Make your own free website on Tripod.com








bprayerbanner.jpg

Dopamine and Other Neurotransmitters














Home | .





This is general information mainly about dopamine. There is further research on another page having to do more specifically with the connection between dopamine, depression, and mania, and how different medications affect dopamine levels.

__________________________________________________________________________
















Our Favorite Neurotransmitters
from McMan's Bipolar Website

Let’s skip the introduction and cut straight to the chase:

The three neurotransmitters we are most familiar with - serotonin, norepinephrine, and dopamine - are classified as monoamines according to their chemical makeup. The monoamine hypothesis holds that mood disorders are caused by a depletion in one or more of these neurotransmitters, which makes sense in a flat earth sort of way, with no reference to recent advances in genomics, neuroscience, and brain imaging. Nevertheless, no one is dismissing any of the big three, not to mention the mighty two (glutamate and GABA), and the unsung one (substance P).

The following is culled from Stephen Stahl MD’s "Essential Pharmacology of Depression and Bipolar Disorder," "Essential Pharmacology of Antipsychotics and Mood Stabilizers," and other sources:

The Big Three

Norepinephrine (also referred to as noradrenaline) is manufactured in the neuron by enzymes acting on the amino acid tyrosine, which convert it into DOPA, then to dopamine (more on dopamine in a minute). Some of the dopamine is then converted to norepinephrine, where it is stored in packages called synaptic vesicles. Just as norepinephrine is created by enzymes, it can also be destroyed by enzymes, such as MAO (which also destroys serotonin and dopamine). Hence the MAO inhibitors that represent the first family of antidepressants.

When the neuron is working right, it releases norepinephrine through alpha 2 autoreceptors into the synapse - the gap between two neurons - which attaches to alpha 1, alpha 2, and beta 1receptors on the neuron on the other side of the synapse. From there, a signal is sent into the cell that cues certain genes to switch on proteins governing all manner of activity.

Most of the norepinephrine action takes place in an area of the brainstem known as the locus coeruleus, which monitors external stimuli and our responses (such as fight or flight) and pain. Norepinephrine and the locus coeruleus are also believed to play a role in cognition, mood, emotions, movement, and blood pressure. Difficulty concentrating, fatigue, apathy, and depression are some of the things that can result from norepinephrine going AWOL.

After norepinephrine is released into the synapse and attaches to receptors on the postsynaptic neuron, the presynaptic neuron vacuums some of the remaining neurotransmitters through a reuptake pump (transporter) for future use. The tricyclic class of antidepressants bind to the receptors that act as reuptake pumps, thus keeping norepinephrine in circulation (they also bind in a similar fashion to serotonin receptors). Several of the newer antidepressants also work in a similar fashion, including Effexor and Cymbalta (expected to be on the market in 2004).

Norepinephrine release can be turned on or off when the alpha 2 autoreceptor is stimulated by norepinephrine. It has a similar effect on serotonin through binding to the presynaptic serotonin heteroreceptors. The antidepressant Remeron works by "cutting the brake cable" (in Dr Stahl’s words) when it blocks the norepinephrine alpha 2 autoreceptors, flooding norepinephrine into the synapse, as well as attaching to the serotonin heteroreceptors, turning on serotonin flow.

Since norepinephrine does not cross the blood-brain barrier, those seeking natural treatment must opt for its building blocks. Tyrosine, a precursor of both norepinephrine and dopamine, can act as an energizer, according to natural treatment advocates, and is available over the counter. Phenylalanine, a precursor, to tyrosine, is also an option.

Serotonin (5HT) is synthesized in the neuron from the amino acid tryptophan, which is converted to 5HTP, then to serotonin. It is released into the synapse in a similar fashion to norepinephrine. Serotonin has some 17 different types and subtypes of receptors, which underscores its importance as a neurotransmitter. Two presynaptic receptors serve as both brakes and enhancers of serotonin release when blocked by serotonin or norepinephrine, while the postsynaptic receptors regulate the release of the serotonin signal into the neuron. Serotonin projects from the raphe nucleus in the brainstem to the basal ganglia, frontal cortex, hypothalamus and limbic system, and down the spinal cord. Serotonin is also found in the GI tract, thus implicating itself in a host of functions, from mood to anxiety to sleep (serotonin makes melatonin, which regulates sleep) to sexual response to food craving and (in)digestion.

