Radical New Life-Saving Technique Borrowed From Science Fiction

Really interesting article!

By Aditya Nair

Modern medicine may be headed into the future. A revolutionary new technique is being tested at the University of Pittsburgh Medical Center Presbyterian Hospital to improve the outcomes of victims of massive blood loss by, almost ironically, bringing the patient as close to the brink of death as is safely possible.

By pumping cold saline directly into the patient’s aorta, surgeons aim to cool the patient’s body temperature to around 50 degrees Fahrenheit. This allows the brain and the heart to recover more efficiently, serving as a damage control mechanism by essentially slowing time down for the body’s cells, giving the cellular machinery a chance to recalibrate its settings. It only takes five minutes for brain cells to begin dying. During a stroke, 2 million brain cells could die for every minute that they are deprived of bloodflow. By cooling the body, it’s possible to slow this…

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Another Reason to Quit Smoking- A Gateway to Cocaine Addictions

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Imagine this, you and your friend arrive at a party and are asked to try cocaine. Your friend has been addicted to cigarettes for years, but you have never tried smoking before. Although you both know that cocaine is an illegal substance that can harm your bodies, you both decide to try it anyways. Three weeks later, you notice that your friend is acting anxious and seems to be going through withdrawal symptoms. When you ask him/her why they have a sudden change in behaviour, he/she tells you that they are addicted to cocaine. Why did the cocaine use from the party affect your friend more than it affected you? Is this even possible?

Although everyone knows that cigarettes and chronic drugs are detrimental to our health, there are many smokers and cocaine users in our society. We all know at least one person that smokes cigarettes, and despite knowing that smoking can cause lung cancer, and other health consequences; they still smoke. Recently, researchers have found another reason to frown upon cigarette use. A new study discovered biological evidence that nicotine, the addictive property in cigarettes, can act as a gateway drug for cocaine addictions1. I bet you didn’t see that one coming did you? I know, it shocked me too.

The term “Gateway Drug” is described in the Merriam-Webster dictionary as a less harmful drug that a person can take, which might stimulate chronic drug addictions. Many epidemiologic studies suggest that there are high correlations between nicotine and cocaine abuse. For example, approximately 90.4% of adults attest to smoking cigarettes before using cocaine1. Other studies have shown that 80% of people who are addicted to cocaine are also addicted to cigarettes1. However, these studies never established a molecular mechanism to explain this high correlation between nicotine and cocaine abuse, but in 2011, Levine et al from Columbia University in New York published an epigenetic2 mechanism for this gateway drug hypothesis in the Journal of Science Translational Medicine proving that nicotine does prime cocaine addictions1.

Both nicotine and cocaine target the reward center2 by increasing dopamine concentrations in synaptic areas of the dopaminergic neurons in the ventral tegmental area of the brain. High dopamine accumulation between synapses enhances signal transduction and cell signaling pathways in the reward center, which leads to a prolonged euphoric2 addictive state. Interestingly, although both drugs increase dopamine levels in the synapse, this dopamine release from each drug activates two distinct intracellular pathways in post-synaptic neurons. More specifically, nicotine and cocaine activate different transcription factors within cells2, which are responsible for producing genes that regulate nicotine and cocaine addictions.

One cellular pathway that is activated in the presence of cocaine targets the transcription of the ΔFosB transcription factor1 in dopamine neurons (Figure 1). When the G-protein dopamine receptors undergo a conformational change with dopamine binding, the receptors activate an intracellular G-protein2, which binds to adenyl cyclase2 and produces cAMP2. This secondary messenger can bind and activate a protein kinase A2 (PKA) that phosphorylates a CREB2 Slide1transcription factor to recruit a CREB binding protein, which activates transcription of ΔFosB. ΔFosB is known to maintain a cocaine addictive state by regulating the transcription of genes involved in drug sensitization2 and drug tolerance2. Nicotine, on the other hand, is not correlated to ΔFosB transcription and targets a different pathway to maintain cigarette addictions.

