Новости о влиянии кокаина на допаминовый метаболизм

Очень интересно: http://www.eurekalert.org/pub_releases/2009-05/muhc-cpa051909.php
Contact: Isabelle Klingisabelle.kling@muhc.mcgill.ca514-843-1560McGill University Health Centre
Cocaine: Perceived as a reward by the brain?
Researchers at the MNI and the MUHC open up a new path for cocaine addiction research
This release is available in French.
Montreal, May 19th 2009 - Cocaine is one of the oldest drugs known to humans, and its abuse has become widespread since the end of the 19th century. At the same time, we know rather little about its effects on the human brain or the mechanisms that lead to cocaine addiction. The latest article by Dr. Marco Leyton, of the Montreal Neurological Institute (MNI), McGill University and the McGill University Health Centre, which was published in the journal Biological Psychiatry on May 15, 2009, not only demonstrates a link between cocaine and the reward circuits in the brain but also associates the susceptibility to addiction with these mechanisms.
The results of this study show that sniffing cocaine triggers high levels of dopamine secretion in a central region of the brain called the striatum. Dopamine is known to play a critical role in the brain's response to reward as well as in its response to addictive drugs.
This study was carried out in ten non-addicted users of cocaine, all of whom sniffed cocaine on one test day and placebo powder on another. Participants underwent blood tests before and after taking the drug, and dopamine release in the brain was measured using PET scans.
"The ability of cocaine to activate dopamine release varies markedly from person to person. Our study suggests that this is related to how much of the drug the person consumed in the past," explained Dr. Leyton. The more cocaine someone has used in his or her lifetime, the more the brain will secrete dopamine during subsequent cocaine use. "It's possible therefore that the intensity of the reward-circuit response is related to increased susceptibility to addiction," stated Dr. Leyton.
Although the relationship between the intensity of dopamine secretion and the frequency of drug use has been demonstrated, researchers still do not fully understand its mechanism of action. Is it the repeated stimulation of the reward circuit that leads to addiction, or is it an inherent sensitivity to addiction that leads to the increased secretion of dopamine? This question is not easy to answer, especially since other factors come into play, such as other aspects of the subject's personal history.
Whatever the answer, the relationship between dopamine and cocaine means that this hormone could be a potential target for treatment against addiction. More research is required before treatments are available, but this study opens a new door in this direction.

Счастливая наследственность?

Прочитано на http://www.scientificblogging.com/news_articles/can_you_inherit_happiness_endorphins_and_biochemistry_inheritance
As if you need another reason for parental guilt, a new article in Bioscience Hypotheses speculates that our feelings could impact our reproduction and affect our children.

Dr Alberto Halabe Bucay of Research Center Halabe and Darwich, Mexico, suggests that a wide range of chemicals that our brain generates when we are in different moods could affect 'germ cells' (eggs and sperm), the cells that ultimately produce the next generation. Such natural chemicals could affect the way that specific genes are expressed in the germ cells, and hence how a child develops.

In his article Halabe suggested that the hormones and chemicals resulting from happiness, depression and other mental states can affect our eggs and sperm, resulting in lasting changes in our children at the time of their conception.

Brain chemicals such as endorphins, and drugs, such as marijuana and heroin are known to have significant effects on sperm and eggs, altering the patterns of genes that are active in them.

"It is well known, of course, that parental behavior affects children, and that the genes that a child gets from its parents help shape that child's character." said Dr. Halabe Bucay. "My paper suggests a way that the parent's psychology before conception can actually affect the child's genes."

"This is an intriguing idea" commented Dr. William Bains, Editor of Bioscience Hypotheses. "We wanted to publish it to see what other scientists thought, and whether others had data that could support or disprove it. That is what our journal is for, to stimulate debate about new ideas, the more groundbreaking, the better."

Article: Alberto Halabe Bucay, 'Endorphins, personality, and inheritance: Establishing the biochemical bases of inheritance', Bioscience Hypotheses, In Press, Corrected Proof, Available online 7 May 2009 doi:10.1016/j.bihy.2009.03.003

Новое о механизмах эффектов экстази

Очень интересно... Как всегда грамотно написано на http://scienceblogs.com/drugmonkey/2009/05/waitcannabis_potentiates_the_e.php

Wait...Cannabis potentiates the effects of Ecstasy?