As in the case of norepinephrine, a presynaptic transporter sucks up excess serotonin from the synapse in preparation for the next release of the neurotransmitter. Both the older tricyclic antidepressants and the newer SSRIs and dual action meds such as Effexor are believed to work by binding to this reuptake pump, thus keeping more serotonin in circulation. Were this completely true, however, antidepressants would have an immediate effect, instead of taking at least two weeks to start making an impression and another two to six weeks to achieve full clinical benefit.

One explanation is that blocking the transporters desensitizes the neuron in a way that dampens normal firing for four weeks. Another explanation is that antidepressants also work on intracellular processes downstream of the neurotransmitters (see article).

Because SSRIs attach themselves to all the postsynaptic receptors, a number of functions are disrupted, resulting in unwanted side effects such as sexual dysfunction and usually transitory anxiety and agitation (which can be less than transitory and highly pronounced for some people). The Holy Grail would be an SSRI that selectively left open some of these receptors. Paradoxically, one antidepressant, Serzone (now only available in generic form), works by blocking the 5HT2A receptor, which, when functioning normally, is thought to inhibit the 5HT1A receptor (ie Serzone indirectly switches the 5HT1A receptor on).

Since serotonin does not cross the blood-brain barrier, those seeking a natural serotonin solution must opt for its building blocks. Tryptophan, the precursor to serotonin, was removed from the US market in 1989 after a manufacturer produced a highly toxic contaminate. Note that tryptophan is not inherently toxic, and that the FDA’s ban may have had something to do with the entry of Prozac into the market around the same time. Tryptophan is still available by prescription. Less is more, with lower doses (one to three gm) more effective than higher doses. Taking the amino acid with carbohydrates helps in its absorption.

The intermediary between tryptophan and serotonin, 5HTP, is available without prescription. An Eli Lilly study found that combining 5HTP with Prozac significantly increased 5HTP in rats’ brains compared to Prozac alone.

Dopamine is manufactured by norepinephrine, which in turn is produced from tyrosine. There are several dopamine pathways in the brain, the one most relevant to our purposes being the mesolimbic dopamine pathway, which projects from the midbrain to the nucleus acubens, a part of the limbic system thought to be involved in pleasure as well as delusions, psychosis, and drug abuse. According to Julia Ross MA, author of The Mood Cure, caffeine is a pathetic attempt to make up for lack of dopamine.

Cocaine is notorious for enhancing dopamine production, while antipsychotics bind to dopamine D2 receptors and thus inhibit too much of a good thing. Unfortunately, antipsychotics don't just limit themselves to the D2 receptors in the mesolimbic dopamine pathway, leading to what Dr Stahl calls a "high cost of doing business," from dulled cognition to Parkinsonian tremors and tardive dyskinesia to hyperlactation. As well as preventing psychosis, antipsychotics are also first line treatment for mania.

The newer atypical antipsychotics such as Zyprexa are thought to have a better side effects profile thanks to their affinity for the serotonin 2A receptors, which set in motion a chain of events that results in looser binding of the dopamine receptors, allowing some dopamine to reach the neuron. This same blocking of the serotonin 2A receptors also produces an antidepressant effect. Eli Lilly has entered the market with a combination Zyprexa-Prozac med (Symbyax) that is thought to result in more dopamine and norepinephrine, and to a lesser extent serotonin, in the prefrontal cortex, which may turbocharge antidepressant performance.

The antidepressant Wellbutrin enhances both dopamine and norepinephrine in the synapse via that faithful old standby, reuptake blockade. A small study found the dopamine agonist (enhancer) Mirapex, an anti-Parkinson’s drug that works on the nigrostratial dopamine pathway (projecting from the substantia nigra of the brainstem to the basal ganglia or striatum), produced a significant response in depressed patients.

