* Scientific study references that back up my points can be clicked on in the text to open the original reports in a separate tab.
In a recent US survey conducted by the Substance Abuse and Mental Health Services Administration, roughly 16% of adults reported some form of drug use. One thing that is quite clear, if we compare these figures to rates of psychiatric diagnoses, is that only a portion of those who have experience with drugs go on to develop full-blown addiction. This begs the question – why is that? Is it possible that some people really are more or less immune than others to the risks of substance abuse?
The idea that some individuals have addictive personalities harks back to old-school personality psychology, which classically considers those with impulsive traits and sensation-seeking tendencies (eg. interests in activities like extreme outdoor sports or swinger parties) to be at greater risk of developing drug addiction than other individuals. Currently, we have good reason to believe that this idea might be grounded in some biological truth – one that doesn’t only apply to humans. Already two decades ago, researchers studying the behaviours of rats observed remarkable variability in their tendency to become addicted to psychostimulants like methamphetamine and cocaine. It turned out that, given equal and total access to an addictive drug, not all rats were equally likely to develop a compulsive habit. Interestingly, a rat’s level of trait impulsivity (that is, a life-long tendency rather than a temporary state of impulsiveness) has been found to predict how likely the animal is to acquire addiction if exposed to cocaine. This raises the interesting question of whether the ‘addictive personality’ is rooted in some biological reality, and whether rats can genuinely shed some light on this.
While the idea that rats have something akin to elements of personality might be surprising, it probably shouldn’t be. It is to be expected that natural variation in the genetic makeup of complex animals causes the brains of different individuals to develop in slightly diverse ways, making them produce behaviours that might be characteristic of some individuals, but not others. Ultimately, this means that some individuals may be biologically predisposed to be more anxious, risk-taking, aggressive, or perhaps addiction-prone. Evidence from research labs tells us that it is indeed possible to produce rats with what appear to be ‘addictive personalities’ – something that was used in a recently published set of experiments by researchers from the University of Michigan.
Their study looked into the genetic factors that might contribute to some rats being at greater risk of developing full-blown cocaine addiction. They started by breeding two colonies of rats that were expected to differ in their natural tendency to become addicted to drugs like cocaine. Specifically, rats in one colony were bred to be highly active and explorative when placed in new environments, while rats from the other colony were less explorative than average. Since high sensation-seeking is a personality trait classically associated with increased likelihood of becoming drug-addicted, the logic of raising these colonies was that researchers created two groups of rats that were, to some extent, ‘biologically destined’ to either struggle with drug addiction or be more resistant to it. This was a reasonable possibility, as the same researchers had previously found that the highly explorative rats were more likely than the less explorative ones to start taking cocaine in the first place. Now, the fact that these rats might also have inbuilt differences in terms of their long-term addictiveness could be used to examine aspects of their biology that might underpin these differences. In other words – if some rats are more likely than others to become hooked on drugs like cocaine, what might be so special about them?
Measuring addictive behaviours in rats
In this experiment, both rat colonies underwent extensive training during which they learned that if they used their noses to poke a particular spot in their chamber, they would get an instantaneous infusion of cocaine into the bloodstream. During the first 20 seconds that the rats were experiencing their high, the spot in the wall that they had poked would light up – this would become relevant later when the researchers tried to assess addictiveness. It turned out that on multiple behavioural measures, the highly explorative rats indeed showed substantially stronger signs of having long-term addictive tendencies. How was this tested?
Firstly, the researchers examined how desperate the rats became at seeking out cocaine even when it was no longer an option for them. Throughout the course of training, the researchers switched on a ‘house light’ on the top of the chamber to indicate to the rats that they were free to approach the spot that resulted in cocaine delivery. On the occasions that this light was switched off, cocaine became unavailable no matter how vigorously the rats would poke the spot – something that they managed to learn quite quickly, as they essentially stopped approaching the area.
