Category Archives: Genetics and physiology in drug addiction

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The Brain on Fire: Depression and Inflammation

According to the World Health Organization, depression is the leading cause of disability. Unfortunately, 30 to 60 percent of patients are not responsive to available antidepressant treatments (Krishnan & Nestler, 2008). In other words, 40 to 70 percent of patients are not helped by existing treatments. One area of research might shed some light on why a sizable portion of patients are not helped by current antidepressants.

There is growing evidence that inflammation can exacerbate or even give rise to depressive symptoms. The inflammatory response is a key component of our immune system. When our bodies are invaded by bacteria, viruses, toxins, or parasites, the immune system recruits cells, proteins, and tissues, including the brain, to attack these invaders. The main strategy is to mark the injured body parts, so we can pay more attention to them. Local inflammation makes the injured parts red, swollen, and hot. When the injury is not localized, then the system becomes inflamed. These pro-inflammatory factors give rise to “sickness behaviors.” These include physical, cognitive and behavioral changes. Typically, the sick person experiences sleepiness, fatigue, slow reaction time, cognitive impairments, and loss of appetite. This constellation of changes that take place when we are sick is adaptive. It compels us to get more sleep to heal and remain isolated so as not to spread infections.

However, a prolonged inflammatory response can wreak havoc in our bodies and can put us at risk of depression and other illnesses. There is plenty of evidence solidifying the link between inflammation and depression. For example, markers of inflammation are elevated in people who suffer from depression compared to non-depressed ones (Happakoski et al., 2015). Also, indicators of inflammation can predict the severity of depressive symptoms. A study that examined twins who share 100 percent of the same genes found that the twin who had a higher CRP concentration (a measure of inflammation) was more likely to develop depression five years later.  

Doctors noticed that their cancer and Hepatitis C patients treated with IFN-alpha therapy (increases inflammatory response) also suffered from depression. This treatment increased the release of pro-inflammatory cytokines, which gave rise to a loss of appetite, sleep disturbance, anhedonia (loss of pleasure), cognitive impairment, and suicidal ideation (Lotrich et al., 2007). The prevalence of depression in these patients was high. These results add credence to the inflammation story of depression.

Subsequent careful studies showed that the increase in the prevalence of depression in patients treated with IFN-alpha was not only because they were sick. Using a simple method of injecting healthy subjects with immune system invaders, researchers found higher rates of depressive symptoms in the ones who were exposed compared to the placebo group. The subjects who were induced to have an inflammatory response complained of symptoms such as negative mood, anhedonia, sleep disturbances, social withdrawal, and cognitive impairments.

The link between inflammation and depression is even more solid for patients who don’t respond to current antidepressants. Studies have shown that treatment-resistant patients tend to have elevated inflammatory factors circulating at baseline than the responsive ones. This is clinically important; a clinician can utilize a measure like CRP levels, which are part of a routine physical, to predict the therapeutic response to antidepressants. In one study, they found that increased levels of an inflammation molecule prior to treatment predicted poor response to antidepressants (O’Brien et al., 2007).

There are environmental factors that cause inflammation and therefore elevate risk for depression: stress, low socioeconomic status, or a troubled childhood. Also, an elevated inflammatory response leads to increased sensitivity to stress. The effect has been reported in multiple studies in mice. For example, mice that have gone under chronic unpredictable stress have higher levels of inflammation markers (Tianzhu et al., 2014). Interestingly, there are individual differences that make some mice more resistant to stress, therefore initiating a calmer immune response (Hodes et al., 2014).

Depression is a heterogeneous disorder. Each patient’s struggle is unique given their childhood, genetics, the sensitivity of their immune system, other existing bodily illnesses, and their current status in society. Being on the disadvantageous end of these dimensions irritates our immune system and causes chronic inflammation. The brain is very responsive to these circulating inflammatory markers and initiates “sickness behavior.” When the inflammation is prolonged by stressors or other vulnerabilities, the sickness behavior becomes depression.

If you are a professional working with patients suffering from depression, I urge you to consider the health of your patients’ immune systems. If you are a patient suffering from an exaggerated immune disorder (e.g., arthritis), do not ignore the depressive symptoms that you might be experiencing. If you are suffering from depression, avoid anything that might exacerbate your immune response. This is another example of the beautiful dance between mind and body!


Haapakoski,R.,Mathieu,J.,Ebmeier,K.P.,Alenius,H.,Kivimäki,M., 2015. Cumulative meta-analysisofinterleukins6 and 1β,tumournecrosisfactorα and C-reactive protein in patients with major depressive disorder. Brain Behav.Immun. 49,206.