In their research, Levine et al decided to examine the reward center in mice when given sequential doses of nicotine before cocaine or cocaine before nicotine1. They hypothesized that mice pretreated with nicotine may be more sensitized to cocaine addictions because nicotine might increase ΔFosB transcription3 in an indirect manner. To test their hypothesis, they looked at the changes in synaptic plasticity2 of the brains in mice, ΔFosB expression, and histone2 acetylation near the ΔFosB gene. Slide2Histone acetylation is known to increase transcriptional activation by opening up the promoter DNA2, which increases accessibility for enzymes involved in transcription to accumulate near the promoter (Figure 2). Thus, if nicotine somehow affects histone acetylation, ΔFosB transcription rates would increase and the cocaine addiction would be enhanced1.

            What did they find? After seven days of nicotine treatment following one hit of cocaine, the mice showed an increase in activation of their reward pathway, higher place preference for cocaine, and reduced long term potential (LTP) within their synapses. LTP measures the frequency of signal transmission between each neuron, so with lower LTP, develop drug tolerance. They concluded that nicotine priming before cocaine injections showed an increase in cocaine drug sensitization and tolerance1. Furthermore, this process was completely unidirectional, so although nicotine can prime cocaine, cocaine cannot prime nicotine addictions.

Not surprisingly, they found that these synaptic changes were induced by enhanced ΔFosB transcription when the mice were pretreated with nicotine. By using reverse transcriptase PCR2, they found a 135% increase in ΔFosB transcription when the mice were given nicotine before cocaine compared to mice given cocaine alone1. But how does nicotine increase ΔFosB transcription if it doesn’t directly activate the phosphorylation pathway induced when cocaine is given?

Levine et al tested how nicotine affects histone acetylation on the histones near the ΔFosB promoter and found that nicotine inhibits histone deacetylase enzymes (HDAC), which are responsible for removing acetyl groups from histones. When nicotine was given to mice, a 50% reduction in HDACs was found in the VTA1. This suggested that nicotine inhibits HDACs, causing the histones to be acetylated for longer periods of time. Remember, acetylated histones cause DNA to open up through repulsions of the acetyl groups with the DNA backbone, so with the DNA accessible to proteins required to activate gene expression, transcription occurs at much higher rates.

Let’s look at the big picture. Take yourself back into the hypothetical situation above where you and your friend have arrived at the party. Don’t forget that your friend has been addicted to cigarettes for a long time, so he/she has plenty of nicotine circulating in his/her reward system. The nicotine in his/her system is most likely inhibiting HDAC enzymes in the dopamine neurons. By inhibiting these enzymes, the histones in the nucleus will be uncoiled for longer periods of time, exposing promoter regions involved in ΔFosB transcription (Figure 3B). Slide4All of a sudden, you both make that bad decision to try cocaine. When this cocaine reaches your reward systems, it will cause high dopamine accumulation in synaptic regions, thus activating the signal transduction pathway to begin ΔFosB transcription. However, this activation will differ between you and your friend. For you, the transcription of ΔFosB will occur at a much lower rate because your ΔFosB promoters will still be coiled in histones prior to cocaine use. For your friend, the ΔFosB transcription will occur at much higher rates because her genes are already primed for transcription (Figure 3C). Therefore, although you will both feel behavioral changes from the cocaine administration, your friend is more likely to develop a cocaine addiction because his/her ΔFosB proteins accumulate more rapidly causing enhanced drug sensitization and drug tolerance through synaptic changes (Figure 4).

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This research brings about an interesting field for future studies in addiction biology. Since 2011, there have been several groups studying if alcohol and marijuana might act as gateway drugs in a similar manner to nicotine1. There are also pharmaceutical companies trying to develop HDAC activators or HAT inhibitors to reduce ΔFosB expression and to treat cocaine addictions1. These findings are also troublesome because people who are currently trying to quit smoking may be taking nicotine replacement therapy; however, most people addicted to nicotine may also be addicted to cocaine, so this treatment may actually be feeding cocaine addictions.

Scary isn’t it? Just when we thought the long list of harmful effects that cigarettes can cause couldn’t be lengthened, Levine et al clearly shows that nicotine can also enhance chronic cocaine addictions. I must admit that before stumbling across this work, I used to think that gateway drugs were myths. What do you think? Do you believe that nicotine can be a gateway drug for cocaine? Hopefully, next time you talk to somebody who smokes you can explain to him or her how nicotine can enhance cocaine addictions, and more importantly, you can give them another reason to quit smoking.