This gradually became an issue for the highly explorative rats. As the experiment progressed, these animals became less and less capable of refraining from poking the spot even when the light was no longer switched on. I should note that it was quite clear that these rats were initially able to conceptualise that they couldn’t get hold of cocaine on these occasions, since earlier on in the experiment they stopped paying attention to the spot for the duration of the light-off period. But the longer they had spent receiving the drug, the more their initial self-restraint began breaking down. Interestingly, only rats from this colony seemed to make this transition to compulsive cocaine use, as the non-explorative rats were consistently able to lay off the drug-delivery spot during the light-off period.
Next, the researchers found that the highly explorative rats were also abnormally sensitive to relapse after a period of abstinence. This was tested by forcing rats from both colonies to go cold-turkey for a month, and subsequently placing them in the same chamber where they would normally be given cocaine. To make this environment all the more similar to times when the rats were free to obtain the drug, the house-light was switched on (as if signalling that cocaine was available). Furthermore, every time the rats used their noses to poke the spot in the wall that used to trigger cocaine infusion, that spot would light up as it had always done during training.
To capture the essence of the situation in fewer words: everything that the rats were experiencing during this test was the same as during their cocaine-taking days apart from the fact that performing the action that normally resulted in cocaine delivery was now entirely futile. This test of so-called cue-induced reinstatement is quite important in drug addiction research, because it is thought to capture an important aspect of drug addiction – namely our tendency to become triggered into old habits by elements of our environment (or ‘cues’) that were previously associated with taking drugs. This is perhaps the single most common problem with recovering drug addicts coming out of rehab, as going back to the same group of friends, the same social venues with the same music and smells as before often makes the temptation to go back to taking drugs too strong to resist. Indeed, one large-scale study has found that roughly a quarter of rehab patients continue taking cocaine on a weekly basis following treatment, while a slightly smaller fraction of patients develop habits severe enough to drive them back into another rehab programme. Thus, it’s reasonable to suppose that measuring rat behaviour during the cue-induced reinstatement test could give us some insights into behaviours that have something in common with recovering cocaine addicts going back to their old environment.
Under these conditions, the highly explorative rats turned out to be substantially more susceptible to relapse than rats from the other colony. This was evident in the fact that these rats reverted back to poking the spot normally associated with cocaine roughly four times more often than the other rats, even though their attempts were clearly futile.
Measuring gene activity in the brains of addiction-prone rats
All in all, the behavioural profile of the highly explorative rats suggested that they had something akin to an addictive personality. For the sake of simplicity, I will now refer to this group of rats as addiction-prone, and the other group as addiction-resistant. To understand this phenomenon from a biological perspective, the researchers examined the brains of addictive and non-addictive rats who either never got to experience cocaine, or consumed it for a prolonged period of time. The experimenters particularly focused on a cluster of neurons called the nucleus accumbens – an essential component of the brain’s reward system that receives large portions of dopamine that is triggered by events such as sugar consumption, money, sex, and drugs like cocaine and amphetamines. Researchers have known for decades that this neurochemical plays a critical role in triggering the sensation of ‘wanting’ something, even in the absence of enjoyment. Given this evidence, it’s to be expected that the dopamine system also has something to do the development of pathological ‘wanting’ that characterises addiction. Thus, the researchers looked into whether brain cells from the nucleus accumbens of the relatively addiction-prone rats might differ from the more addiction-resistant animals in terms of the activity of certain genes.
How do we measure gene activity? One commonly used method involves looking at the amount of messenger RNA (mRNA) that can be detected in a brain region of interest. This is because whenever a gene is being actively used to produce protein, its DNA is first used to make strands of a molecule called mRNA, which acts as a ‘portable script’ containing the instructions, or code, for the production of a specific protein (explanation below). It is thus often assumed that the more copies of a particular mRNA we find inside a cell, the more actively that gene is being used to make protein.
Using the method of measuring mRNA, experimenters found that two genes in particular appeared to show different levels of activity in the studied part of the brain’s reward system in addiction-prone rats compared to their less addictive peers.
