2/17/1997 • Correlated reductions in cerebrospinal fluid 5-HIAA and MHPG concentrations after treatment with selective serotonin reuptake inhibitors.

2/17/1997 • Correlated reductions in cerebrospinal fluid 5-HIAA and MHPG concentrations after treatment with selective serotonin reuptake inhibitors.

Sheline Y, Bardgett ME, Csernansky JG
Department of Psychiatry, Washington University School of Medicine, St.
Louis, Missouri 63110, USA.

J Clin Psychopharmacol 1997 Feb 17 1 11-4

Drug treatment, overall, was associated with significant decreases in 5-HIAA and MHPG and a trend toward a reduction in HVA levels. Levels of 5-HIAA, MHPG, and HVA were reduced by 57%, 48%, and 17%, respectively.

Correlated reductions in cerebrospinal fluid 5-HIAA and MHPG concentrations after treatment with selective serotonin reuptake inhibitors.

http://www.ncbi.nlm.nih.gov/htbinpost/Entrez/query?uid=9004051&form=6&db=m&Dopt=b

Sheline Y, Bardgett ME, Csernansky JG
Department of Psychiatry, Washington University School of Medicine, St.
Louis, Missouri 63110, USA.

J Clin Psychopharmacol 1997 Feb 17 1 11-4

Drug treatment, overall, was associated with significant decreases in 5-HIAA and MHPG and a trend toward a reduction in HVA levels. Levels of 5-HIAA, MHPG, and HVA were reduced by 57%, 48%, and 17%, respectively.

We sought to determine whether fluvoxamine and fluoxetine, two different antidepressants with in vitro selectivity for the serotonin uptake transporter also demonstrated similar selectivity in vivo. To accomplish this, we measured cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and homovanillic acid (HVA) before and after 6 weeks of treatment with these two drugs. Twenty-four subjects who had major depression according to DSM-III-R criteria gave written, informed consent for the collection of CSF during a double-blind comparative treatment trial of fluvoxamine (50-150 mg/day) and fluoxetine (20-80 mg/day). The symptoms of subjects were assessed clinically on a weekly basis throughout the treatment trial. CSF samples were obtained after a 7- to 14-day washout period before treatment and again at the end of treatment. CSF samples were analyzed for 5-HIAA, HVA, and MHPG using high-pressure liquid chromatography coupled to electrochemical detection. Fluvoxamine- and fluoxetine-treated patients did not differ in clinical outcome or in the CSF concentrations of monoamine metabolite levels before or after treatment. Therefore, the CSF data were pooled. Drug treatment, overall, was associated with significant decreases in 5-HIAA and MHPG and a trend toward a reduction in HVA levels. Levels of 5-HIAA, MHPG, and HVA were reduced by 57%, 48%, and 17%, respectively. In addition, the magnitude of the decreases in 5-HIAA and MHPG appeared to be correlated (r = 0.83) across the subjects, although a Spearman rank correlation indicated that outlying values had an undue effect on this relationship. These results suggest that treatment with selective serotonin reuptake inhibitors, which are selective for serotonin uptake in vitro, does not show a similarly selective effect on serotonin in vivo during treatment of patients.
Publication Types:
Clinical trial PMID: 9004051, UI: 97157772

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1996 – Mutant Mice May Hold Key To Human Violence – An Excess Of Serotonin.

http://articles.latimes.com/1996-06-06/local/me-12113_1_male-mice

SCIENCE FILE
Of Mice and Mayhem

The Fierce Tempers of Mutant Rodents Born With Their Brains Awash in the Chemical Serotonin May Provide a Clue to Violent Behavior Among Humans

June 06, 1996|TERENCE MONMANEY | TIMES MEDICAL WRITER

The scientist grabs Mutant #9 by the tail, lifts the mouse out of its shoebox-size cage, and lowers it gently into another, identical container, the reeking, sawdust-floored home of Mutant #4.
Blind and jittery, the mice are freaks of nature, products of a genetic engineering experiment that did not go exactly as planned. But, oddly, their encounter in this fifth-floor laboratory at the USC School of Pharmacy may reveal something vital about human nature.

They square off, sniffing furiously, then inch closer. Within seconds, #9 corners #4. And then they dive at each another–a rolling, squeaking, clawing gray blur. Sawdust and fur fly.

Jean Chen Shih, a USC biochemist and promoter of this unlikely murine bout, jumps back, startled by the attack even though she was expecting it. “Normal mice fight also, but not so rapidly as these,” Shih says.