Tyrosine, the precursor to norepinephrine that in turn makes dopamine, is favored by natural treatment proponents.

The Mighty Two

Glutamate and GABA represent the yin-yang of the neurotransmitters, Darryle Schoepp PhD of Eli Lilly explained in a session at the 2003 American Psychiatric Association annual meeting, both present in nearly all synaptic function all over the brain, with the former acting in an excitatory capacity and the latter in an inhibitory role. The mood stabilizers are thought to act on one or the other or both.

There are two types of glutamate receptors, ionotropic (iGluR), including NMDA, kainate, and AMPA receptors; and metabotropic (mGluR), which mediate numerous chemical actions. When the NMDA receptor is working right, glutamate and glycine bind to the receptor, which opens up its corresponding ion channel and permits calcium entry into the neuron. This in turn promotes intracellular signaling essential to plasticity and survival.

Husseini Manji MD, Chief of the Laboratory of Molecular Pathophysiology at the NIMH, at the same APA session, reported what can go wrong: In response to stress and mood episodes, glutamate reuptake in the synapse is compromised, resulting in increased calcium influx through the NMDA receptors and ion channels into the neuron and the activation of certain calcium-dependent enzymes that can result in cell atrophy and death. In some patients, Dr Manji observed, their mood disorder may be fundamentally atrophic rather than symptomatic.

In an article in the May 2003 Biological Psychiatry, Dr Manji et al listed a number of experimental drugs that target the NMDA receptors. One small study found that the anesthetic, ketamine, an “NMDA receptor antagonist,” resulted in rapid improvement in depressed patients. The anticonvulsant felbamate, and a drug used in Germany to treat memory loss, memantine, are also being investigated for treating depression.


Meanwhile, over at the AMPA receptors, which are tied to MAP kinase and other processes, “AMPA receptor potentiators” (ARPs) may modulate these receptors and enhance MAP kinase activation. Several compounds are being investigated.

The mood stabilizer, Lamictal, with demonstrated efficacy for bipolar depression, is an antiglutamate agent. A drug currently on the market to treat ALS, riluzole, inhibits glutamate. A pilot study at the NIMH is underway to investigate its antidepressant effects.


GABA is formed in the brain from glutamate, glucose, and glutamine, and binds to one of two receptors on the postsynaptic neuron. GABA A receptors regulate excitability and anxiety, panic, and stress, and are the targets of benzodiazepines such as Ativan, barbiturates, and alcohol. Depressed individuals have decreased GABA in their cerebral spinal fluid and plasma.

Gerard Sanacora MD, PhD of Yale has used magnetic resonance spectroscopy to measure GABA in the brain, finding that those with melancholic depression show low GABA concentrations in the occipital cortex, while the depletion is not as pronounced for those with atypical depression, indicating a diagnostic potential for subtypes of depression (March, 2003 American Journal of Psychiatry). Before and after scans of eight patients who had ECT found a doubling of GABA, and similar scans of patients on SSRIs showed a slow rise in GABA levels in nine of 11 of them.

Julia Ross of Mood Cure fame refers to GABA as "our natural valium," and recommends it to her clients for calming down. However, as this neurotransmitter does not easily cross the blood-brain barrier, you may wind up instead with very expensive urine.

The Unsung One

At the 2003 APA meeting, Alan Schatzberg MD of Stanford, Richard Hargreaves PhD of Merck, and A John Rush MD of the University of Texas Southwestern Medical Center staged a coming out party of sorts for substance P, which is the target of a new class of antidepressants:

Substance P was discovered in 1931. Its role in pain and inflammation was identified in 1961, and in depression in 1988. As opposed to the three neurotransmitters we know best, which are monoamines, substance P is a peptide derived from two different types of amino acids, and is localized in brain regions controlling affective behavior.