Hodes GE, Pfau ML, Leboeuf M, Golden SA, Christoffel DJ, Bregman D et al (2014). Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci USA 111: 16136–16141.

Krishnan V, Nestler EJ (2008). The molecular neurobiology of depression. Nature 455: 894–902.

Lotrich,F.E.,Rabinovitz,M.,Gironda,P.,Pollock,B.G., 2007. Depression following pe-gylated interferon-alpha:characteristics and vulnerability.J.Psychosom.Res.63, 131–135.

O’Brien, S.M., Scully, P., Fitzgerald, P., Scott, L.V., Dinan, T.G., 2007a. Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy. J. Psychiatr. Res. 41, 326e331.

Tianzhu, Z., Shihai, Y., Juan, D., 2014. Antidepressant-like effects of cordycepin in a mice model of chronic unpredictable mild stress. Evid. Based Complement. Altern. Med. 2014, 438506.

The Serotonin Transporter Gene and Depression

A new large-scale study casts doubt on a widely reported association.

Why some people develop major depressive disorder and others do not is a complex and not well-understood process. Several factors have been discussed to contribute to depression, among them:

Genetic variation: Individuals carrying one or two copies of a specific risk allele on one or more “depression gene/s” have a higher risk of developing depression.

Environmental influences: Negative life events such as trauma, negligence, or abuse increase the risk of developing depression.

Gene-by-environment interactions: Negative life events only lead to depression in individuals with a specific genetic set-up that makes them risk-prone to develop depression.

The gene most commonly associated with depression is the serotonin transporter gene SLC6A4 (Bleys et al., 2018). Serotonin is a neurotransmitter affecting multiple physiological processes and cognitivebrain functions, among them mood and emotions, which is why it has been linked to mood disorders such as depression. Indeed, low serotonin levels have been associated with depressed mood (Jenkins et al., 2016), and selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants. SSRIs block the reuptake of serotonin during cellular communication in the brain, making more serotonin available, and thus in theory helping to reduce depression.

Along these lines, the idea that the serotonin transporter gene could affect depression risk or severity intuitively made sense. Specifically, many scientists focused on the so-called 5-HTTLPR polymorphism in the promoter region of the serotonin transporter gene to research the effects of this gene on depression. Genetic polymorphism means that at a specific location in the genome, different people might have slight variations in their DNA which could affect how well the protein that the gene produces could do its job. In the case of the 5-HTTLPR polymorphism, there is a short allele (s) and a long allele (l). Already back in the 1990s, researchers showed that people with two or one short alleles have a higher chance of developing depression than those with two long alleles, as the short allele leads to reduced expression of the serotonin transporter (Collier et al., 1996).

This initial study sparked interest in the 5-HTTLPR polymorphism, but not all empirical works could find a clear association. In 2003, a surprising finding seemingly resolved this controversy. In a widely cited study, Caspi and colleagues were able to show that the effects of 5-HTTLPR polymorphism genotype on depression were moderated by a so-called gene-by-environment interaction (Caspi et al., 2003). This means that the genotype would only have an effect if individuals were also subjected to specific environmental conditions. Specifically, the scientists found that individuals reacted differently to highly stressful life events, depending on the 5-HTTLPR genotype. People with at least one short allele on the 5-HTTLPR polymorphism developed more depressive symptoms if they experienced a highly stressful life event than people with two long alleles. However, without a stressful life event, the genotype did not have an effect on the probability to develop depression.

This study further increased the interest in the 5-HTTLPR polymorphism and its relation to depression, leading to more studies on this topic. However, a problem of many of these studies was that their sample sizes were comparably small for genetic studies, potentially leading to erroneous results and overblown effects.

Almost a decade ago, Risch and co-workers (Risch et al., 2009) conducted a so-called meta-analysis, a statistical integration of empirical studies. They analyzed 14 studies on the 5-HTTLPR polymorphism and its relation to depression and on whether this relation was influenced by stressful life events as had been suggested by Caspi et al. (2003). Their result was clear: While more stressful life events led to a higher risk of depression, there was no effect of the 5-HTTLPR genotype on depression and no gene-by-environment interaction effect between genotype and stressful life events.