By any measure, the mice, called Tg8, are among the most aggressive in captivity.

This odd little spectacle is part of the quest for answers to the violence clawing at American’s soul. A Tg8 is born with its brain awash in an excess of serotonin, a neurotransmitter chemical that helps regulate mood and mental health, and Shih and her co-workers believe that that excess greatly contributes to the mouse’s fierce temper.

To be sure, a brawl between blind mice in an ivory tower is a far cry from the mayhem and brutality perfected by such brainy animals as ourselves. But the work does appear to touch on human experience: The Tg8’s cardinal biochemical defect was originally discovered in numerous related Dutchmen who committed arson, attempted rape and assault.

The Tg8 mice are the first laboratory animals to share both the biochemical defect and the behavior observed in a pedigree of violent criminals. In that sense, the mice are an important new tool for probing the physiology of running amok. By studying the mice’s trigger-happy biology, researchers hope to understand aggression better and perhaps develop new drugs that control it.

But for every potential new use of such information, critics envision a new abuse. Steven Rose, a biologist at the Open University in England, is an outspoken critic of the idea that one’s genetic makeup determines behavior–a scientific premise he calls “neurogenetic determinism.”

Sociologist Dorothy Nelkin of New York University says that conservatives might seize on biological explanations of violence to “dismantle the welfare state,” because controlling aggression with drugs could well be much cheaper than rehabilitation programs.

She also fears that if certain biochemical signatures became associated with violence or criminal behavior, people with such a makeup could be wrongly implicated and stigmatized as potential threats to society–the physiological equivalent of a bad credit rating. The Tg8 research and similar studies, she says, “open up a whole set of problems that are worthy of careful consideration.”

No such heady dilemmas weighed upon scientists at the Pasteur Institute near Paris when they accidentally created the Tg8 mouse strain two years ago. Olivier Cases and colleagues were trying to develop a novel gene therapy by injecting a one-celled embryo of a special lab strain of blind mice with a shred of foreign DNA. But instead of resulting in a “new” mouse pup with a bolstered immune system, the experiment led to a strain of male mice with a really bad temper.

The first indicator of that ill nature was painfully obvious: The mice nipped the researchers’ fingers. When caged together, male Tg8s–the Tg is for “transgenic”–tore each other apart. And the researchers also found that when male and female mice mated, the males were especially quick, grabby and forceful, eliciting more female squeaks, on average, than other males did.

Those traits may be reminiscent of any number of men, but the French researchers were put in mind of certain Dutch males in one extended family described in the medical literature. Over four generations, a remarkable number of those males were accused or convicted of rape, assault and arson, leading local psychologists as well as law enforcement authorities to watch them very closely.

After much study, Dutch scientists reported a finding in 1993 that, they believed, helped explain the aggressive males’ behavior: They were missing an enzyme called monoamine oxidase A, or MAO-A, which breaks down a variety of neurotransmitters, including serotonin. Lacking the MAO-A enzyme, the affected males, who also had borderline mental retardation, had extra-high levels of several neurotransmitters, including serotonin.

The genetic defect found in the violent Dutchmen is probably very rare, researchers say, and certainly doesn’t account for what makes most aggressive people act that way. Still, the finding offers a unique window into how disruptions in brain chemistry can be correlated with a pattern of antisocial behavior.

Given the Dutch findings, then, it was logical for the sore-fingered French researchers to want to know if their mutant mice also lacked the MAO enzyme. That’s where Shih, a world expert on that family of enzymes, came in. Not long after she agreed to test the Tg8 mice for the enzyme, a shipment of the creatures arrived from France (having spent weeks in quarantine at Los Angeles International Airport).

It took Shih and her co-workers several months of painstaking lab work to establish that the male mice were indeed lacking the gene for the MAO-A enzyme–just like the affected Dutchmen. “When this gene is missing, the animals are very aggressive and hyperactive,” Shih says.

Her Tg8 study, says Randy Nelson, a behavioral psychologist at Johns Hopkins University, was “one of the first to show a biological mechanism for aggressive behavior in an animal.” Follow-up studies published this spring in the journal Neuron suggest that the neurotransmitter defect actually affects the structure of the Tg8’s brain, most likely by skewing growth and development in fetal and newborn mice.

Nelson says it’s no surprise that genes affect temperament. “Anybody who knows the difference between a pit bull and a Labrador retriever knows that aggressive behavior has a genetic basis,” he says.

