Posts tagged dopamine
Articles and news from the latest research reports.
Uncovering the underlying causes of Parkinson’s disease
A breakthrough investigation by UTS researchers into the underlying causes of Parkinson’s disease has brought us a step closer to understanding how to manage the condition.
The team, led by UTS postdoctoral fellow Dr Dominic Hare and Professor Philip Doble, has produced the first empirical evidence that an imbalance of iron and dopamine in the substantia nigra pars compacta (SNc) region of the brain is the root cause of the neurodegenerative condition.
Caused by the slow loss of neurons in the SNc that control autonomous movement, Parkinson’s disease causes persistent shaking, gastrointestinal problems and a variety of other ailments.
More than 80,000 Australians suffer from the illness, most over the age of 60.
Hare’s findings, before only assumptions in the scientific community, finally validate the theory that iron and dopamine react to create free radicals in the brain that slowly destroy neuron pathways and bring about the onset of Parkinson’s.
"When these two chemicals react, it forms a toxic species of dopamine that essentially reacts like bleach in the brain," said Hare.
To conduct their research Hare and his team used a unique tagging technique using antibodies labelled with gold nanoparticles that acted as proxies for dopamine molecules. This enabled the team to monitor and “co-localise” metals with other molecules and proteins in the brain.
And the findings of this work, said Hare, were revelatory.
"What we found is those particular cells (in the SNc) have what you could call an ‘anti-Goldilocks effect’ – they have just the right amount of iron and just the right amount of dopamine to cause damage," said Dr Hare.
"When we give mice a toxin that mimics the effects of Parkinson’s disease, these cells degenerate."
Hare theorises that this effect is likely a natural result of aging, when the brain’s ability to securely store iron diminishes and allows iron molecules to “leak” into critical areas such as the SNc.
Finding ways to design drugs that can get into the brain and eliminate surplus iron – an initiative that is already well underway in the process of treating other illnesses like cancer and Alzheimer’s disease – is now the next step forward in research.
Preventative measures to halt the build-up of iron in the brain as humans undergo the aging process are also touted by Hare as an important next step, and is something he is now working on.
"I think the real hope is, while we might not necessarily find a cure, prevention is actually not that far away," said Hare.
"So it’s a case where you can wake up and say, ‘my Parkinson’s is flaring up again’, take a tablet and go about your business."
Scientists Pinpoint Neurons Where Select Memories Grow
Memories are difficult to produce, often fragile, and dependent on any number of factors—including changes to various types of nerves. In the common fruit fly—a scientific doppelganger used to study human memory formation—these changes take place in multiple parts of the insect brain.
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have been able to pinpoint a handful of neurons where certain types of memory formation occur, a mapping feat that one day could help scientists predict disease-damaged neurons in humans with the same specificity.
“What we found is that while a lot of the neurons will respond to sensory stimuli, only a certain subclass of neurons actually encodes the memory,” said Seth Tomchik, a TSRI biologist who led the study, which was published March 27, 2014, online ahead of print by the journal Current Biology.
The researchers examined a type of neuron called dopaminergic neurons—which respond to dopamine, a well-known neurotransmitter—and are involved in shaping diverse behaviors, including learning, motivation, addiction and obesity.
In the study, the scientists followed the stimulation of a large number of these neurons when an odor was paired with an aversive event such as a mild electric shock. The scientists then used imaging technology to follow changes in the brains of live flies, mapping the activation patterns of signaling molecules within the neurons and observing learning-related plasticity—in which neurons change and develop memory traces.
The scientists found that the neurons that did encode memories responded to a cellular signaling messenger known as cAMP (cyclic adenosine monophosphate) that is vital for many biological processes. cAMP is involved in a number of psychological disorders such as bipolar disorder and schizophrenia, and its dysregulation may underlie some cognitive symptoms of Alzheimer’s disease and Neurofibramatosis I.
In fact, the study pointed to a specific location in the brain—a particular lobe with a region known as the mushroom body—where the neurons appear to be particularly sensitive to elevated amounts of cAMP.
According to Tomchik, that’s an important finding in terms of human memory because olfactory memory formation in the fruit fly is very similar to human memory formation.
