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        New Message Board Archives >> 2005 General Board Posts >> Circadian Rhythms Drug Addiction
        
(Message started by: ben_uk on Nov 7^th, 2005, 6:14pm)

Title: Circadian Rhythms Drug Addiction
Post by ben_uk on Nov 7^th, 2005, 6:14pm

Circadian Rhythms Drug Addiction

http://www.sciencedaily.com/releases/2005/08/050805180443.htm
http://tinyurl.com/8yg2e
Although expressed primarily in the brain's circadian command center, biological clock genes have also been found in areas of the brain involved in reward and addiction.
A team led by researchers from the University of Texas Southwestern Medical Center at Dallas and including Northwestern University's Joseph S. Takahashi, Walter and Mary Elizabeth Glass Professor in the Life Sciences and a Howard Hughes Medical Institute investigator, used mice lacking the Clock gene to examine the possible involvement of the biological clock system in the rewarding properties of cocaine. (In 1997, Takahashi led the team that cloned Clock, the first mammalian circadian gene to be cloned.)
In the study, mice that lacked the Clock gene were injected with cocaine. Not only did the mice experience problems with their circadian cycles -- not sleeping as much and becoming more hyperactive -- they also found cocaine more rewarding than control mice, demonstrated by their strong preference for the location where the drug was administered.
In addition, Clock-deficient mice produced more dopamine than control mice did, suggesting that the gene controlling circadian rhythms is a key regulator of the brain's reward system and may influence the addictive properties of drugs such as cocaine. (Dopamine is a neurotransmitter associated with the "pleasure system" of the brain, providing feelings of enjoyment from certain activities.)
In addition to Takahashi, other authors on the PNAS paper are lead author Colleen A. McClung, M.D., senior author Eric J. Nestler, M.D., and Donald Cooper, M.D., of UT Southwestern; Martha Vitaterna of Northwestern University; Kyriaki Sidiropoulou of the University of Crete in Heraklion; and Francis J. White of the Rosalind Franklin University of Medicine and Science.
The study was supported by grants from the National Institute on Drug Abuse, the National Institute of Mental Health and the Onassis Public Benefit Foundation

:o

Title: Re: Circadian Rhythms Drug Addiction
Post by ben_uk on Nov 7^th, 2005, 6:52pm

Gene Controlling Circadian Rhythms Linked To Drug Addiction, UT Southwestern Researchers Find
http://www.sciencedaily.com/releases/2005/06/050614001947.htm
http://tinyurl.com/csr9t

DALLAS (June 13, 2005) -- The gene that regulates the body's main biological clocks also may play a pivotal role in drug addiction, researchers at UT Southwestern Medical Center have found.

The Clock gene not only controls the body's circadian rhythms, including sleep and wakefulness, body temperature, hormone levels, blood pressure and heart activity, it may also be a key regulator of the brain's reward system.
UT Southwestern researchers showed that, in mice, the Clock gene regulates the reward response to cocaine, suggesting that similar actions take place in humans. Findings from the multi-center study are available online in the Proceedings of the National Academy of Sciences. "We found that the Clock gene is not only involved in regulating sleep/wake cycles, but is also very involved in regulating the rewarding responses to drugs of abuse," said Dr. Colleen A. McClung, assistant instructor of psychiatry at UT Southwestern and the study's lead author. "It does so through its actions on dopamine pathways."
Dopamine is a neurotransmitter associated with the "pleasure system" of the brain, providing feelings of enjoyment from certain activities. Dopamine is released by naturally rewarding experiences such as food, sex and the use of certain drugs.
In the study, mice that lacked the Clock gene were injected with cocaine. Not only did the mice experience problems with their circadian cycles (not sleeping as much and becoming more hyperactive) they also found cocaine more rewarding than control mice, demonstrated by their strong preference for the location where the drug was administered.
In addition, Clock-deficient mice produced more dopamine than control mice did, suggesting that the gene controlling circadian rhythms is a key regulator of the brain's reward system and may influence the addictive properties of drugs such as cocaine.
"We tracked dopamine cells in the mice brains and found that these cells fired more rapidly and showed a pattern called bursting, which leads to an usually large dopamine release," Dr. McClung said. "We also found that more dopamine is produced and released in these mice under normal conditions and particularly after exposure to cocaine."
Dr. Eric Nestler, chairman of psychiatry at UT Southwestern and the study's senior author, said the results suggest there may be a link in disruption of circadian rhythms and the tendency to abuse drugs.
"Most work on Clock has focused on the brain's master pacemaker, located in a brain area called the suprachiasmatic nucleus," said Dr. Nestler. "The novelty of Dr. McClung's findings is the role Clock plays in brain reward pathways. The next step is to examine Clock and related genes in human addicts."
###
Dr. Donald Cooper, assistant professor of psychiatry at UT Southwestern, also contributed to the study, as did researchers from the University of Crete in Heraklion; the Rosalind Franklin University of Medicine and Science in North Chicago; and the Howard Hughes Medical Institute at Northwestern University.
The study was supported by grants from the National Institute on Drug Abuse, the National Institute of Mental Health and the Onassis Public Benefit Foundation.

