action of another enzyme connected to the neuron’s cell-membrane – Adenylyl cyclase, which converts ATP (your cell’s energy reserves) into a messenger chemical called cyclic AMP or cAMP. As a result, whenever dopamine arrives at the D4 receptor, it reduces the number of cAMP molecules within the cell body of the neuron (in comparison with normal levels). But what does cAMP do?

  1. Neuronal firing: Loosely put, more cAMP = more likelihood of the neuron firing. i.e. more excitable neurons. (That’s why D4 receptors reduce cAMP levels to inhibit the neuron)
  2. Processing glucagon and adrenaline: It helps cells process hormones like glucagon (converts glycogen and fat into glucose, increasing the amount of energy available for burning. i.e. metabolism) and adrenaline (prepares the body for rapid response to threats by activating our fight-or-flight response or stress response).
  3. Facilitating long-term changes to the neuron: It helps in the transcription of a bunch of other proteins within the cell that aid in a number of processes including long-term memory formation, synaptic plasticity as well as time-keeping.

Since the 7R allele is less effective in reducing the number of cAMP molecules within the neuron, all of these processes become amplified compared to neurons with the 4R allele. i.e.

  1. Neurons with D4 receptors become more excitable than they should be under the inhibitory action of the D4 receptors. In other words, less inhibited than they should be – under-inhibited.
  2. Dopamine-based control of metabolism works less efficiently, making cells process more than normal amounts of glucagon. This might lead to neurons with D4 receptors running out of energy quicker than usual.
  3. Dopamine-based control of stress response works less efficiently, making cells stay in stress response for longer than normal. This might lead to stress-response mediating neurons with D4 receptors over-activate stress induced behaviours.

Sidenote: There is an exception to the general trend. In some neurons, the D4 receptors are present on the presynaptic neurons too (in much lesser numbers than on the postsynaptic neurons) to help them self-regulate the amount of dopamine they release by inhibiting their own continued activation. In such cases, the neurons end up releasing more dopamine than normal due to inefficient self-inhibition. Depending on whether the postsynaptic neurons interacting with such neurons have excitatory or inhibitory dopamine receptors, the end result on them varies from over-excitation to over-inhibition instead of under-inhibition.

 


 

If there’s one thing our brains are really great at, it’s adapting to new challenges – both in the external environment as well as in our internal environment. Naturally, all of these changes brought about by the 7R allele are met by adaptation processes that try to counter these effects. This adaptation can happen locally at the level of individual neurons or globally at the level of the individual’s behaviour.

Local adaptation can happen in 2 broad ways that compensate for the inefficiency of the D4 receptors:

  1. Increase the amount of dopamine available to the D4 receptors: This involves epigenetic changes to the presynaptic neurons that might make them –
    • Release more dopamine than normal, and/or
    • Slow down the rate at which neurons reabsorb the dopamine released by them (dopamine reuptake), thereby prolonging the duration for which it stays in the synapse
  2. Increase the number of D4 receptors on the postsynaptic neurons: This involves epigenetic changes to the postsynaptic neurons that might increase the number of D4 receptors present on their membrane. If there is a frequent occurrence of more dopamine in the synapse than what the receptors can process, then this triggers an epigenetic process that produces more receptors in response to this excess dopamine. (However, if the excess dopamine exceeds a particular threshold and stays high for extended periods of time, then the postsynaptic neuron ends up going through epigenetic changes that reduce the number of receptors on its surface – creating the opposite adaptation.)

Sidenote: Since the inefficiency arising from the 7R allele primarily affects the postsynaptic neurons, they are more likely to go through these epigenetic changes than the presynaptic neuron.