Category: Cannabis • MDMA
Posted on: May 15, 2009 5:35 PM, by DrugMonkey

Along with alcohol, caffeine and nicotine, the most-active ingredient in cannabis (Δ9-THC; "THC") is frequently co-ingested with MDMA by the Ecstasy user. There are, in fact, some suggestions that cannabis may be consumed in some cases specifically to assist with modulating the MDMA high.

Now, those that are aware of the tetrad test for cannabinoid action (necessary back before the first cannabinoid receptor was cloned in the early 90s) might think to themselves of a specific protective effect. One of the hallmarks of THC is that it reduces body temperature in rats. So if one of the problems with MDMA is that it results in high body temperature, it might be convenient if smoking a little dope had an action that reversed this physiological outcome.

This was supported by a paper by Morley et al (2004) which reported that yes indeed, if you inject a rat with 2.5 mg/kg THC i.p. it completely blocks the tympanic temperature elevation produced by 5 mg/kg MDMA i.p.

A recent study in humans suggests that caution is warranted.

Cannabis Coadministration Potentiates the Effects of "Ecstasy" on Heart Rate and Temperature in Humans. Dumont G, Kramers C, Sweep F, Touw D, van Hasselt J, de Kam M, van Gerven J, Buitelaar J, Verkes R. Clin Pharmacol Ther. 2009 May 13.

This study reports on the effects of 100 mg oral MDMA, three inhalations of about 6 mg THC (spaced at 90 min) and the combination in 13 human subjects. Plasma kinetics for the exogenous drugs, for norepinephrine and epinephrine and heart rate are reported. One of the more interesting bits, however, is reported in the following figure.

Tympanic temperature was increased by oral consumption of MDMA, reaching a peak about 90 minutes after ingestion (consistent with the plasma peak), as one might expect*. inhaling vaporized THC did not block this effect. The first inhalation of THC (timed to pill ingestion) looks to have delayed the onset of the temperature increase. However the second inhalation did not induce further delay and temperature ultimately reached a peak change approximately equal to the one after MDMA alone. The elevated temperature was sustained up to the end of the 300 min observation interval in the THC-MDMA combined condition compared with MDMA alone.

Hmm. Looking for differences here. The biggest thing would seem to be that this level of THC inhalation did not produce a reduction in body temperature by itself in humans. The doses that decrease body temperature in rodents are fairly high ones so what were these humans receiving? Well, the inhalation procedure in this study resulted in plasma levels of 60-80 ng/ml. This NHTSA site claims that 100-200 ng/ml of THC are "routinely" observed in cannabis smokers. See this, this, this for confirmation. So the present study was perhaps on the low side of things, but then speculating exactly how much cannabis an Ecstasy user might smoke is.....well, speculative. And the study did report about a 20-30 bpm elevation in heart rate after THC inhalation that appeared to be independent of MDMA (which itself elevated heart rate by about 20-30 bpm). So it was certainly in the range of physiological relevance.

Give that this study is in humans, given the doses seem more in line with what would be expected in the user population, I'd have to put more confidence in this study than in the Morley et al (2004) rat paper. Thus it appears unlikely that cannabis smoking in the recreational Ecstasy user provides any protection against MDMA-induced hyperthermia.

The prolongation of the elevated body temperature that was the excuse for using "Potentiates" in the title? Doesn't support a strong conclusion at this stage but it certainly brings up some other scenarios for risk with subsequent dosing.

__
*Actually it is not entirely true that one might expect this. This is well below the doses used in the clinical trials. One of the initial results seems to imply not just that mean temp did not significantly increase but that no individual experienced a 1 deg Celsius increase in temperature. Liechti and Vollenweider (2000) reported no effect of 1.5 mg/kg oral MDMA on axillary temperature. Nevertheless in a dedicated experiment using an ingested remote device to measure gastric ("core") temperature Freedman and colleagues (2005) found that 2 mg/kg oral MDMA did increase body temperature under cool and warm laboratory conditions.

Курение поможет аллергикам???

Сенсационно! http://www.scientificblogging.com/news_articles/solution_allergies_cigarettes:
Smoking is bad for you, but it can also help with allergies, according to a new study which says that cigarette smoke can prevent allergies by decreasing the reaction of immune cells to allergens.