Title: Re: Circadian Rhythms Drug Addiction
Post by ben_uk on Nov 7^th, 2005, 7:34pm

Faulty body clock can drive people to drink
By Andy Coghlan
From issue 2479 of New Scientist magazine, 25 December 2004, page 9

http://www.newscientist.com/channel/health/mg18424794.700.html

http://tinyurl.com/9mkpt

SOME people may drink too much in an attempt to compensate for a faulty body-clock gene that locks them into a state of perpetual jet lag. The discovery could explain why an existing drug helps a few alcoholics stay dry.

Urs Albrecht and his team at the University of Fribourg in Switzerland studied mice with a defect in Per2, a key clock gene that helps set and maintain our 24-hour body cycle. Given the chance, the mutant mice drank three times as much alcohol as non-mutant mice. The team found that the hypothalamus, the brain area housing the body's master clock, was flooded with the neurotransmitter glutamate in the defective mice.

Albrecht wondered if the glutamate build-up was somehow stimulating the craving for alcohol. If so, a drug called acamprosate, given to recovering alcoholics to help prevent relapse and known to drive down glutamate levels, might have some effect. Sure enough, when mice with the Per2 mutation were given acamprosate they drank even less than non-mutant mice (Nature Medicine, DOI: 10.1038/nm1163).

Next, team member Michael Soyka of the University of Munich in Germany looked for Per2 mutations in human DNA samples. In a study of 215 individuals, he found that one particular Per2 variation does indeed appear to be linked with heavy drinking.

This raises another intriguing possibility: could this gene variation explain why acamprosate prevents relapse in only 10 to 20 per cent of those prescribed it? Next year, Soyka plans to see if drinkers with defective clock genes respond better to the drug than other drinkers. If they do, screening for carriers could be a good way of optimizing treatment with acamprosate, which is already available in Europe and was approved in the US last July.

The findings might also explain why airline staff and shift workers who experience constant jet lag often become habitual drinkers. "They have a normal but desynchronized clock, and drink to reset it," Albrecht says.

Title: Re: Circadian Rhythms Drug Addiction
Post by ben_uk on Nov 7^th, 2005, 7:36pm

Sorry to double post
Thought I’d bring these together.

Mess with the body clock at your peril

From issue 2496 of New Scientist magazine, 23 April 2005, page 16

By Helen Phillips

http://www.newscientist.com/channel/being-human/mg18624964.900.html

http://tinyurl.com/adzlb

THE way patterns of shift work are organized could be causing major health problems, according to a pair of reports commissioned by the UK government body that regulates workplace safety.

The reports, prepared for the Health and Safety Executive (HSE), show that offshore oil workers adopting the most popular shift pattern have a higher risk of heart disease and diabetes. This pattern also makes workers more tired and inattentive, increasing the chance of accidents and mistakes.