Some researchers expect that the biochemical analysis of behavior will pay off. Dr. Frederick Moeller, a psychiatrist at the University of Texas in Houston, hopes that the missing-enzyme research leads to new drugs for treating criminals and other violent people who simply can’t control their aggression. “I treat individuals who . . . can’t keep from assaulting hospital staff even long enough to get out of the hospital,” he says.

“The goal isn’t to control everybody and make them less aggressive,” he says. “The goal is to work with real people who have a real problem with aggression.”

For her part, Shih is a little dismayed to find herself in the middle of such a hot controversy. “I like to avoid the political issues,” the biochemist says.

Even though she is no sociologist, Shih believes that she can make a contribution to understanding human behavior by studying the Tg8’s biology.

That possibility is apparent to her whenever she returns the mice to their cages in the locked, windowless animal room across the hall from her office. Normal mice fare perfectly well living four to a cage. But the Tg8 males are held in solitary confinement, too hostile for mouse society.

______________________________________

08/11/1996 • Mutant Mice May Hold Key To Human Violence–An Excess Of Serotonin, A Chemical That Helps Regulate Mood And Mental Health, Causes Mayhem

Jean Chen Shih

Portland Press Herald

A Tg8 is born with its brain awash in an excess of serotonin, a neurotransmitter chemical that helps regulate mood and mental health, and [Jean Chen] Shih and her co-workers believe that that excess greatly contributes to the mouse’s fierce temper.

Mutant Mice May Hold Key To Human Violence–An Excess Of Serotonin, A Chemical That Helps Regulate Mood And Mental Health, Causes Mayhem

http://library.northernlight.com/PN20000204060229119.html?inid=fSkmPX9kaDkMdwNrex8GWAFSUEADERBDewp1EQFmBQ%3D%3D&cbx=0#doc

Jean Chen Shih

Portland Press Herald

A Tg8 is born with its brain awash in an excess of serotonin, a neurotransmitter chemical that helps regulate mood and mental health, and [Jean Chen] Shih and her co-workers believe that that excess greatly contributes to the mouse’s fierce temper.

The scientist grabs Mutant 9 by the tail, lifts the mouse out of its cage, and lowers it into another, identical container, the reeking, sawdust-floored home of Mutant 4. Blind and jittery, the mice are freaks of nature, products of a genetic engineering experiment that did not go exactly as planned. But, oddly, their encounter in this fifth-floor laboratory at the University of Southern California School of Pharmacy may reveal something vital about human nature. This odd little spectacle is part of the quest for answers to the violence clawing at America’s soul. A Tg8 is born with its brain awash in an excess of serotonin, a neurotransmitter chemical that helps regulate mood and mental health, and [Jean Chen] Shih and her co-workers believe that that excess greatly contributes to the mouse’s fierce temper.

5,725 total views, 4 views today

7/23/1996 • Effect of acute and chronic fluoxetine on extracellular dopamine levels in the caudate-putamen and nucleus accumbens of rat.

7/23/1996 • Effect of acute and chronic fluoxetine on extracellular dopamine levels in the caudate-putamen and nucleus accumbens of rat.

Clark RN, Ashby CR Jr, Dewey SL, Ramachandran PV, Strecker RE
Department of Psychiatry and Behavioral Sciences, State University of New York at Stony Brook 11794, USA.

Synapse 1996; Jul; 23 (3); 125-31

Extracellular levels of the 5-HT metabolite 5HIAA were consistently decreased at all doses of fluoxetine in both structures.

Effect of acute and chronic fluoxetine on extracellular dopamine levels in the caudate-putamen and nucleus accumbens of rat.

http://www.ncbi.nlm.nih.gov/htbinpost/Entrez/query?uid=8807740&form=6&db=m&Dopt=b

Clark RN, Ashby CR Jr, Dewey SL, Ramachandran PV, Strecker RE
Department of Psychiatry and Behavioral Sciences, State University of New York at Stony Brook 11794, USA.

Synapse 1996; Jul; 23 (3); 125-31

Extracellular levels of the 5-HT metabolite 5HIAA were consistently decreased at all doses of fluoxetine in both structures.