Substance P is released in response to stress and binds preferentially to the neurokinin-1 (NK-1) receptors, resulting in mood and emotional changes. Mice genetically engineered with no NK-1 receptors have greater firing of the serotonin neurons. A similar effect was found when the mice were administered a substance P antagonist that binds highly selectively to the NK-1 receptors, thus blocking out substance P.

Merck began experimenting with MK-0869, which led to aprepitant (Emend), which was approved in April 2003 by the FDA for treating chemo-induced nausea and vomiting. A 1998 phase II trial of 213 depressed patients found a better than 50 percent response over six weeks for those on Emend, which beat 20 mg of Paxil by a small margin and the placebo by a much wider margin. Seventy-two percent of the Emend patients completed the trial vs 64 percent of those on Paxil. The drug was also as effective as Paxil in reducing anxiety. A 2001 trial of 700 mild to moderately depressed patients on different doses of Emend or 20 mg Prozac or a placebo, however, failed, with all the groups showing similar improvement. Phase III trials proved a disappointment, and in Nov 2003 manufacturer Merck withdrew the drug from FDA consideration.

Merck also has another substance P antagonist up its sleeve, Compound A, in phase II development, and several companies have their own versions. Hopefully, one or more will make it beyond phase III.



Functions of Dopamine in the Brain


Role in Movement

Dopamine plays a critical role in the way our brain controls our movements and is thought to be a crucial part of the basal ganglia motor loop. Thus, shortage of dopamine, particularly the death of dopamine neurons in the nigrostriatal pathway, is a cause of Parkinson's disease, in which a person loses the ability to execute smooth, controlled movements.
[edit]

Role in Cognition and Frontal Cortex Function

In the frontal lobes, dopamine plays a role in controlling the flow of information from other areas of the brain. Dopamine disorders in the frontal lobes can cause a decline in neurocognitive function, particularly those linked to the frontal lobes, such as memory, attention and problem solving. This function is particularly related to the mesocortical dopamine pathway.
[edit]

Role in Pleasure and Motivation

Dopamine is commonly associated with the 'pleasure system' of the brain, providing feelings of enjoyment and reinforcement to motivate us to do, or continue doing, certain activities. Certainly dopamine is released (particularly in areas such as the nucleus accumbens and striatum) by naturally rewarding experiences such as food, sex, drugs of abuse and neutral stimuli that become associated with them. This theory is often discussed in terms of drugs (such as cocaine) which seem to directly produce dopamine release in these areas, and in relation to neurobiological theories of addiction, which argue that these dopamine pathways are pathologically altered in addicted persons.

However, the idea that dopamine is the 'reward chemical' of the brain now seems too simple as more evidence has been gathered. Dopamine is known to be released when unpleasant or aversive stimuli are encountered, suggesting that it is not only associated with 'rewards' or pleasure. Also, the firing of dopamine neurons occur when a pleasurable activity is expected, regardless of whether it actually happens or not. This suggests that dopamine may be involved in desire rather than pleasure. Drugs that are known to reduce dopamine activity (e.g. antipsychotics) have been shown to reduce people's desire for pleasurable stimuli, despite the fact that they will rate them as just as pleasurable when they actually encounter or consume them. It seems that these drugs reduce the 'wanting' but not the 'liking', providing more evidence for the desire theory.

Other theories suggest that the crucial role of dopamine may be in predicting pleasurable activity. Related theories argue that dopamine function may be involved in the salience ('noticeableness') of perceived objects and events, with potentially important stimuli (including rewarding things, but also things which may be dangerous or a threat) appearing more noticeable or more important. This theory argues that dopamine's role is to assist decision making by influencing the priority of such stimuli to the person concerned.


Dopamine and Psychosis

Disruption to the dopamine system has also been strongly linked to psychosis and schizophrenia. Dopamine neurons in the mesolimbic pathway are particularly associated with these conditions. This is partly due to the discovery of a class of drugs called the phenothiazines (which block D2 dopamine receptors) which can reduce psychotic symptoms, and partly due to the finding that drugs such as amphetamines and cocaine (which are known to greatly increase dopamine levels) can cause psychosis when used in excess. Because of this, all modern antipsychotic medication is designed to block dopamine function to varying degrees.