Chronobiologist Josephine Arendt and her team at the University of Surrey in Guildford and psychologist Andrew Smith and colleagues at Cardiff University in Wales separately studied the physiological and psychological health of a group of 45 men working on offshore oil rigs. Both teams compared the two main shift schedules operated on a two-week tour of duty. One was a simple 12-hour shift, with workers staying on night shifts or day shifts for the full two weeks. The other was a split rota of seven night shifts followed by seven day shifts. This was more popular with the workers because they were already adapted to night sleeping when they returned home. But it proved worst for their health.

Urine tests from workers on the split shift revealed that levels of melatonin, the sleep-regulating hormone normally secreted at night, did not become synchronized to the new sleep times after shift changes. As well as being more tired and less attentive on the job, these unadapted workers showed signs of being at risk of long-term health effects. The men had abnormally high levels of fatty acids circulating in their blood after meals, compared with the day shift or adapted workers. This increases the risk of heart disease, diabetes and other metabolic disorders. "The swing shift is the killer," says Arendt.

“Workers adopting the most popular shift pattern were at increased risk of heart disease and diabetes” The obvious conclusion is that workers should try to avoid split shifts and other schedule changes that put their body clocks out of kilter, but Smith points out that the there will be exceptions. "A one-size-fits-all approach is a mistake," he says.

The HSE plans to publicize the findings to employers, and to issue recommendations for minimizing the dangers, for example by avoiding fatty or sugary snacks at night. But legislation forcing companies to adopt particular shift schedules is unlikely. "It won't change overnight," says Smith. "But it would be rather foolish not to take this on board."
:o

Title: Re: Circadian Rhythms Drug Addiction
Post by ben_uk on Nov 7^th, 2005, 7:57pm

Found this - Red Bull

http://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind0107&L=kbs-list&T=0&F=&S=&P=3052

http://tinyurl.com/bjxvc

In response to Robin Room's query about linked effects of taurine and
alcohol, recent research (abstracted by Current Contents), almost entirely
on rats, suggests the following possibilities (allowing for my lack of
biological background):

Taurine levels increase (in the brain, at least) after alcohol intake as
part of the body's efforts to reduce toxic effects of alcohol. Taurine may
gentle the consequences of alcohol consumption in part by increasing the
activity/efficacy of aldehyde dehydrogenase (getting rid of bad
acetaldehyde faster) and by otherwise speeding the elimination of alcohol
from the body (RJ Ward et al., "Taurine modulates catalase, aldehyde
dehydrogenase, and ethanol elimination in rat brain," ALCOHOL AND ALCOHLISM
36:1 (Jan-Feb 2001), 39-43; H Harada et al., "Oral taurine supplementation
prevents the development of ethanol-induced hypertension in rats,"
HYPERTENSION RESEARCH 23:3 (May 2000), 277-284). Taurine doses may also
help to block release of glutamate during alcohol withdrawal, i.e. reducing
unpleasant excitability and DT's (Dahchour & De Witte, "Taurine block the
glutamate increase in the nucleus accumbens microdialysate of
ethanol-dependent rats," PHARMACOLOGY, BIOCHEMISTRY, AND BEHAVIOR 65:2
(February 2000), 345-350.) If taurine reduces acute adverse effects of
alcohol and adverse experiences of withdrawal, then increased levels of
taurine may make it easier for drinkers to consume larger amounts of
alcohol for longer amounts of time (speculative extension of findings,
e.g., from E Quertemont et al., "Taurine and ethanol preference: a
microdialysis using Sardinian alcohol-preferring and non-preferring rats,"
EUROPEAN NEUROPSYCHOPHARMACOLOGY 10:5 (September 2000), 377-383).

Also: Dosing with taurine might also reduce liver damage from chronic heavy
drinking (MDJ Kerai et al., "Reversal of ethanol-induced hepatic steatosis
and lipid peroxidation by taurine: A study in rats," ALCOHOL AND ALCOHOLISM
34:4 (July-August 1999), 529-541).

And: One of the reasons for the ability of acamprosate to reduce alcohol
craving and relapse risks in recovering alcoholics may be that it
prevents taurine from gentling the effects of alcohol (JY Wu et al.,
"Neurotoxic effects of acamprosate, N-acetyl homotaurine, in cultured
neurons," JOURNAL OF BIOMEDICAL SCIENCE 8:1 (January-February 2001), 96-103).