“We have a good model in these two classes of neurons, one that encodes and one that doesn’t,” he said. “Now we know exactly where the memory formation should be and where to look to see how disease may disrupt it.”
Tamara Boto, the first author of the study and a member of Tomchik’s laboratory, added, “We know where, but we don’t yet know the mechanism of why only these subsets are affected. That’s our next job—to figure that out.”
(Source: scripps.edu)
Genetic factor contributes to forgetfulness
University of Bonn psychologists prove genetic variation is underlying factor in higher incidence of forgetfulness
Misplaced your keys? Can’t remember someone’s name? Didn’t notice the stop sign? Those who frequently experience such cognitive lapses now have an explanation. Psychologists from the University of Bonn have found a connection between such everyday lapses and the DRD2 gene. Those who have a certain variant of this gene are more easily distracted and experience a significantly higher incidence of lapses due to a lack of attention. The scientific team will probably report their results in the May issue of “Neuroscience Letters,” which is already available online in advance.
Most of us are familiar with such everyday lapses; can’t find your keys, again! Or you walk into another room but forgot what you actually went there for. Or you are on the phone with someone and cannot remember their name. “Such short-term memory lapses are very common, but some people experience them particularly often,” said Prof. Dr. Martin Reuter from the department for Differential and Biological Psychology at the University of Bonn. Mistakes occurring due to such short-term lapses can become a hazard in cases where, e.g., a person overlooks a stop sign at an intersection. And in the workplace, a lack of attention can also become a problem–so for example when it results in forgetting to save essential data.
A gene “directing” your brain
"A familial clustering of such lapses suggests that they are subject to genetic effects," explained Dr. Sebastian Markett, the principal author and a member of Prof. Reuter’s team. In lab experiments, the group of scientists had already found indications earlier that the so-called dopamine D2 receptor gene (DRD2) plays a part in forgetfulness. DRD2 has an essential function in signal transmission within the frontal lobes. "This structure can be compared to a director coordinating the brain like an orchestra," Dr. Markett added. In this simile, the DRD2 gene would correspond to the baton, because it plays a part in dopamine transmission in the brain. If the baton skips a beat, the orchestra gets confused.
The psychologists from the University of Bonn tested a total of 500 women and men by taking a saliva sample and examining it using methods from molecular biology. All humans carry the DRD2 gene, which comes in two variants that are distinguished by only one letter within the genetic code. The one variant has C (cytosine) in one locus, which is displaced by T (thymine) in the other. According to the research team’s analyses, about a quarter of the subjects exclusively had the DRD2 gene with the cytosine nucleobase, while three quarters were the genotype with at least one thymine base.
The scientists then wanted to find out whether this difference in the genetic code also had an effect on everyday behavior. By means of a self-assessment survey they asked the subjects to state how frequently they experience these lapses–how often they forgot names, misplaced their keys. The survey also included questions regarding certain impulsivity-related factors, such as how easily a subject was distracted from actual tasks at hand, and how long they were able to maintain their concentration.
Lapses can clearly be tied to the gene variant
The scientists used statistical methods to check whether it was possible to associate the forgetfulness symptoms elicited by means of the surveys to one of the DRD2 gene variants. The results showed that functions such as attention and memory are less clearly expressed in persons who carry the thymine variant of the gene than in the cytosine type. “The connection is obvious; such lapses can partially be attributed to this gene variant,” reported Dr. Markett. According to their own statements, the subjects with the thymine DRD2 variant more frequently “fall victim” to forgetfulness or attention deficits. And vice versa, the cytosine type seems to be protected from that. “This result matches the results of other studies very well,” added Dr. Markett.
Carriers of the gene variant linked to forgetfulness may now find solace in the fact that they are not responsible for their genes, and that this is just their fate….but Dr. Markett doesn’t agree. “There are things you can do to compensate for forgetfulness; writing yourself notes or making more of an effort to put your keys down in a specific location–and not just anywhere.” Those who develop such strategies for the different areas of their lives are better able to handle their deficit.