Global adaptation, on the other hand, can occur in ways as diverse as the individuals possessing the 7R allele. These arise from the brain changing its overall behaviour and personality to compensate for the inefficiencies brought about by the 7R allele. We can bucket them broadly into 2 categories:

  1. Strong preference for being in environments that are rich in dopamine-triggering stimuli. While novelty and rewards (especially social rewards since they are inherently variable in nature and variable rewards trigger more dopamine release than predictable rewards) are probably the most popular dopamine-triggering stimuli, risk and uncertainty are equally powerful in triggering dopamine release. This might be the reason why novelty-seeking and risk-taking traits are more common in individuals with the 7R allele. They are also more likely to thrive in environments that offer frequent opportunities for social interactions – making them prefer such contexts.
  2. They are more likely to develop an attraction to substances that increase the amount of dopamine available to the postsynaptic neurons. Most addictive drugs come under this category – increasing the prevalence of substance abuse in such individuals. Interestingly, even most ADHD medications work either by artificially increasing the amount of dopamine released by the presynaptic neurons or by blocking dopamine reuptake to various levels.
  3. Greater affinity to glucose-generating sources of food, from sugars to simple carbs, to compensate for glucose overconsumption by cells. This might manifest as frequent cravings for high-carb foods. This also suggests that maintaining a regular inflow of glucose-rich foods in tiny quantities might help improve mental performance.
  4. They’re oversensitive to long-term effects of stress and might display symptoms of burnout and chronic stress even under moderate levels of stress. This might lead them to avoid stress-inducing experiences at all cost. At the same time, they are better at dealing with stressful situations in the short-run since they can mobilize their stress-response systems faster than others. This might make them chase stressful situations if they are guaranteed to be short-lived.

Which of these local and global adaptations manifest in an individual is largely determined by their life experiences, especially from childhood and adolescence. In fact, studies have shown that kids and teenagers who have access to healthy sources of dopamine – like positive social interactions, warmth and affection from parents – tend to exhibit less of these adaptations. Further, since every individual with the 7R allele is likely to evolve a unique combination of these adaptations based on their unique life experiences, the impact of this allele will also be very different in different individuals.

 


 

What happens when these adaptations fail? How will the 7R allele affect an individual’s day-to-day life? We can anticipate some of these effects using what we’ve discussed so far about the role of D4 receptors:

  1. Dopamine-mediated processes show various levels of dysregulation based on the extent to which D4 dopamine receptors are involved in them. This includes attention, motivation, cognitive control, working memory, learning, and motor functioning. Dysregulation doesn’t necessarily mean a deficit. Instead, it fluctuates between hyper and hypo states in a way that’s not under the control of the individual. Hyper-performance in these areas generally requires an environment rich in dopamine-inducing stimuli – novelty, risk, uncertainty, and rewards.
  2. Because of cAMP’s effect on glucose processing, they are more likely to have higher than average levels of metabolism. They can lose weight easily and struggle to gain weight. They are also more likely to be physically active, which in turn increases their likely lifespan (by as much as 10% in some studies). They may also be more likely to chase sugar or simple carbs since they are easy sources of glucose. This craving combined with poor impulse control may make them susceptible to overeating disorders – which might affect their metabolism and weight.
  3. They’re likely to have a faster response to adrenaline-inducing experiences due to increased sensitivity to glucagon and adrenaline, making them better at dealing with such situations for short durations. However, if the effects of adrenaline extend longer, the negative effects might accumulate very quickly. This might result in a bipolar pursuit of stress-inducing experiences – alternating between chasing them actively and avoiding them at all costs.
  4. Their long-term memory is biased strongly in favour of storing and recalling negative experiences. Even individuals with the 4R allele display the same bias, but it is further enhanced in those with 7R. Further, owing to difficulties with working memory and attention, they may prefer simplistic interpretations of the world around them as opposed to complex ones. This may come across as seeing the world in black and white, with black being more prominent than white.
  5. Dopamine-rich, low-stress environments prove highly advantageous to individuals with the 7R allele, especially during childhood and adolescence. Low-dopamine, high-stress environments, on the other hand, end up being more detrimental than it is for individuals with the 4R allele. This amplifies the consequences of both good and bad upbringing on their adult life. They’re also more likely to chase dopamine-rich environments or avoid high-stress environments even when the costs seem high to those with the 4R allele. As a result, they’re more prone to novelty-seeking, substance-abuse as well as quitting stressful situations.
  6. Rewards/threats need to be very high in order to result in effective learning of associated behaviours. This is because the strength of learning needs to be strong enough to regulate future behaviour despite a weaker inhibitory action of D4 receptors. On the other hand, low rewards/threats are practically the same as no rewards/threats since the level of neural activity produced by them may not be sufficient to cross the threshold for inhibitory action. As a result, they may be bad at picking up social norms and practices with low consequences compared to their peers with the 4R allele (a lot of adulting depends on such practices). At the same time, they may be better than their peers at picking up social norms and practices that have very high consequences, resulting in a “sharp-around-the-edges and flat-everywhere-else” kind of personality. They may also have difficulty mustering enough motivation to function normally in low-reward or even average-reward environments. This is very similar to Dr. Russel Barkley’s views on ADHD –