I could not find any recent research on the combined effects of alcohol and
taurine on either behavioral impairment (e.g. in animals) or on subjective
desirable feelings of intoxication (in humans). In fact, the most recent
research articles on taurine plus alcohol do not refer to human alcohol
consumers at all. It may be a while before the research catches up with
innovation in the arts of intoxication.

Richard W. Wilsnack
Department of Neuroscience
University of North Dakota School of Medicine & Health Sciences
Grand Forks, ND 58202-9037

Title: Re: Circadian Rhythms Drug Addiction
Post by ben_uk on Nov 7^th, 2005, 8:21pm

Pain – nicotine - trigeminal nerve

BITTER TASTE MECHANISMS: NICOTINIC AND MUSCARINIC RECEPTORS IN RAT TASTE RECEPTOR CELLS
S. A. Simon, GQ Chang, L. Liu, and YQ. Jiao.
Dept. of Neurobiology, Duke University Medical Center, Durham, NC 27710.
Alkaloids, such as nicotine and atropine, can evoke both a bitter sensation and burning sensation when placed on lingual epithelium. In rats, we found that lingual application of many alkaloids, including nicotine, activate neurons from trigeminal nerve (for the burning sensation) and neurons from the chorda tympani and glossopharnygeal nerve (for the bitter taste sensation). RT-PCR reveals that neurons from the trigeminal ganglion contain all the known neuronal nicotinic receptor subunits present in mammals. The gustatory recordings suggest that nicotine activates receptors on taste receptor cells (TRCs). Although there have been many studies regarding the cellular mechanisms involved in bitter taste, none have directly addressed the question of the presence of nicotinic acetylcholine receptors (nAChR) and muscarinic acetylcholine receptors (mAChRs) in TRCs. Using immunocytochemical methods we found that TRCs in both fungiform and circumvallate papillae have both nicotinic (nAChR) and muscarinic (mAChR) receptors. Specifically, nAChRs in TRCs in both types of papillae have alpha 7, alpha 4 and ß 2 subunits. These are found in a large percentage of TRCs and are intracellular and on both the apical and basolateral surfaces. Muscarinic receptors are also found in most TRCs, although we have not classified the various subtypes present. These data reveal potentially new transduction mechanisms for bitter tastants involving nAChRs and mAChRs.

“the trigeminal ganglion contain all the known neuronal nicotinic receptor subunits present in mammals”
:o

Title: Re: Circadian Rhythms Drug Addiction
Post by ben_uk on Nov 10^th, 2005, 8:18am

Interesting “thingy” on Glutamate -

http://www.newscientist.com/article.ns?id=mg18124375.400
http://tinyurl.com/brmhs
From issue 2437 of New Scientist magazine, 06 March 2004, page 34

The master switch

LATE last year, researchers at pharmaceutical giant Eli Lilly's labs in Indianapolis, Indiana, suffered a rude shock. Mice involved in tests of one of the company's most promising drugs - a new treatment for anxiety - were having seizures. Lilly put the drug on hold and suspended a clinical trial involving 1900 people. It is still trying to work out what went wrong, and whether trials of the drug can be revived.
Talk to Lilly and you could be forgiven for thinking that the drug's woes came as a huge surprise. But perhaps the real surprise is that the drug ever got so far. The compound Lilly was testing was designed to plug into a brain circuit that pharmacologists have long considered a no-go area. Fiddle with it, the orthodoxy goes, and all you get for your troubles is hallucinations, psychosis and seizures.
Yet Lilly, and most of its competitors, now believe that this circuit is the key to a new class of molecule that will revolutionise the treatment of mental illness - including many currently intractable or poorly treated diseases such as addiction, anxiety, schizophrenia, epilepsy and chronic pain. Almost every major pharmaceutical company is developing similar molecules. And while none is yet close to the market, some neuroscientists believe they will be the biggest shake-up in central nervous system medicine for decades.
The compounds that are getting neuroscientists excited are based on glutamate, the brain's primary neurotransmitter, or communication molecule. Just about every circuit in the central nervous system uses glutamate, so in theory, drugs that target glutamate signalling have the potential to treat almost any brain disorder.
But there is a catch. Glutamate signalling is so pervasive in the brain that interfering with it usually leads to horrendous side effects. And so neuroscientists working in the pharmaceutical industry have generally steered clear of it. But not any more. As researchers discover more about the glutamate system, they have found a promising way to get a handle on it without causing side effects. For the first time, there is the real prospect of taking control of the brain's master switch.
"It's a huge conceptual leap," says Bita Moghaddam, a neuroscientist at the University of Pittsburgh in Pennsylvania. "For the past few decades, the concepts behind treatment haven't changed. We are stuck on serotonin for depression, dopamine for schizophrenia and GABA for anxiety. This is the first time we're going beyond these old ideas."
That is not to deny the importance of serotonin, dopamine and GABA (gamma aminobutyric acid). GABA is the brain's main inhibitory molecule - the "off" signal for neurons - while serotonin and dopamine help fine-tune communication between brain cells. But none is as important as glutamate. Whenever you have a thought or take an action, glutamate is right at the heart of it, transmitting "on" signals from neuron to neuron. The sender releases a puff of glutamate which diffuses across the synapse, binding to receptors on the other side.