See the article on the dopamine hypothesis of psychosis for a wider discussion of this topic.


THE ROLE OF DOPAMINE



Dopamine is a chemical messenger (neurotransmitter) that is not very common in the brain. Scarcely more than 0.3% of the neurons in the brain produce dopamine. Nevertheless, these neurons play an essential role in many of our behaviours.

Model of a dopamine molecule


For example, they are involved in controlling the body’s movements. When some of these neurons are destroyed, the person displays the trembling characteristic of Parkinson’s disease.

The opposite problem–too much dopamine in certain regions of the brain–produces the terrible symptoms associated with schizophrenia. In fact, the most effective medications for treating schizophrenia are those that prevent dopamine from binding to dopamine receptors.

Lastly, certain dopamine-producing neurons, such as those discussed here, come into play when the person or animal in question experiences desire or pleasure.





Dopamine System Stabilizers

by Thomas AM Kramer, MD
Medscape Psychiatry & Mental Health eJournal 7(1), 2002.


It has now been established that all substances that trigger dependencies in human beings increase the release of a neuromediator, dopamine, in a specific area of the brain: the nucleus accumbens.

But not all drugs increase dopamine levels in the brain in the same way.
• Some substances imitate natural neuromediators and take their place on their receptors. Morphine, for example, binds to the receptors for endorphin (a natural "morphine" produced by the brain), while nicotine binds to the receptors for acetylcholine.
• Other substances increase the secretion of natural neuromediators. Cocaine, for example, mainly increases the amount of dopamine in the synapses, while ecstasy mainly increases the amount of serotonin.
• Still other substances block a natural neuromediator. Alcohol, for example, blocks the NMDA receptors.



INTRODUCTION
We are now being told that just as we became accustomed to a whole new generation of antipsychotic medications, they will soon be replaced by an even newer generation.

Just as we got used to the idea that antipsychotic medications needed to block both dopamine and serotonin receptors, specifically the D-2 receptor and the 5HT-2A receptor, and these (somewhat begrudgingly) became the standard of care, we are now told that soon they will be pass. This is not going to be easy for the psychopharmacology world. After all, these drugs are so much better than their predecessors.

As a teacher of psychopharmacology, I have always insisted that residents shy away from the term "atypical antipsychotic" because these are the drugs that should be used typically, as the rule, not the exception. I always encouraged the use of the term "new-generation antipsychotic" to describe serotonergic/dopaminergic blockers to treat psychosis. These new-generation antipsychotics appear to be safer (as far as causing tardive dyskinesia), better tolerated, and have greater effectiveness in that the patients appear to not only have diminished symptoms, but also seem to be more functional. To supplant these drugs, the next generation must be truly extraordinary by comparison.

And indeed, as described, they are. These medications, referred to as dopamine system stabilizers and exemplified by the prototype drug aripiprazole, sound magical. They are described as binding to dopamine receptors, particularly D-2 receptors, in such a way that they are neither agonists nor antagonists, but instead magically affect the receptor in just the right way to make the patient better. This sounds too good to be true.

The problem with understanding this concept is how we are taught, for the most part, about receptors and psychopharmacology. If we are told that a drug is active at a certain receptor, our next question is whether it is an agonist or antagonist. That is, either the drug binds to the receptor but doesn't activate it, which makes it an antagonist, or it binds to the receptor and activates it as if it were the actual neurotransmitter the receptor was designed for, which makes it an agonist. In most discussions of psychopharmacology, this is presented as an all-or-nothing, on-or-off, binary situation.

If the drug binds to the receptor, there is only 1 of 2 things it can do and it does either one with some absolute quality. We deal with the issue of different affinities for the receptor with dosing. Thus, a drug with a high affinity for the D-2 receptor, like haloperidol, can be used in relatively low dose because it has a very high affinity for the dopamine receptor, while chlorpromazine has a relatively low affinity for the D-2 receptor and, as such, requires considerably higher numbers of milligrams to get the same effect.