Recent studies indicate that an increase in serotonergic (5-HT) activity in the nucleus accumbens (NAc) produces an increase in dopamine (DA) release, providing a possible mechanism for the involvement of DA in the therapeutic action of selective serotonin reuptake inhibitor (SSRI) antidepressants. However, acutely administered fluoxetine (2.5, 5.0, or 10.0 mg/kg, i.p.) failed to elevate extracellular levels of DA, or its metabolites in the NAc or caudate-putamen (CP). In fact, the highest dose produced a small (20%) decrease in DA levels in the NAc. Extracellular levels of the 5-HT metabolite 5HIAA were consistently decreased at all doses of fluoxetine in both structures. Since SSRIs generally require several weeks of treatment to be effective clinically, a second experiment examined the effect of chronic administration of fluoxetine. Chronic (21 day) daily treatment with 5 mg/kg had no effect on NAc basal levels of DA, DA metabolites, or 5HIAA, relative to a saline-treated control group. Finally, pretreatment with fluoxetine appeared to slightly enhance the elevation of NAc DA induced by an injection of cocaine (10 mg/kg, i.p.), an effect that was not quite significant (P < .06). In conclusion, the 5-HT-induced facilitation of NAc DA neurotransmission described in the literature may not be relevant to the therapeutic action of fluoxetine. PMID: 8807740, UI: 96401364

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NPR Shelly slender – Kathy Farmer

NPR Shelly slender – Kathy Farmer

      1. NPR Shelly slender - Kathy Farmer

1,358 total views, 1 views today

4/15/1993 • Cerebrospinal fluid monoamine metabolites in fluoxetine-treated patients with major depression and in healthy volunteers.

4/15/1993 • Cerebrospinal fluid monoamine metabolites in fluoxetine-treated patients with major depression and in healthy volunteers.

De Bellis MD, Geracioti TD Jr, Altemus M, Kling MA
Clinical Neuroendocrinology Branch, National Institute of Mental Health,National Institute of Health, Bethesda, Maryland.

Biol Psychiatry 1993 Apr 15-May 1; 33 (8-9); 636-41

CSF 5-HIAA and MHPG decreased significantly… following fluoxetine treatment.
Cerebrospinal fluid monoamine metabolites in fluoxetine-treated patients with major depression and in healthy volunteers.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7687151&dopt=Abstract

De Bellis MD, Geracioti TD Jr, Altemus M, Kling MA
Clinical Neuroendocrinology Branch, National Institute of Mental Health,National Institute of Health, Bethesda, Maryland.

Biol Psychiatry 1993 Apr 15-May 1; 33 (8-9); 636-41

CSF 5-HIAA and MHPG decreased significantly… following fluoxetine treatment.

Cerebrospinal fluid (CSF) levels of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and homovanillic acid (HVA) were measured in three groups: 46 healthy volunteers; 9 medication-free patients with DSM III-R major depressive disorder, recurrent; and these same 9 patients following at least 4 weeks of fluoxetine treatment at 20 mg/day. CSF monoamine metabolite levels in medication-free patients did not differ from healthy volunteers; however, CSF 5-HIAA and MHPG decreased significantly from 95.9 +/- 24.6 (all values +/- SD) to 64.2 +/- 26.1 pmol/ml and from 46.7 +/- 14.2 to 42.6 +/- 11.6 pmol/ml, respectively, following fluoxetine treatment. Fluoxetine also significantly decreased mean Hamilton Depression Rating Scale scores from 23.2 +/- 6.5 to 17.4 +/- 5.0 and significantly increased the CSF HVA/5-HIAA ratio.
PMID: 7687151, UI: 93320172

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5/17/1975 • Fenfluramine in man: hypophagia associated with diminished serotonin turnover.

5/17/1975 • Fenfluramine in man: hypophagia associated with diminished serotonin turnover.

Shoulson I, Chase TN

Clin Pharmacol Ther 1975 May 17(5) 616-21

The results support the contention that the effect of fenfluramine on human dietary intake may be mediated by alterations in serotonergic rather than dopaminergic mechanisms.
Fenfluramine in man: hypophagia associated with diminished serotonin turnover.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1092516&dopt=Abstract

Shoulson I, Chase TN

Clin Pharmacol Ther 1975 May 17(5) 616-21

The results support the contention that the effect of fenfluramine on human dietary intake may be mediated by alterations in serotonergic rather than dopaminergic mechanisms.

A double-blind trial of orally administered fenfluramine was conducted in 7 non-obese adults with various neurological disorders. Caloric intake and body weight fell significantly after 8 days of treatment although there was no definite change in appetite ratings. Average central turnover of serotonin, as estimated by the cerebrospinal fluid (CSF) accumulation of 5-hydroxyindoleacetic acid (5-HIAA) during probenecid loading, decreased by 66%. No significant change in homovanillic acid, the major dopamine product, was apparent.
Publication Types: Clinical trial Controlled clinical trial PMID: 1092516, UI: 75148833

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