Title: Re: Circadian Rhythms Drug Addiction
Post by ben_uk on Nov 10^th, 2005, 8:19am

Cont;
Until recently, neuroscientists thought that there was only one type of glutamate receptor. Known as ionotropic receptors, they function like the lock on a gate. Binding of glutamate molecules opens the gate, allowing charged particles to rush into the neuron and trigger the electrical current or nerve impulse.
It was investigations of these receptors that earned glutamate a reputation as a no-go area. Glutamate blockers were tested as a treatment for stroke, but were scrapped because they induced psychosis. Similarly, the illicit drug PCP (also known as angel dust) was found to induce its hallucinogenic and psychotic effects by blocking ionotropic glutamate receptors. "Glutamate is too broad a hammer on too many circuits," says Jeffrey Conn, a neuroscientist at Vanderbilt University in Nashville, Tennessee, who has been studying glutamate receptors for 20 years.
But in the mid-1980s, neuroscientists began to suspect that there was a different class of glutamate receptor in the brain - the so-called metabotropic receptor. This class of receptor was already well known to neuroscientists, though it was always associated with neurotransmitters other than glutamate. Serotonin and dopamine, for example, work largely by acting on metabotropic receptors. In 1991 the hunch was confirmed when groups in the US and Japan cloned the first metabotropic glutamate receptor (mGluR).
Metabotropic receptors have a slower, more subtle effect than ionotropic receptors. If these are an on-off switch, then metabotropic receptors are a dimmer, turning the strength of the signals up or down. They do this by triggering a cascade of metabolic reactions inside the neuron that either increases or decreases its excitability. For example, they may alter the ion channels that have an impact on the electrical properties of the cell, or affect enzymes that make neurotransmitters.
This action to modulate signal strength makes metabotropic receptors particularly good as drug targets. "They are having a more subtle effect than drugs that directly target glutamate," says Conn. "You're not hitting [the brain] with a sledgehammer and causing the toxicity you would get when you go after the main circuits." Hence the pharmaceutical industry's focus on serotonin and dopamine.
But going after serotonin and dopamine is inherently limited because both are just bit-part players in the brain. Only about 10,000 of the brain's 100 billion neurons produce dopamine, and serotonin circuits are confined mainly to the midbrain. That's why the discovery of metabotropic glutamate receptors holds such promise. Like serotonin and dopamine receptors, they act as a dimmer switch on glutamate signalling. But they are much more widespread than the serotonin and dopamine receptors. Wherever you have glutamate circuits, there are metabotropic glutamate receptors modulating them: "mGluRs give the opportunity of direct but subtle manipulation of brain circuits," says Conn.
The receptors have another important advantage: they come in several different flavours. Eight types have been identified so far and, crucially, these are not uniformly distributed throughout the brain. Some are found only in certain parts. The receptor known as mGluR4, for example, is confined largely to the basal ganglia, an area that is damaged in Parkinson's disease. And mGluR5 is linked to an ionotropic glutamate receptor, the malfunction of which is strongly linked to schizophrenia. So by designing drugs that target the different mGluR receptors, pharmacologists believe they will be able to modulate glutamate signalling in highly selective and valuable ways.