This, however, is not the way psychopharmacology, or pharmacology in general for that matter, works. There are many compounds that bind to receptors and have both antagonistic and agonistic properties. An example of this is pentazocine (Talwin).

Pentazocine is an opiate-based painkiller that can function both as an agonist and an antagonist at opiate receptors. It can be quite effective in pain control; we can also see some patients become dependent on it and abuse it. However, severe heroin or morphine addicts will often tell healthcare professionals that they have an allergy to pentazocine. They know that this means they will never receive the drug. They hate the drug because it interferes (as an antagonist) with the effect of the drug to which they are addicted. Thus, for some people, the drug works as an agonist, and for others, it works as an antagonist. How can this be?

The answer to this dilemma lies in a rethinking of how we understand and discuss drugs and their effect at the receptor. When a drug binds to a receptor, the effect will be different from the effect of the neurotransmitter for which the receptor was designed. It may be less intense, it may be more intense, but to say that it is either going to have an effect or no effect makes things too simple.

All things that bind to a receptor can have a full spectrum of effect, starting from having absolutely no effect but blocking anything else from binding to the receptor, to having a mild effect, to having a more intense effect than the actual intended neurotransmitter. One thing that is fairly universal is that when drug is bound to the receptor, nothing else can bind to it for the period of time the drug is there. As such, one of the ways to understand receptor affinity is to consider how long the drug sticks around.

This may be the best way to understand what these magical new drugs called dopamine system stabilizers do. They bind to dopamine receptors. Once they are there, they prevent dopamine from binding to the receptor for as long as they are bound. They have a mild effect similar to dopamine in the receptor, but less intense. Since we assume that the state of being psychotic has something to do with an overactivity in the dopamine system, if you put in a drug that gets in the way of dopamine but still does some of the good stuff that dopamine does, you will effectively "stabilize" the system.

Thus, these drugs are agonist/antagonists and they work, in large part, by getting in the way transiently of dopamine binding. In doing so, they behave like a milder form of dopamine.

One way to understand the virtue of this activity is to think about chairs at a party. If everyone sits down in a chair and stays there (the analogy to something with very high affinity that binds to the receptor and doesn't leave), the party will not get too wild, but nobody will stand up, and the party is sort of dead.

This may be a good example of what happens with dopamine antagonists such as haloperidol. If, however, you have people who sit down in chairs but then stand up and are constantly sitting down and standing up, getting out of the chair and getting into the chair, you probably have a pretty good party. Guests are only sitting down for part of the time and then allowing other people to sit down so that everybody there has a chance to sit in the chairs.

This kind of movement not only makes for a good party; it is illustrative of probably the best way for dopamine receptors to be occupied (ie, transiently so that they are bound part of the time but also allow some opportunity for dopamine to bind occasionally). In other words, you want movement in and out of the seats so that no one sits too long and everyone has a chance for a seat. This is probably the stabilizing effect.

Generally, the new concept of antipsychotic medication is that transient occupancy of the D-2 receptor is probably responsible for the increased benefit of newer antipsychotic medications. What are currently called atypical antipsychotics do this in part by blocking some D-2 receptors and also blocking serotonin receptors that have a downstream effect of pushing more dopamine into the system. This, in effect, competes with the dopamine blockade of the original drug. What dopamine system stabilizers may do is make this feedback loop effect simpler, more direct, and more effective: fundamental ways to improve the clinical pharmacology of any disorder.


A dopamine uptake inhibitor as you call it, is already in you in the form of Wellbutrin.
? A number of medications can cause parkinsonism by lowering dopamine levels. These are referred to as dopamine receptor antagonists or blockers.


? Nearly all antipsychotic or neuroleptic medications such as chlorpromazine (Thorazine), haloperidol (Haldol), and thioridazine (Mellaril) can induce the symptoms of parkinsonism.


? The medication valproic acid (Depakote), a widely use antiseizure medication, may also cause a reversible parkinsonism.