(Source: www3.uni-bonn.de)
Study uncovers surprising differences in brain activity of alcohol-dependent women
A new Indiana University study that examines the brain activity of alcohol-dependent women compared to women who were not addicted found stark and surprising differences, leading to intriguing questions about brain network functions of addicted women as they make risky decisions about when and what to drink.
The study used functional magnetic resonance imaging, or fMRI, to study differences between patterns of brain network activation in the two groups of women. The findings indicate that the anterior insular region of the brain may be implicated in the process, suggesting a possible new target of treatment for alcohol-dependent women.
"We see that the network dynamics of alcohol-dependent women may be really different from that of healthy controls in a drinking-related task," said Lindsay Arcurio, a graduate student in the Department of Psychological and Brain Sciences. "We have evidence to suggest alcohol-dependent women have trouble switching between networks of the brain."
The research is part of a larger new effort to understand the differences between men and women with respect to alcohol. Arcurio said most of the research on alcohol dependence has been conducted with men or groups of men and women. Yet several factors make looking at women “really important.”
One such factor is that the physiological effects of drinking alcohol, which include liver damage, heart disease or breast cancer, set in much earlier in women than in men. For this reason, the suggested limit on the number of drinks per week that women can safely consume is eight, whereas for men, it is 14. Secondly, binge-drinking in women is on the rise. One in five adolescent girls is binge-drinking three times a month. In women between the ages of 18 and 54, that number is one in eight.
A ‘sledgehammer’ approach to defining differences in brain network activation
Research on decision-making mechanisms in alcohol-dependent individuals typically involves a general risk-taking situation in which money or points are at stake. In this study, participants were placed in the fMRI brain scanner and asked to consider low-risk and high-risk situations specifically related to alcohol — what the researchers describe as “ecological” tasks. Participants were then asked to make decisions regarding control stimuli — food as well as a presumably neutral stimuli, a stapler — to observe whether risky behavior was greater with respect to drinking than with these other items. The same picture cues were used to present high-risk and low-risk scenarios, and these two extremes were as follows:
For the low-risk situation, participants were told: Imagine you are at a bar. You are offered a drink, already paid for, with two shots of alcohol, and you have a safe ride home. For the high-risk, they were told: You are at a bar and are offered a drink already paid for, with six shots of alcohol, but you do not have a safe ride home.
The reason for such an extreme contrast between the two situations, Arcurio said, is that “as one of the first ecological tasks used in the scanner, we wanted to take a sledgehammer approach to really find the differences between cases that are definitely high-risk and those that are definitely low-risk.”
The findings, however, reflect an equally sharp contrast in differences between the brain network activation in alcohol-dependent women versus the controls.
For the control group, high-risk decisions to drink led to the deactivation of regions associated with “approach behavior,” deciding to take the drink in a risky situation. Conversely, women in the control group activate regions associated with the default mode network, a region traditionally thought to involve resting-state behavior or inactive or relaxed mental state, but which some now speculate plays a role in conceptualizing one’s future.
"It gets really interesting," Arcurio said, "comparing this pattern of activation to those in alcohol-dependent women, who behaviorally say they’re more likely to take the high-risk drink compared to the controls. They don’t deactivate anything. In contrast to the controls, alcohol-dependent women activate all three regions in question. They activate regions associated with reward (which release dopamine). They also activate frontal control regions involved in cognitive control and regions associated with the default mode network, involved in resting-state behavior. They are activating everything."
The investigators infer from these findings that alcohol-dependent women have trouble switching between networks. Being unable to activate one region and deactivate another in response to an alcohol-related situation means they are unable to use one strategy over another.
Furthermore, Arcurio said, “a lot of evidence suggests that switching between networks is influenced by the anterior insular and anterior cingulate regions of the brain, and we did find major differences in the insula between the alcohol-dependent women and controls. We’re thinking the issue is pinpointed to that region.”
The researchers are now running analyses to test the hypothesis that the insula helps in this process, which could offer new possibilities for intervention, with both behavioral therapy and medication.