Title: Re: Circadian Rhythms Drug Addiction
Post by ben_uk on Nov 10^th, 2005, 8:19am

Cont;
According to Conn, the pharmaceutical potential of mGluRs was obvious 20 years ago. Only now, though, is the research approaching fruition, with pharmaceutical companies racing to develop compounds that target them. The field is secretive but a number of big players have declared their hands. For example, Merck recently published research on mGluR4 and Parkinson's disease. Novartis is developing a mGluR5 antagonist for pain and anxiety, and Lilly is working with compounds that act on mGluR2, which have potential to treat anxiety, addiction and possibly pain. These trial drugs include the one that caused seizures in mice last year.
Such is the secrecy in the field that Lilly will not specify how far the compound, called LY544344, had progressed before being put on hold, other than saying it was in "late-stage development". Lilly began testing the drug in humans in the mid-90s and says the clinical results looked promising. The compound is the only mGluR-targeting drug that has been tested in humans to date. Lilly says the significance of the mouse seizures for humans remains unknown.
The drug represents a wholly new approach to treating anxiety. Existing medications, such as diazepam (Valium) and the other benzodiazepines, quiet the brain by ramping up the inhibitory GABA system. But they also cause grogginess and can be addictive. LY544344 decreases glutamate's excitatory action by binding to pre-synaptic mGluR2 receptors and inhibiting glutamate release.
The seizures occurred in mice given chronic high doses, a routine part of testing for drugs intended to treat lifelong conditions such as anxiety. It is no real surprise that the molecule induces seizures: LY544344 has a degree of selectivity for mGluR2 receptors, but it also binds to other glutamate receptors so it lacks the specificity drug makers search for. Lilly says it has not given up on the drug and is making new derivatives to test. It is also working with the FDA to design new clinical trials.
But even failure will not mean the end of the mGluR story. Other researchers are taking a different tack that promises to make the problems encountered by LY544344 look like a hiccup rather than a terminal blow. "The molecule is a breakthrough, but it's not exactly the type of molecule we want to develop," says Vincent Mutel, president of Addex Pharmaceuticals, a drug development company in Geneva, Switzerland, which focuses on addiction and is developing mGluR drugs. He says the way forward is not to go straight for the glutamate binding sites, but to tinker with them indirectly. "We are more interested in modulators," he says. "They are a safer and softer way."
Imagine the receptor as a lock and glutamate as the key. LY544344 and glutamate act directly on the lock. But other compounds bind at sites on the receptor molecule close to the lock, changing how easily it is opened or how long it stays open. These spots, known as allosteric binding sites, vary from receptor to receptor, and each has its own key.
According to Conn, allosteric binding sites have previously been found on ionotropic receptors, but their discovery on metabotropic receptors is very recent. No one knows what, if anything, binds to the sites naturally. It's possible that they have no normal function, but just happen to bind drug molecules.

Title: Re: Circadian Rhythms Drug Addiction
Post by ben_uk on Nov 10^th, 2005, 8:20am

Cont;

ADDICTION
Drugs that bind to mGluRs also show potential to prevent addiction. Most addiction treatments focus on dopamine, which helps mediate the pleasurable effects of addictive drugs. But new research shows that glutamate also plays a role.
For reasons that are not understood, mice lacking the mGluR5 receptor are immune to cocaine addiction, says Mark Epping-Jordan, a pharmacologist with Addex Pharmaceuticals in Geneva, Switzerland. Normal mice will self-administer cocaine. But mice lacking the mGluR5 receptor, or mice that have had it blocked with drugs, are not interested in cocaine. The same holds true of alcohol and nicotine. Could compounds that target the mGluR5 receptor prevent people from developing addictions?
There is another link between mGluRs and addiction. "Cocaine cause long-term changes to mGluR2 receptors in areas known to be important in addiction - the prefrontal cortex and nucleus accumbens" says Peter Kalivas, an addiction researcher at the Medical University of South Carolina. Researchers predict that activating mGluR2 will compensate for these changes and lessen some symptoms of addiction, though it is unclear if this will cure it.

