This testimony should help strengthen our case for warnings for S...

If Singulair penetrates the blood brain barrier, then the progression would be:

cysLT1
cysLT2
Calcium channel (???)
Nitric Oxide (????)
glutamate
astrocyte activation
glycolysis
GABA

I just have the bare bones of this outline so far but I am working on it. Some days I forget which direction I went. It's like driving a car across a country with zillions of roads without a road map.

I don't know how we go from GABA to increased risk of suicide, depression, aggression but Dr. Trimble does.

In the brain, cysLT1 and cysLT2 are activated when the brain is under a stress, such as metabolic or oxidative deprivation. Glutamate is formed which activates the astrocytes which are capable of production of a very small amount "brain nutrition" to keep the brain cells from dying from deprivation. GABA is a chemical which is supposed to calm down the neurotranmissions caused by the "emergency."

If we could establish that Singulair penetrates the blood brain barrier and then causes the "emergency" in the brain, we could then use studies that have been done on GABA to find out why the result is depression, aggression, etc.
It is theorized that alcohol dependence is a substitute for GABA.

"The central amygdala, a part of the brain involved in emotions such as stress and fear, is important in regulating alcohol consumption. Most central amygdala neurons communicate via a chemical signal known as GABA, which is an inhibitory neurotransmitter. " We can connect GABA to the central amygdala and emotions such as stress and fear. The missing part is what happens to GABA as a result of the activation of cysLT2. I need to find studies on calcium signalling.

As a matter of policy, all drugs that act on receptors that are known to have genetic variations (especially G-protein coupled receptors) should carry a special warning.

New study reveals brain cell mechanism of alcohol dependence
Findings support new possible treatment for alcohol abuse

A study released today reveals a cellular mechanism involved in alcohol dependence. The study, in the May 28 issue of The Journal of Neuroscience, shows that gabapentin, a drug used to treat chronic pain and epilepsy, reduces alcohol intake in alcohol-dependent rats by normalizing chemical communication between neurons, which is altered by chronic alcohol abuse, according to Eurekalert, the news service of the American Association for the Advancement of Science.

The central amygdala, a part of the brain involved in emotions such as stress and fear, is important in regulating alcohol consumption. Most central amygdala neurons communicate via a chemical signal known as GABA, which is an inhibitory neurotransmitter. Alcohol dependence has been associated with the strengthening of inhibitory synapses in this brain region.

Gabapentin (known commercially as Neurontin) is structurally similar to GABA and increases GABA neurotransmission. In alcoholics, gabapentin has been shown to effectively treat alcohol withdrawal and reduce alcohol consumption and cravings following detoxification. However, how gabapentin acts in the brain to combat alcohol dependence has been unclear.

The study’s authors, led by Marisa Roberto, PhD, at the The Scripps Research Institute, made rats dependent on alcohol by chronically exposing them to ethanol in an aerosol or in their food. They then tested how much alcohol the rats voluntarily drank and examined neural signaling in the central amygdala.

The study authors found that gabapentin reduced alcohol intake in rats chronically exposed to alcohol, but not in rats that were chronically unexposed. Gabapentin reduced alcohol intake in alcohol-dependent rats whether it was given systemically or infused directly into the central amygdala, supporting the importance of the central amygdala in alcohol dependence.

“What I find to be important about this paper is that gabapentin’s effect on alcohol consumption is only seen in alcohol-dependent rats,” said Julie Blendy, PhD, at the University of Pennsylvania, an expert unaffiliated with the study. “For me, this speaks volumes to the addiction field, in that therapeutic targets for addiction—which have been few and far between—may be missed when examined in animal studies that use only minor exposures of alcohol,” said Blendy.

Gabapentin corrected the cellular effects of chronic alcohol exposure. Both gabapentin and alcohol increase GABA neurotransmission in the central amygdala of non-alcohol-dependent rats, but in alcohol-dependent rats, gabapentin reduced it, suggesting that altered GABA neurotransmission is key to alcohol dependence.

In the study, gabapentin and chronic alcohol exposure both affected GABA B (GABAB) receptors. The authors believe that alcohol abuse alters the function of these receptors, and gabapentin may be able to counteract alcohol dependence by regulating their function.

“This study provides important mechanistic insights,” said Robert Messing, MD, at the Ernest Gallo Clinic and Research Center at the University of California at San Francisco, an expert also uninvolved with the study. “Because gabapentin is well tolerated, this paper provides a strong rationale for large clinical trials testing whether gabapentin is an effective treatment for alcoholism in both detoxified and actively drinking alcoholics,” Messing said.

The Journal of Neuroscience, February 11, 2004, 24(6):1478-1485; doi:10.1523/JNEUROSCI.4734-03.2004
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Neurobiology of Disease
Dysregulation in the Suicide Brain: mRNA Expression of Corticotropin-Releasing Hormone Receptors and GABAA Receptor Subunits in Frontal Cortical Brain Region

Zul Merali,1,2 Lisheng Du,1 Pavel Hrdina,1 Miklos Palkovits,3 Gabor Faludi,4 Michael O. Poulter,5 and Hymie Anisman1,5

1University of Ottawa Institute of Mental Health Research, and 2Departments of Psychology, Psychiatry, and Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada, 3Laboratory for Neuromorphology, Hungarian Academy of Sciences and Semmelweis University, 1094 Budapest, Hungary, 4Semmelweis University Hospital, 1125 Budapest, Hungary, and 5Institute of Neuroscience, Carleton University, Ottawa, Ontario, K1S 5B6 Canada

Corticotropin-releasing hormone (CRH) and GABA have been implicated in depression, and there is reason to believe that GABA may influence CRH functioning. The levels of CRH, and mRNA for CRH-binding protein, CRH1, and CRH2 receptors, as well as various GABAA receptor subunits (1, 2, 3, 4, 5, , and 2), were determined in several frontal cortical brain regions of depressed suicide victims and nondepressed individuals who had not died by suicide. Relative to the comparison group, CRH levels were elevated in frontopolar and dorsomedial prefrontal cortex, but not in the ventrolateral prefrontal cortex of suicide victims. Conversely, using quantitative PCR analyses, it was observed that, in frontopolar cortex, mRNA for CRH1, but not CRH2, receptors were reduced in suicide brains, possibly secondary to the high levels of CRH activity. In addition, mRNA of the 1, 3, 4, and receptor subunits was reduced in the frontopolar region of suicide victims. Interestingly, a partial analysis of the GABAA receptor functional genome revealed high cross-correlations between subunit expression in cortical regions of nondepressed individuals, suggesting a high degree of coordinated gene regulation. However, in suicide brains, this regulation was perturbed, independent of overall subunit abundance. These findings raise the possibility that the CRH and GABAA receptor subunit changes, or the disturbed coordination between these GABAA receptor subunits, contribute to depression and/or suicidality or are secondary to the illness/distress associated with it.