Despite this finding, hundreds of studies on the 5-HTTLPR polymorphism and depression have been published since 2009 (the scientific search engine PubMed lists more than 800 hits for the search term “5-HTTLPR depression” as of early May 2019). A new study recently published by Richard Border and colleagues in The American Journal of Psychiatry(Border et al., 2019) aimed to resolve the controversy about whether or not the 5-HTTLPR genotype affects depression and whether there is a gene-by-environment interaction between this genotype and stressful life events once and for all. To avoid the statistical problems of previous studies, they obtained data from several large genetic datasets available to researchers, leading to a sample size of several hundred thousand individuals. The results of the analysis were clear as well: There was no statistical evidence for a relation between the 5-HTTLPR polymorphism and depression, and there was also no evidence that traumatic life events or adverse socioeconomic conditions might show a gene-by-environment interaction with this genotype.

This, of course, does not mean that there is no relationship between serotonin and depression (there clearly is, as shown by the treatment success of SSRIs), but it lends further support to an emerging insight in psychiatry genetics: Mental illness is a highly complex process that is likely influenced by a large number of genetic and non-genetic effects. As such, it is unlikely that single genetic variations such as the 5-HTTLPR polymorphism have a huge impact on whether or not an individual develops depression or any other form of mental illness. Future psychiatry genetic studies will need to take this complexity into account by analyzing genetic variation across the whole genome and epigenome and relating it to mental illness (Meier & Deckert, 2019).

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The interaction of environmental cues and triggers that promote drug relapse have a genetic and epigenetic basis that can be modified in the experiment below. Epigenetics is the modification of DNA expression as a result of environmental triggers. It would be great to induce modification of an addicts DNA to decrease cravings from triggers and cues as shown in the experiment below with mice and cocaine addiciton. The articles are scavenged per the sources:


Epigenetics of addiction: Epigenetic study untangles addiction and relapse in the brain


September 27, 2017


Medical University of South Carolina


New research uncovers an epigenetic reason why drug users who attempt to quit are prone to relapse despite negative consequences to their health and livelihood. The findings help to explain how casual drug use can produce long-lasting brain changes that increase vulnerability to relapse in individuals suffering from substance use disorders.

Science Daily article link here:

Why do some drug users continue to seek out drugs despite the prospect of losing family, friends, health or livelihood?

There are notable features — cues — of the early drug-using environment that often develop into persistent and powerful triggers for relapse. Epigenetic factors — enzymes in the brain that alter the packaging and accessibility of genes without changing the genes themselves — influence this process, according to research at the Medical University of South Carolina (MUSC) appearing online on September 27, 2017 in Neuron.

A major challenge in addiction science is to understand how transient experiences lead to long-lasting risk for relapse in users who try to quit, according to MUSC professor Christopher W. Cowan, Ph.D., William E. Murray SmartState® Endowed Chair in Neuroscience, and senior researcher on the project. “Our goal was to discover the brain mechanisms responsible for the rewarding effects of the drug and the motivation to seek it even after long periods of abstinence,” says Cowan.

The brains of drug users who have progressed to addiction differ markedly from those of early or casual users. Long-lasting associations form between the early use of a drug and different aspects of the early drug-using environment, such as the location in which a drug was first taken or the emotions a user was experiencing at the time. This can cause addicted users who have quit to experience cravings when in a similar setting. Understanding these connections could lead to better treatments for addiction.

Cowan’s challenge was to determine which genes were activated in the early drug-using environment. Cowan and his fellow researchers had previously found that the epigenetic enzyme histone deacetylase 5 (HDAC5) slows the rodent brain from forming associations between cocaine and simple cues in the environment, such as light and sound. HDAC5 is found in high amounts in neurons in the nucleus accumbens, part of the reward center of the brain that reacts strongly to cocaine, opioids and alcohol — both in rodents and humans. When HDACs are in the nucleus of neurons, they change the way genomic DNA is packaged in the cell nucleus and often block the ability of certain genes to be turned on.

In the new study, rodents were trained to press a lever to receive a dose of cocaine. Each time they received a dose, a lamp went on above the lever and a brief sound was generated. These served as simple environmental cues for drug use. Next, some rodents were given a form of HDAC5 that traveled straight to the nuclei of neurons. Those rodents still pressed the lever just as many times to receive drug, meaning that HDAC5, on its own, was likely not blocking genes that promoted early drug-seeking behavior.