Smoking can cause lung cancer, pulmonary disease, and can even affect how the body fights infections but along with many harmful effects, smoking cigarettes has a surprising benefit: cigarettes can protect smokers from certain types of allergies. The new study says that cigarette smoke decreases the allergic response by inhibiting the activity of mast cells, the major players in the immune system's response to allergens.

Researchers at Utrecht University in the Netherlands found that treatment of primary cultured murine mast cells with a cigarette smoke-infused solution and activated with IgE and antigen or lipopolysaccharide (LPS) prevented the release of inflammation-inducing proteins in response to allergens, without affecting other mast cell immune functions.

The mast cells used in the study were derived from mice, but they say it is likely that the same anti-allergy effect will hold true in humans. While taking up smoking to cure allergies is unwise, Thomson concludes that the findings presented in this study are "consistent with a dampening of allergic responses in smokers."

Article: Mortaz E, Folkerts G, Engels F, Nijkamp FP, Redegeld FA, 'Cigarette smoke suppresses in vitro allergic activation of mouse mast cells', Clin Exp Allergy. 2009 May;39(5):679-87. Epub 2009 Mar 2

Больше думаем - сложнее выбор

Too much information: Process thinking can lead to difficult choices - отличная статья на http://www.eurekalert.org/pub_releases/2009-05/uocp-tmi051209.php

Choosing among products can be more difficult if you tend to think more about the process of using an item rather than the outcome of the purchase, according to a new study in the Journal of Consumer Research.

"Marketers often try to tempt consumers to buy their products by encouraging them to imagine themselves using the product," write authors Debora Viana Thompson (Georgetown University), Rebecca W. Hamilton (University of Maryland, College Park), and Petia K. Petrova (Dartmouth College). But this "process-oriented" thinking can lead to confusion.

"In this research, we show that when consumers are choosing among products, focusing on the process of using a product (versus on the outcomes) can increase decision difficulty and hinder consumers' motivation to subsequently implement their choices," the authors explain.

Consumer decisions often involve trade-offs between means and end benefits, such as weighing quality versus price, rewards versus risks, or enjoyment versus effort. Process-oriented thinkers tend to focus on both ends and means, making decisions more difficult.

For example, in one experiment, participants were asked to choose between a small apartment that required a short commute and one that was larger but required a longer commute. The researchers instructed participants to either think about how living in the apartment would affect their daily routine and habits (process-oriented thinking) or to think about what they would gain from living in the apartment (outcome-oriented thinking). "Process-oriented participants thought about both the size of the apartment and the length of the commute, were less likely to choose the larger apartment, and experienced more difficulty making the choice," the authors write.

"This experience of difficulty can have various negative consequences for consumers. It can lower consumer satisfaction with the decision process, increase willingness to postpone choices, increase the likelihood they will change their minds later and switch to a different option, and reduce motivation to implement the decision," the authors conclude.

###

Debora Viana Thompson, Rebecca W. Hamilton, and Petia K. Petrova. "When Mental Simulation Hinders Behavior: The Effects of Process-Oriented Thinking on Decision Difficulty and Performance." Journal of Consumer Research: December 2009 (published online April 9, 2009).

О влиянии кокаина на экспрессию генов

Новые исследования описаны на http://www.scientificblogging.com/news_articles/cocaine_regulates_gene_expression_and_has_longlasting_impact_behavior
New research sheds light on how cocaine regulates gene expression in a crucial reward region of the brain to elicit long-lasting changes in behavior. The study in Neuron provides insight into the molecular pathways regulated by cocaine and may lead to new strategies for battling drug addiction.

It is well established that addictive drugs induce persistent changes in the brain's reward circuits. Previous research has indicated that addiction to drugs such as cocaine is associated with altered gene expression in the nucleus accumbens (NAc), a region of the brain that is involved in motivation, pleasure, and reward.

"Although we have known for some time that changes in gene expression contribute to the long-lasting regulation of the brain's reward circuitry that is seen during drug addiction, how those specific genes are regulated is not well understood," explains senior study author, Dr. Eric J. Nestler from the Department of Neuroscience at the Mount Sinai School of Medicine.

Dr. Nestler and colleagues combined sophisticated and highly sensitive genetic isolation and screening techniques to study regulation of gene transcription in the mouse NAc, including regulation of chromatin structure, after repeated administration of cocaine. The results of this novel analysis significantly refined the understanding of cocaine-regulated gene transcription in general, and advanced knowledge of the specific role of two transcription factors known to play a prominent role in cocaine-induced addiction.