The research is part of a whole research program, both planned and in the works, to further explore the questions about risky decision-making in alcohol-dependent women: studies of adolescent drinking, risky sexual behavior in alcohol-dependent women, the interaction of visual networks with decision-making networks, as well as the way music (or auditory networks) interacts with decision-making mechanisms in alcohol-dependent women. In the latter experiment, college-age participants choose a song that they associate with drinking and one with quiet reflection.
"There’s a lot of Miley Cyrus in the first category," Arcurio said.
(Source: news.indiana.edu)
Promise of a bonus counter-productive in brains with high dopamine levels
Some people perform better and others worse when promised a high bonus. Brain researcher Esther Aarts of the Donders Institute in Nijmegen has demonstrated for the first time that the amount of dopamine in the brain plays a role in this regard. The journal Psychological Science will publish the results on February 13.
It has been known for some time that not everyone performs better after being promised a bonus. Scientists have published contradictory results regarding the cause. The study by Esther Aarts now shows that the differences can be explained by differences in the level of dopamine in the brain. People with a high level of dopamine in a specific brain region – the striatum – perform worse after a being promised a bonus, and people with a low level of dopamine in the same area perform better. Aarts used a PET (Positron Emission Tomography) scanner to examine the amount of dopamine in the brains of subjects. She conducted this research in Berkeley, California (USA), where she worked as a post-doctoral researcher for two years.
Overdose of dopamine
The promise of a bonus provides an additional spurt of the ‘motivation substance’ dopamine in the brain. ‘For people who usually have high levels of dopamine, the promise of a bonus causes a type of dopamine overdose in the striatum’, explains Aarts. ‘Our test subjects were asked to perform a task that required considerable concentration. An overdose of dopamine makes this difficult. People who usually have less dopamine are less likely to have an overdose of dopamine, and they therefore perform better after being promised a bonus.’
Concentration desired
Test subjects performed a computer task that elicited conflicting reactions, therefore requiring considerable concentration: an arrow appears on the screen, pointing either left or right. The word ‘left’ or ‘right’ is written in the middle of the arrow. Subjects were asked to ignore the direction indicated by the arrow and mention only the direction described by the word. For half of the attempts, a bonus of 15 cents was promised for a correct answer. In the other half, the subjects received only 1 cent for each correct answer. People who usually have a high level of dopamine performed better in the low-pay condition than they did in the high-pay condition. The reverse was observed for people with low levels of dopamine: they performed better with high rewards than they did with low rewards.
Flexibility or focus
‘This knowledge could make it possible to apply bonuses more effectively, but it would require observing the standard dopamine levels of people, as well as the nature of the task that they must perform’, reports Aarts. ‘It makes quite a difference whether the task is flexible and creative or whether it requires a great deal of focus. Our research shows how people perform on tasks that require considerable focus’. Given the high cost of PET scans, Aarts is now looking for easier ways of measuring dopamine levels. ‘I hope to be able to relate dopamine levels to scores on questionnaires. In the future, this might eliminate the need for PET scans for determining the quantity of dopamine in the brain’.
Long-term spinal cord stimulation stalls symptoms of Parkinson’s-like disease
Researchers at Duke Medicine have shown that continuing spinal cord stimulation appears to produce improvements in symptoms of Parkinson’s disease, and may protect critical neurons from injury or deterioration.
The study, performed in rats, is published online Jan. 23, 2014, in the journal Scientific Reports. It builds on earlier findings from the Duke team that stimulating the spinal cord with electrical signals temporarily eased symptoms of the neurological disorder in rodents.
"Finding novel treatments that address both the symptoms and progressive nature of Parkinson’s disease is a major priority," said the study’s senior author Miguel Nicolelis, M.D., Ph.D., professor of neurobiology at Duke University School of Medicine. "We need options that are safe, affordable, effective and can last a long time. Spinal cord stimulation has the potential to do this for people with Parkinson’s disease."
Parkinson’s disease is caused by the progressive loss of neurons that produce dopamine, an essential molecule in the brain, and affects movement, muscle control and balance.