    “If you want to make an individual with ADHD fail, keep them in an environment with no (or low) consequences”

  7. In the romantic domain, reducing the number of D2-like inhibitory dopamine receptors (of which D4 is one) before two people have fallen in monogamous love (or to use the technical term, pair-bonding) reduces the chances of falling in love i.e. D2-like receptors are involved in forming pair-bonds. On the other hand, reducing D2-like receptors after they have fallen in love makes them less likely to cheat (probably because it reduces the chances of falling in love with someone else). At the same time, increasing D1-like receptors (excitatory) after they have fallen in love increases the likelihood of positive, pleasurable associations with the relationship and hence increases the chances of sustaining their love (might also be the mechanism behind the love haze period of love where everything about the other person appears amazing). As an extrapolation of this study, an already inefficient D4 receptor system might make it harder for people to fall in monogamous love. Further, a higher ratio of D2 to D1 receptors, in some studies, has shown a greater likelihood of stable relationships. This suggests that it might be harder for 7R allele carriers to sustain stable relationships.

 


 

Lastly, we’re gonna look at the applications of all this knowledge about the DRD4 gene and its 7R variant. Is there anything individuals with the 7R allele can do to enhance its advantages as well as protect themselves from its disadvantages? It’s hard to answer this question since genes are influenced by a million other things in the real world – from life experiences to diet and lifestyle. However, we can evolve a broad framework to experiment with likely hacks that may work well for us – healthy ways of maintaining optimum levels of dopamine as well as stress:

  1. Ensure we have access to enough healthy sources of dopamine – so that the temptation to seek out unhealthy sources in times of need is reduced. A few common healthy sources:
    • Dopamine rich foods – eggs, lean meat, diary, almonds, walnuts, salmon, mackerel, bananas, dark chocolate, berries
    • Positive social interactions (since every interaction with real people is unpredictable, it usually triggers dopamine more reliably than non-social activities)
    • Harmless avenues for exploration like travelling or frequently exploring new projects, books, events
    • Positive channels of risk, uncertainty and rewards like social games (boardgames, mafia, chess, etc)
    • Frequently learning something new whenever your motivation is high enough to make an effort (learning something new is usually accompanied by dopamine release)
    • Physical activity, even short and mild versions of it can give a temporary boost of dopamine
  2. Ensure we have access to healthy sources of stress – they usually tend to be short-lived, moderate and occur in environments where we feel safe to reduce the temptation to chase unhealthy sources. A few examples:
    • Games and sports
    • Performance arts
    • Adventurous activities
    • Meeting new people in safe settings
    • Competitions and contests we find interesting

As is often the case in matters that involve dopamine or stress, the hardest trick to learn is saying no. Saying no to experiences that we know are unhealthy is as important as being aware of the healthy alternatives – saying no to unhealthy sources of food, sex, social interactions, risky gambles or substances.

Finally, one big disclaimer: a single gene can never define who you are. So I urge you to take everything I have discussed about the DRD4 gene with a pinch of caution. Although I’ve tried to be comprehensive in my analysis of how the 7R allele of this gene might influence an individual, the extent of influence in different aspects of life can vary a lot from one individual to another. The best use of the information discussed in this article is not to evaluate whether you have the 7R allele or not, but to understand how various dopamine-dependent systems affect our life so that we can deal with any ill-effects with greater awareness and confidence.

Good luck! 🙂

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