1: Refer to Recent Literature Page for references used in this blog

2: Refer to Blog Dictionary Page for defined scientific terminology through-out this blog

Internet Addiction Genes Target the Same Pathway as Illicit Drugs

Can’t stop yourself from going online? Then you are not alone. We shop online, we communicate online, and we learn online, and with all of the applications that the World Wide Web has to offer, most people could not spend a whole day without the Internet. Think about it, what are you doing right now?

As a busy university student, I find myself constantly online. However, I’ve never felt truly addicted to the Internet, so I have always questioned the existence of “Internet Addiction Disorders”. After researching this disorder, it turns out that it is quite real and it affects almost 4% our world’s population. Luckily for me, I received a low score on Kimberly Young’s Internet Diagnosis Test (a national test to diagnose Internet addictions), which suggests that I am not an addict.

Internet Addiction Disorder (IAD) is a new term that is being reviewed for entry into the American Psychiatric Association’s DSM1. Internet abusers are known to have certain addictive behaviours such as euphoric1 sensations when spending time online, and even withdrawal symptoms when they are away from the net such as feeling lonely and angry from deprivation and lying about their Internet habits. National statistics suggests that approximately 1 in 8 Americans have been diagnosed with IAD, but little research has been conducted to characterize the molecular basis of this addiction. However, over the past decade, several studies2 have suggested that non-drug and illicit drug addictions both work by affecting the dopamine reward system1. These findings concluded that there may be genetic pre-dispositions correlated to Internet addictive behaviours.

You heard me right. You’ve spent your whole life escaping addictions by staying away from illegal substances, and you find out your genes might make you more prone to IAD. Great. How are you suppose to know if you are more susceptible to this addiction, and how are you going to keep yourself away from the Internet? Today, people are diagnosed with IAD when they develop anxiety from being away from social media, and Internet websites. Before I explain to you why your genes can make you more susceptible to the Internet addictions, you’ll have to understand the brain’s chemical rewards system.

Basically, the brain’s reward pathway is controlled by dopamine, which sends our “happy feelings” to the limbic system1, and tells our brains to adopt a “feel good” behaviour. The brain has several parts involved in the reward pathway including the mesolimbic dopamine system1, which transmits dopamine from the ventral tegmental area1 (VTA) of the brain to the limbic system through the nucleus accumbens region1 (Figure 1). Slide2Dopamine is a neurotransmitter that is released into the VTA when you feel pleasure, and it is dopamine that activates the euphoric signal to be sent from the VTA to your prefrontal cortex1. Without dopamine release and neural stimulation, we would never develop pleasurable feelings. However, like everything else in our bodies, dopamine must be regulated to control the activity of the reward pathway.

Typically, in a normal brain, dopamine is released from a presynaptic neuron into the synaptic area between dopaminergic neurons. While in the synapse, dopamine will bind to dopamine receptors (D2 receptors) on the post-synaptic neuron causing the activation of the receptors by a conformational change. The D2 receptors are G-protein coupled receptors1, and when they are activated, they activate a G-protein that directly stimulates adenyl cyclase1 to produce cAMP1 in the cell, thus causing a signal transduction pathway. This conduction will continue the signal transmission to the prefrontal cortex, until a sense of euphoria is released. After this signal transmission is sent, the dopamine molecules in the synapse must be removed to regulate neural signaling. Several proteins in the synaptic area are involved in sequestering dopamine from the synapse including dopamine re-uptake pumps, which bring dopamine back into the pre-synaptic neuron, dopamine transporters that carry the dopamine to the re-uptake pumps, and enzymes involved in dopamine cleaving (Figure 2A). An example of an enzyme that degrades dopamine in the synapse is the catecholamine-o-methyltransferase enzyme.

But how is the dopamine pathway involved in addiction? Almost all recreational drugs affect the dopamine pathway in a similar manner. Drugs cause high concentrations of dopamine to accumulate in the synaptic areas of the dopaminergic neurons for long periods of time. With high dopamine present in the synapse, the reward signal to brain becomes more intense and continuous for the drug user, thus giving them a euphoric high. Different drugs cause high dopamine accumulation in different ways by interacting with the proteins responsible for dopamine degradation and removal from the synapse. Stimulants, like Cocaine, bind to the dopamine re-uptake pumps on the presynaptic neurons and stop dopamine from being removed from the synaptic region thus increasing its concentration in the synapse and prolonging the high (Figure 2B). After a couple of hours, cocaine concentrations decrease, and dopamine re-uptake will resume.