L-dopa, the standard drug treatment for Parkinson’s disease, works by replacing dopamine. While L-dopa helps many people, it can cause side effects and lose its effectiveness over time. Deep brain stimulation, which emits electrical signals from an implant in the brain, has emerged as another valuable therapy, but less than 5 percent of those with Parkinson’s disease qualify for this treatment.
"Even though deep brain stimulation can be very successful, the number of patients who can take advantage of this therapy is small, in part because of the invasiveness of the procedure," Nicolelis said.
In 2009, Nicolelis and his colleagues reported in the journal Science that they developed a device for rodents that sends electrical stimulation to the dorsal column, a main sensory pathway in the spinal cord carrying information from the body to the brain. The device was attached to the surface of the spinal cord in rodents with depleted levels of dopamine, mimicking the biologic characteristics of someone with Parkinson’s disease. When the stimulation was turned on, the animals’ slow, stiff movements were replaced with the active behaviors of healthy mice and rats.
Because research on spinal cord stimulation in animals has been limited to the stimulation’s acute effects, in the current study, Nicolelis and his colleagues investigated the long-term effects of the treatment in rats with the Parkinson’s-like disease.
For six weeks, the researchers applied electrical stimulation to a particular location in the dorsal column of the rats’ spinal cords twice a week for 30-minute sessions. They observed a significant improvement in the rats’ symptoms, including improved motor skills and a reversal of severe weight loss.
In addition to the recovery in clinical symptoms, the stimulation was associated with better survival of neurons and a higher density of dopaminergic innervation in two brain regions controlling movement – the loss of which cause Parkinson’s disease in humans. The findings suggest that the treatment protects against the loss or damage of neurons.
Clinicians are currently using a similar application of dorsal column stimulation to manage certain chronic pain syndromes in humans. Electrodes implanted over the spinal cord are connected to a portable generator, which produces electrical signals that create a tingling sensation to relieve pain. Studies in a small number of humans worldwide have shown that dorsal column stimulation may also be effective in restoring motor function in people with Parkinson’s disease.
"This is still a limited number of cases, so studies like ours are important in examining the basic science behind the treatment and the potential mechanisms of why it is effective," Nicolelis said.
The researchers are continuing to investigate how spinal cord stimulation works, and are beginning to explore using the technology in other neurological motor disorders.
Scientists Develop Promising Drug Candidates for Pain, Addiction
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have described a pair of drug candidates that advance the search for new treatments for pain, addiction and other disorders.
The two new drug scaffolds, described in a recent edition of The Journal of Biological Chemistry, offer researchers novel tools that act on a demonstrated therapeutic target, the kappa opioid receptor (KOR), which is located on nerve cells and plays a role in the release of the neurotransmitter dopamine. While compounds that activate KOR are associated with positive therapeutic effects, they often also recruit a molecule known as βarrestin2 (beta arrestin), which is associated with depressed mood and severely limits any therapeutic potential.
“Compounds that act at kappa receptors may provide a means for treating addiction and for treating pain; however, there is the potential for the development of depression or dysphoria associated with this receptor target,” said Laura Bohn, a TSRI associate professor who led the study. “There is evidence that the negative feelings caused by kappa receptor drugs may be, in part, due to receptor actions through proteins called beta arrestins. Developing compounds that activate the receptors without recruiting beta arrestin function may serve as a means to improve the therapeutic potential and limit side effects.”
The new compounds are called “biased agonists,” activating the receptor without engaging the beta arrestins.
Research Associate Lei Zhou, first author of the study with Research Associate Kimberly M. Lovell, added, “The importance of these biased agonists is that we can manipulate the activation of one particular signaling cascade that produces analgesia, but not the other one that could lead to dysphoria or depression.”
The researchers note that the avoidance of depression is particularly important in addiction treatment, where depressed mood can play a role in relapse.
The two drug candidates also have a high affinity and selectivity for KOR over other opioid receptors and are able to pass through the blood-brain barrier. Given these promising attributes, the scientists plan to continue developing the compounds.
(Source: scripps.edu)
Researchers find rare genetic cause of Tourette syndrome
A rare genetic mutation that disrupts production of histamine in the brain is a cause of the tics and other abnormalities of Tourette syndrome, according to new findings by Yale School of Medicine researchers.