The researchers also identified a previously unrecognized family of genes, called the sirtuins, as being involved in cocaine addiction in the NAc. Chronic cocaine administration was linked with an increase in sirtuin gene transcription while increased sirtuin activity in NAc neurons was associated with a potentiation of the rewarding effects of cocaine. Importantly, pharmacological inhibition of sirtuins in the NAc reduced the rewarding effects of cocaine and the motivation to self-administer the drug.

Taken together, the results identify a subset of genes that are highly likely to be targets of cocaine and shed light on the specific mechanisms that underlie cocaine-induced changes in the NAc. "Our findings underscore the vast clinical potential of the many new gene targets identified in this study for the development of more effective treatments of cocaine and potentially other drug addictions," concludes Dr. Nestler.

The researchers include William Renthal, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX; Arvind Kumar, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX; Guanghua Xiao, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX; Matthew Wilkinson, Mount Sinai School of Medicine, New York, NY; Herbert E. Covington III, Mount Sinai School of Medicine, New York, NY; Ian Maze, Mount Sinai School of Medicine, New York, NY; Devanjan Sikder, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX; Alfred J. Robison, Mount Sinai School of Medicine, New York, NY; Quincey LaPlant, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, Mount Sinai School of Medicine, New York, NY; David M. Dietz, Mount Sinai School of Medicine, New York, NY; Scott J. Russo, Mount Sinai School of Medicine, New York, NY; Vincent Vialou, Mount Sinai School of Medicine, New York, NY; Sumana Chakravarty, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX; Thomas J. Kodadek, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX; Ashley Stack, Florida State University, Tallahassee, FL; Mohamed Kabbaj, Florida State University, Tallahassee, FL; and Eric J. Nestler, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, Mount Sinai School of Medicine, New York, NY.

Снова о репарации ДНК

Отличная статья на http://www.biologynews.net/archives/2009/05/05/stopgap_dna_repair_needs_a_second_step.html
Оne can have a dream, two can make that dream so real, goes a popular song. Now a Weizmann Institute study has revealed that it takes two to perform an essential form of DNA repair.
Prof. Zvi Livneh of the Weizmann Institute's Biological Chemistry Department has been studying DNA repair for some two decades: 'Considering that the DNA of each cell is damaged about 20,000 times a day by radiation, pollutants and harmful chemicals produced within the body, it's obvious that without effective DNA repair, life as we know it could not exist. Most types of damage result in individual mutations – genetic 'spelling mistakes' – that are corrected by precise, error-free repair enzymes. Sometimes, however, damage results in more than a mere spelling mistake; it can cause gaps in the DNA, which prevent the DNA molecule from being copied when the cell divides, much like an ink blot or a hole on a book page interferes with reading. So dangerous are these gaps that the cell resorts to a sloppy but efficient repair technique to avoid them: It fills in the missing DNA in an inaccurate fashion. Such repair can save the cell from dying, but it comes at a price: this error-prone mechanism, discovered at the Weizmann Institute and elsewhere about a decade ago, is a major source of mutations.'
In a recent study he conducted with graduate students Sigal Shachar and Omer Ziv, as well as researchers from the US and Germany, Livneh revealed how the error-prone repair works. The team found that such repair proceeds in two steps and requires two types of enzymes, belonging to the family of enzymes called DNA polymerases, which synthesize DNA. First, one repair enzyme, 'the inserter,' does its best to fit in a genetic 'letter' into the gap, opposite the damaged site in the DNA molecule; several enzymes can perform this initial step, which often results in the insertion of an incorrect genetic letter. Next, another enzyme, 'the extender,' helps to restore regular copying of DNA by attaching additional DNA letters after the damaged site; only one repair enzyme is capable of performing this vital second step. These findings were published recently in the EMBO Journal.

Understanding how this major form of DNA repair works can have significant clinical implications. Since defects in this process increase the risk of cancer, clarifying its nuts and bolts might one day make it possible to enhance it in people whose natural DNA repair is deficient. In addition, manipulating this mechanism can improve the effectiveness of cancer drugs. Cancer cells can resist chemotherapy by exploiting their natural repair mechanisms, and blocking these mechanisms may help overcome this resistance, leading to a targeted destruction of the cancerous tumor.

Source : Weizmann Institute of Science