Drug addictions are characterized by their ability to sensitize your brain and to cause tolerance. Drug sensitization occurs when users feel a high euphoric feeling after they take a drug that stimulates their reward system; however, when a user takes a drug over and over again they develop drug tolerance. Your neurons are smarter than you think, so when you’re ready to use the drug for a second time, your cells will try everything they can to reduce the continuous dopamine transmission in the synaptic area to regulate the reward pathway. One way they try to decrease this activation is by reducing the number of dopamine receptors on the postsynaptic neuron. With fewer receptors available, a reduced signal is transmitted. Hence, the user develops tolerance towards the drug and needs more concentrations of the drug in the future to feel the same reward.

Following me so far? Here comes the interesting part: People with Internet Addiction Disorder seem to have similar addiction symptoms as drug users, and this may be because high levels of dopamine has been seen to accumulate in the synaptic areas of the reward pathway after Internet use. However, there have been many studies on non-drug addictions, such as gambling and food addictions that suggest that these non-drug addictions may only develop in people who have certain genetic pre-dispositions that can stimulate an addictive pattern. Therefore, unlike drug addictions that can affect anyone who uses drugs, non-drug addictions only affect people with certain genes that make them more susceptible to becoming an addict.

In hopes to determine if there was a genetic susceptibility to IAD, Han et al2 from Harvard Medical School, did a study focusing on Internet addictions in video game play in 2007. In their studies, they found two conserved single nucleotide polymorphisms in the D2 dopamine receptor and in the catecholamine-O-methyltransferase genes, respectively, in people who were addicted to Internet games compared to those who do not game online excessively. Single nucleotide polymorphisms1 are small changes found in a genetic code compared to a norm group. Why is this so interesting? These exact polymorphisms are also correlated to gambling addictions.

When comparing Internet addicts and a norm group, they found high variations in the Taq1A1 locus of the D2 receptor gene in excessive Internet users alone. They also found that most Internet addicts were homozygous for this allele. They suggested that this conserved change among addicts might lead to a decrease in the density of the D2 receptors on the post synaptic neurons; consequently, decreasing pleasure transmittance and increasing the users tolerance to achieve reward. They also found a conserved SNP in the catecholamine-o-methyltransferase gene in Internet users alone. They suggested that this SNP may impair the enzyme’s activity to degrade dopamine in the synapse. This would allow for increased dopamine concentration in the synapse for longer periods of time causing a longer high.

Furthermore, in 2012, Hou et al2 at the University School of Medicine in Zhejiang, China, used a radioactive label to label dopamine transporters in the synapse and found that there is was a large reduction in the amount of dopamine transporter proteins in people with IAD compared to a norm group. This transporter protein binds to dopamine and carries it to the neural presynaptic terminal after signal transmission to help decrease dopamine from the synaptic area. Thus, fewer transporters would increase dopamine concentrations in the synapse.

So, next time someone tells you that the Internet can’t be truly addictive, you can tell them they’re wrong. These findings suggested that there might be genetic predispositions correlated with Internet addiction disorders. See Figure 2C for an overview of how dopamine concentrations may be accumulating in the dopaminergic neural synaptic areas of people with IAD.

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Although this is still all new science and no major conclusion about IAD has been made, many researchers are beginning to focus their addiction studies in this field as the Internet is so prominently used in our society. Because our generation runs on the World Wide Web, some pharmacologists have already begun running clinical trials on the use of the FDA approved drug Bupropion, a drug used to treat nicotine addictions, on Internet users. How fascinating is it that both substance and non-substance dependent addictions show common biological backgrounds and perhaps may be treated the same way? So, what do your genes say about you? We are the most active generation of Internet users and without proper caution into how much time we spend online; this addiction disorder may take over faster than we think.

Thinking you might have Internet Addiction Disorder?
Check out Kimberly Young’s Diagnosis Test to see where you fall with respect to IAD.  This is the standard test to diagnose IAD, and ironically it’s online!

1: See Blog Definitions Page for full definitions of scientific terms

2: See Recent Literature Page for references used in this blog and additional papers regarding IAD