Clues from the dopamine system
Firstly, addictive rats with no experience of cocaine turned out to have significantly weaker activity of a gene that is used to produce a particular type of dopamine receptor, known as the D2 receptor. We know that receptors are tiny proteins that pepper the membranes of brain cells and work by capturing molecules of neurochemicals that are being released by other neurons, and triggering reactions to these signals. Receptors are the foundation of the ability of brain cells to communicate with each other through chemical signals, and sometimes they are also found in locations that allow them to have slightly different functions. This is the case for D2 receptors, which are often anchored to the endings of dopamine-releasing cells. There, they keep track of levels of dopamine in their surroundings and accordingly use this information to suppress further dopamine release from the neuron and prevent neurochemical build-up.
The fact that the researchers observed low levels of D2 gene activity in the nucleus accumbens of addiction-prone rats, before they’ve ever experienced cocaine, tells us that the reward system of their brain is likely producing fewer of these receptors compared to the more addiction-resistant rats. As a consequence, the brains of rats susceptible to addiction might be intrinsically less capable of keeping a lid on the release of dopamine that is triggered by substances like cocaine, which allows the neurochemical to reach high levels and perhaps to have a greater influence on the brain cells that it targets. The fact that this was observed in the animals who hadn’t even experienced cocaine might go a long way towards explaining why these animals are inherently more sensitive to the addictive effects of this drug (which is widely known to trigger dopamine release). Furthermore, this abnormality of the dopamine system might also partially lie at the root of why these rats have explorative personalities, as you might expect brains that are more sensitive to rewards to become more active at pursuing exciting and rewarding experiences.
In a further turn of events, the researchers uncovered something interesting about the histone proteins that ‘package’ DNA in some parts of the D2 gene, in the brains addiction-prone rats. That is, these proteins carried a particular chemical mark (H3K9me3) that is considered to permanently suppress gene activity. The mark achieves this by causing the proteins to wrap around the DNA so tightly that they make the gene inaccessible to components of the cell that are required to begin ‘reading’ it out to begin producing protein (explanation below).
As a result, the presence of this suppressive mark in parts of the D2 gene in addiction-prone rats means that this gene is essentially unreadable, forced into a state of long-term hibernation (which explains why this gene was found to have low levels of activity). The fact that this is found in rats with no actual experience of cocaine suggests that this situation is already in place early on in life, which might be one factor predisposing these animals to respond to cocaine differently from their addiction-resistant peers. Interestingly enough, rats with the greatest attachment between the suppressive chemical mark and the D2 gene turned out to be the ones who were most likely to relapse after a period of abstinence from cocaine.
Links to a gene… with links to anxiety
In a further turn of events, the experiment revealed that the brains of addiction-prone rats have substantially higher activity of a gene coding for the protein FGF2 (Fibroblast Growth Factor 2). This effect was apparent both in individuals who never actually experienced cocaine and in those who had extensive exposure, which raises the possibility that high activity of the FGF2 gene is an inherent characteristic of brains that are more likely to become addicted.
What do we know about the FGF2 protein? It is uncertain exactly why it might be associated with cocaine addiction, since it appears to be generally involved in the proliferation (multiplication) and maturation of brain cells. What is perhaps more intriguing about the involvement of this gene is the fact that it is also associated with disorders of anxiety. Specifically, researchers have found that the rats with heightened levels of anxiety show weaker activity of the FGF2 gene, and that this anxious phenotype can be reversed by treating rat pups with high doses of FGF2 early in life. This same treatment, which results in higher levels of FGF2, also enhances the likelihood that rats given the opportunity to take cocaine will go on to develop addiction. It appears that the naturally high levels of FGF2 gene activity in highly explorative rats might predispose them to addiction from the very beginning of their lives.
While I admit this to be quite speculative, it’s tempting to consider the intriguing possibility that anxiety and proneness to addiction might in some ways be opposing ends of a biological spectrum. It is possible that those genetic factors which predispose individuals to high levels of anxiety also serve to protect them from the risks of drug addiction. Irrespective of whether this is true, the evidence is quite clear that some animals, including humans, really might be inherently more likely to develop substance addiction than others, and that genetic factors have a role to play in this story.