Yet the next experiment proved that HDAC5 reduced drug-seeking behavior during abstinence. To simulate withdrawal and abstinence, rodents were given rest without cocaine for one week, followed by a period during which they had access to the lever again. To simulate relapse, the rodents were shown the environmental cues again, this time without having pressed the lever. The presentation of the cues triggered robust lever pressing, indicating drug seeking, in control animals, proving that the associations between drug and environment persisted in their brains. In contrast, animals who had the nuclear form of HDAC5 did not press the lever nearly as often, even after the experimenters gave the animals a small priming dose of cocaine, which often produces strong drug-seeking behaviors.

HDAC5, the gene suppressor, did not prevent addiction-like behaviors from forming, but it did prevent later drug seeking and relapse during abstinence — at least in rodents.

The researchers next used a cutting-edge technique that encourages epigenetic enzymes to bind to DNA, allowing them to identify all the genes inhibited by HDAC5. The gene for NPAS4 was a top hit, and significant for an important reason: it is an early-onset gene, meaning that its effects could be exerted on the brain rapidly unless HDAC5 was there to inhibit it — just the molecular event Cowan and his team were seeking.

In similar experiments, animals with less NPAS4 in the nucleus accumbens took more time to form those early connections between environmental cues and cocaine, but they still sought the drug just as often during later simulated relapse. Apparently, NPAS4 accounts for some addiction-related learning and memory processes in the brain, but not all of them, meaning that HDAC5 must be regulating additional genes that reduce relapse events. Cowan thinks uncovering additional downstream genes could help researchers untangle the details of how the brain transitions from early drug use to addiction, and how new treatments might be developed to reduce relapse in individuals suffering from substance use disorders.

Animals in the research setting may not mimic the full complexity of human addiction. However, abstinent patients report cravings when given reminders of their drug-associated environment or cues, and animals and humans share similar enzyme pathways and brain structures. Perhaps most exciting for addiction research is that these processes may be similar in the transition to cocaine, alcohol and opioid addictions. “We might have tapped into a mechanism with relevance to multiple substance use disorders,” says Cowan.


Nuclear HDAC5 in the NAc attenuates relapse-like drug-seeking behaviors

ChIP-seq revealed numerous HDAC5-associated target genes including Npas4

NPAS4 in NAc (Nucleus accumbens)  is induced in subset of FOS+ neurons during cocaine-context learning

HDAC5 and NPAS4 in NAc are involved in cocaine-conditioned behaviors


Individuals suffering from substance-use disorders develop strong associations between the drug’s rewarding effects and environmental cues, creating powerful, enduring triggers for relapse. We found that dephosphorylated, nuclear histone deacetylase 5 (HDAC5) in the nucleus accumbens (NAc) reduced cocaine reward-context associations and relapse-like behaviors in a cocaine self-administration model. We also discovered that HDAC5 associates with an activity-sensitive enhancer of the Npas4 gene and negatively regulates NPAS4 expression. Exposure to cocaine and the test chamber induced rapid and transient NPAS4 expression in a small subpopulation of FOS-positive neurons in the NAc. Conditional deletion of Npas4 in the NAc significantly reduced cocaine conditioned place preference and delayed learning of the drug-reinforced action during cocaine self-administration, without affecting cue-induced reinstatement of drug seeking. These data suggest that HDAC5 and NPAS4 in the NAc are critically involved in reward-relevant learning and memory processes and that nuclear HDAC5 limits reinstatement of drug seeking independent of NPAS4.

DOI: 10.3410/f.731384905.793538334

The molecular mechanisms underlying the association between environmental cues and drug reward are of great interest. Furthermore, the contribution of specific enzymes that participate in chromatin remodeling in response to drugs of abuse is an active area of research.

Taniguchi et al. report that the dephosphorylated, nucleus localized HDAC5 in the nucleus accumbens (Nac) acts as a protective molecule that reduces the association between context cues and cocaine reward. Using Chip-seq, the authors identified the IEG Npas4 as one of the gens that associate with nuclear HDAC5. The authors further show that HDAC5 negatively regulates Npas4 expression and that both drug and environmental cues produce a rapid and transient increase in Npas4 expression in a small subpopulation of cFos-positive Nac neurons. Finally, the authors show that Npas4 contributes to learning and memory processes associated with cocaine reward.

This is a very elegant study that identified a novel signaling pathway in which the key participants contribute in opposite directions to cocaine reward seeking behaviors. Specifically, nuclear HDAC5 gates behaviors associated with cocaine reward whereas Npas4 promotes them. Also of note is the finding that Npas4’s expression is induced by cocaine only in a subpopulation of Nac neurons. The consequences of the manipulation of both genes in these specific neurons would be an interesting future direction.

F1000 article link


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