SCHIZOPHRENIA
"All drug treatments for schizophrenia target dopamine," says Bita Moghaddam of the University of Pittsburgh in Pennsylvania. But there is a lot of evidence to show that an underactive glutamate system plays a big role in the disease. For example, if you give healthy people drugs that block glutamate receptors, they become psychotic.
According to Moghaddam and her colleague John Krystal of Yale University in Connecticut, drugs that stimulate mGluR5 might help people with schizophrenia by turning up the volume on their glutamate signalling. Drugs that target this receptor are in development, she says, and have shown promise in animal models.
Krystal also thinks that Lilly's mGluR2 agonist might help. In new work being reviewed for publication, he gave the compound to healthy people along with another drug, ketamine, which causes psychosis and loss of working memory - symptoms associated with schizophrenia. The mGluR2 agonist helped preserve working memory, Krystal says.

ANXIETY
According to Darryle Schoepp of Lilly Research Labs in Indianapolis, Indiana, all mGluRs are potential targets for anxiety treatment. LY544344, the company's experimental drug for generalised anxiety disorder, targets mGluR2, though trials of it are currently on hold. But there is evidence that other receptors are involved. "In lab animals, knocking out different receptors has different effects: mGluR7 knockouts respond differently to fear, while mGluR8 knockouts are more susceptible to stress," he says.

Title: Re: Circadian Rhythms Drug Addiction
Post by ben_uk on Nov 10^th, 2005, 8:21am

Cont;
CHRONIC PAIN
Glutamate is an important mediator of inflammation. This is usually a useful response to injury - a painful, swollen ankle reminds us to stay off our feet. However, sometimes the process goes awry. In rheumatoid arthritis, cancer or backache, for example, pain is no longer serving a useful purpose.
Rob Gereau of Washington University School of Medicine in St Louis, Missouri, believes that targeting mGluRs will tame the pain. According to his research, activating mGluR1 and mGluR5 prolongs the time an injured mouse is hypersensitive to heat. But activating mGluR2 receptors, which decrease the release of glutamate, has the opposite effect. So drugs that activate mGluR2 or inhibit mGluR1 or mGluR5 may help relieve chronic pain.
Emily Singer is a science writer based in Boston
:o

Title: Re: Circadian Rhythms Drug Addiction
Post by Karla on Nov 10^th, 2005, 7:13pm

I just read an article a couple of days ago that was talking about dopamine levels, the clock, and thaumus being the cause of schizaphrenia. I've got sz, ch, and am a recovering drug addict. Maybe there is something going on here.? ::) I am skrewed!

Title: Re: Circadian Rhythms Drug Addiction
Post by Jonny on Nov 10^th, 2005, 7:25pm

Damn Ben...a couple of links would have worked.....LOL ;;D ;)

Title: Re: Circadian Rhythms Drug Addiction
Post by Jasmyn on Nov 11^th, 2005, 2:45am

on 11/10/05 at 19:25:41, Jonny wrote:

Damn Ben...a couple of links would have worked.....LOL ;;D ;)

But thanks Ben for considering those people with slow dial-ups. ;)

Very good and important info to note.

Title: Re: Circadian Rhythms Drug Addiction
Post by Beastfodder on Nov 11^th, 2005, 6:34am

Fascinating reading - lots to take in.

Came across a CH sufferers website - http://www.miqel.com/clusterheadaches/clusterheadaches.html

which covers some of this ground about the hypothalamus and circadian rythymns it's well done. Following extract gives food for thought:-

"The drugs effective in the treatment of the cluster headache syndrome are those that ENHANCE serotonergic neurotransmission".
(Mushrooms ARE a serotonergic neurotransmission hyper-super-booster which works for about 5 hours, and apparently when the hypothalamus settles back down from the mushroom-trip serotonin flood ...
it 'Reboots' or resets itself to it's NORMAL, non-Cluster-headache cycle routine)