The findings, reported Jan. 8 in the journal Neuron, suggest that existing drugs that target histamine receptors in the brain might be useful in treating the disorder. Tourette syndrome afflicts up to 1% of children, and a smaller percentage of adults.
“These findings give us a new window into what’s going on in the brain in people with Tourette. That’s likely to lead us to new treatments,” said Christopher Pittenger, associate professor in the psychiatry and psychology departments and in the Yale Child Study Center, and senior author of the paper.
Histamine is commonly associated with allergy, but it also plays an important role as a signaling molecule in the brain. Interactions with this brain system explain why some allergy medications cause people to feel sleepy.
In 2010, Yale researchers showed that a family with nine members suffering from Tourette’s carried a mutation in a gene called HDC that disrupts the production of histamine. The new work demonstrates that this mutation causes the disorder. Mice with the same mutation develop symptoms similar to those found in Tourette’s, the Yale team showed. Also, these mice and the patients that carry the HDC mutation showed abnormalities in signaling by the neurotransmitter dopamine in parts of the brain associated with Tourette’s and related conditions.
Drug companies have developed medications that target brain-specific histamine receptors in an effort to treat schizophrenia and ADHD. While not approved for general use yet, those drugs or others that target histamine receptors should be tested to see whether they can treat symptoms of Tourette syndrome, Pittenger said.
Gel reduced daily tremors in Parkinson’s disease
An experimental treatment for Parkinson’s disease reduced by nearly two hours on average the period each day when medication failed to control patients’ slowness and shaking, according to results from a double-blind, phase III clinical trial published in December 2013, in Lancet Neurology.
The study compared AbbVie’s levodopa-carbidopa intestinal gel against the same medication in pill form in patients with advanced disease.
The University of Alabama at Birmingham was among the sites for the study, with David G. Standaert, M.D., Ph.D., chair of the UAB Department of Neurology, an author. Led by the Mount Sinai School of Medicine, preliminary results from the study were first presented at the annual meeting of the American Academy of Neurology in April 2012.
Parkinson’s disease results from the loss of brain cells that make dopamine, which helps to control movement. As dopamine levels fall, patients experience tremors, muscle stiffness and loss of balance. A commonly prescribed treatment, the levodopa-carbidopa combination works as the body converts levodopa into dopamine and carbidopa escorts levodopa to the right part of the brain. The problem is that patients face hours of uncontrolled slowness, freezing and tremors each day — called “off-time” — as the treatment gets into place or wears off.
One reason for the break in treatment coverage is that it comes in a pill, and pills sit in the stomach for up to six hours waiting for it to empty into the small intestine. It is only there that levodopa encounters the proteins capable of transporting it into the bloodstream en route to the brain. Thus, researchers envisioned a system that steadily delivers levodopa gel directly into the small intestine through a surgically placed tube, and with the help of a pump worn on the belt.
“The results are very exciting, considering that other recently approved drugs on the market reduce off-time by, at most, just over an hour,” said Standaert. “In the study, the gel treatment helped patients who had run out of alternatives with current medications. We believe it may be an important new option for patients with severe Parkinson’s, with benefits comparable to more invasive techniques like deep brain stimulation.”
Patients using the gel system saw an average reduction in daily off-time of 1.91 hours, and an increase in “on-time” without troublesome dyskinesia of 1.86 hours compared with the pill form. Nearly all subjects experienced at least one side effect, although most were short-lived and moderate.
(Source: uab.edu)
Molecule discovered that protects the brain from cannabis intoxication
Two INSERM research teams led by Pier Vincenzo Piazza and Giovanni Marsicano (INSERM Unit 862 “Neurocentre Magendie” in Bordeaux) recently discovered that pregnenolone, a molecule produced by the brain, acts as a natural defence mechanism against the harmful effects of cannabis in animals. Pregnenolone prevents THC, the main active principle in cannabis, from fully activating its brain receptor, the CB1 receptor, that when overstimulated by THC causes the intoxicating effects of cannabis. By identifying this mechanism, the INSERM teams are already developing new approaches for the treatment of cannabis addiction.
These results are to be published in Science on 3 January.
Over 20 million people around the world are addicted to cannabis, including a little more than a half million people in France. In the last few years, cannabis addiction has become one of the main reasons for seeking treatment in addiction clinics. Cannabis consumption is particularly high (30%) in individuals between 16 to 24 years old, a population that is especially susceptible to the harmful effects of the drug.
While cannabis consumers are seeking a state of relaxation, well-being and altered perception, there are many dangers associated to a regular consumption of cannabis. Two major behavioural problems are associated with regular cannabis use in humans: cognitive deficits and a general loss of motivation. Thus, in addition to being extremely dependent on the drug, regular users of cannabis show signs of memory loss and a lack of motivation that make quite hard their social insertion.
The main active ingredient in cannabis, THC, acts on the brain through CB1 cannabinoid receptors located in the neurons. THC binds to these receptors diverting them from their physiological roles, such as regulating food intake, metabolism, cognitive processes and pleasure. When THC overstimulates CB1 receptors, it triggers a reduction in memory abilities, motivation and gradually leads to dependence.
Increase of dopamine release
Developing an efficient treatment for cannabis addiction is becoming a priority of research in the fiend of drug addiction.
In this context, the INSERM teams led by Pier Vincenzo Piazza and Giovanni Marsicano have investigated the potential role of pregnenolone a brain produced steroid hormone. Up to now, pregnenolone was considered the inactive precursor used to synthesize all the other steroid hormones (progesterone, estrogens, testosterone, etc.). The INSERM researchers have now discovered that pregnenolone has quite an important functional role: it provide a natural defence mechanism that can protect the brain from the harmful effects of cannabis.
Essentially, when high doses of THC (well above those inhaled by regular users) activate the CB1 cannabinoid receptor they also trigger the synthesis of pregnenolone. Pregnenole then binds to a specific site on the same CB1 receptors (see figure) and reducing the effects of THC.
The administration of pregnenolone at doses that increase the brain’s level of this hormone even more, antagonize the behavioral effects of cannabis.
At the neurobiological level, pregnenolone greatly reduces the release of dopamine triggered by THC. This is an important effect, since the addictive effects of drugs involve an excessive release of dopamine.
This negative feedback mediated by pregnenolone (THC is what triggers the production of pregnenolone, which then inhibits the effects of THC) reveal a previously unknown endogenous mechanism that protects the brain from an over-activation of CB1 receptor.
A protective mechanism that opens the doors to a new therapeutic approach.
The role of pregnenolone was discovered when, rats were given equivalent doses of cocaine, morphine, nicotine, alcohol and cannabis and the levels of several brain steroids (pregnenolone, testosterone, allopregnenolone, DHEA etc..) were measured. It was then found that only one drug, THC, increased brain steroids and more specifically selectively one steroid, pregnenolone, that went up3000% for a period of two hours.
The effect of administering THC on the pregnenolone synthesis (PREG) and other brain steroids
This increase in pregnenolone is a built-in mechanism that moderates the effects of THC. Thus, the effects of THC increase when pregnenolone synthesis is blocked. Conversely, when pregnenolone is administered to rats or mice at doses (2-6 mg/kg) that induce even greater concentrations of the hormone in the brain, the negative behavioural effects of THC are blocked. For example, the animals that were given pregnenolone recover their normal memory abilities, are less sedated and less incline to self-administer cannabinoids.
Experiments conducted in cell cultures that express the human CB1 receptor confirm that pregnenolone can also counteract the molecular action of THC in humans.
Pier Vincenzo Piazza explains that pregnenolone itself cannot be used as a treatment “Pregnenolone cannot be used as a treatment because it is badly absorbed when administerd orally and once in the blood stream it is rapidly transformed in other steroids”.
However, the researcher says that there is strong hope of seeing a new addiction therapy emerge from this discovery. “We have now developed derivatives of pregnenolone that are well absorbed and stable. They then present the characteristics of compounds that can be used as new class of therapeutic drugs. We should be able to begin clinical trials soon and verify whether we have indeed discovered the first pharmacological treatment for cannabis dependence.”