__________________________________________________________________________

The neurochemical basis of cognitive deficits induced by brain iron deficiency: involvement of dopamine-opiate system
by
Youdim MB, Yehuda S.
Technion-Faculty of Medicine,
Eve Topf and National Parkinson Foundation (US),
Centers for Neurodegenerative Diseases Research,
Department of Pharmacology,
Haifa, Israel.
youdim@techunix.technion.ac.il
Cell Mol Biol (Noisy-le-grand) 2000 May;46(3):491-500

ABSTRACT
Iron is an essential element in maintaining normal structure and functions of the central nervous system. Dangerous effects of decreases in the bioavailability of iron in the brain are shown to affect brain biochemistry, neurotransmitters production and function, mainly in the dopamine-opiate systems well as cognitive functions (learning and memory) and a number of physiological variables such motor activity and thermoregulation. Recent research has shown the added complications and deficits that are introduced in the endocrine and the immune system activity. While iron deficiency is not perceived as a life threatening disorder, it is the most prevalent nutritional disorder in the world and a better understanding of the modes and sites of action, can help devise better treatment programs for those who suffer from it.

II. Basic Central/Peripheral Mechanisms Working Group

Chair: Mark Hallett, M.D., NINDS

Research Directions and Priorities

The group summarized general areas for research directions and priorities: anatomy; oscillations; RLS pathophysiology; RLS epidemiology; RLS animal models; PLMD; opiate sensitivity; iron; muscle tone; nerve tissue banks; and the dopamine connection.

A. Anatomy

Dopamine pathways need to be re-explored because previous studies did not necessarily use good methods. Good methods, which use the dopamine transporter to label the pathways, are now available. Both surveys and focal studies should be done. Surveys have trouble being funded, even though they are probably useful. The brain and the spinal cord, especially descending dopamine pathways, should be explored. All pathways into and out of the hypothalamus should explored, because these are important regions for sleep disorders. Particular attention should be paid to dopamine pathways, but opiate and orexin pathways should also be considered. Neuroanatomic studies should be functional, not merely tract-tracing. Receptors need to be considered.

B. Oscillations

Circadian rhythms are clearly relevant, particularly with the 24-hour periodicity of dopamine. PET scans and lumbar puncture are methods that could be used. Such studies are difficult and costly to do because they take place during the middle of the night, but would be particularly valuable. Iron and opiates should be studied as circadian markers.

Ultradian rhythms and sleep-wake rhythms are part of understanding oscillations. The anatomy and functional pathways of ultradian rhythms and sleep-wake rhythms should be studied.

A 20-second oscillation occurs in the firing rates in dopamine-sensitive neurons in basal ganglia. With increased dopamine concentration, these oscillations increase in frequency. This might have something in common with 20-second periodicity in PLMD. The 20-second periodicity is also noted in isolated spinal cord, so an oscillator must be present in the spinal cord. It would be valuable to find the 20-second oscillator.

Oscillations in sensory pathways such as sensory feelings experienced by RLS patients, have not yet been examined.

For all oscillations, basic mechanisms (cellular events) should be studied.

C. RLS pathophysiology

RLS’s major feature is the sensory symptoms. These should be better characterized, especially in relation to their circadian modulation. There is probably an additional oscillation of these sensory symptoms on the 20-second oscillation thought of in RLS. It appears that limb movement eases symptoms, which then worsen before the next movement. This suggests 2 different oscillations for the sensory symptoms: gross circadian oscillation, plus a superimposed 20-second oscillation related to movement. The following questions should be answered: What is the effect of movement on sensory symptoms? Is oscillation of sensory symptoms due to movement (involuntary, voluntary)? What is the relationship of akathisia to RLS sensory symptoms? Where is the locus of the urge to move? Is it coming through the spinal cord?

D. RLS epidemiology

More comprehensive studies of RLS epidemiology are needed. The relationship between RLS and attention deficit hyperactivity disorder should be studied. The responsiveness of RLS to opiates and to dopamine agonists should be compared.

E. RLS animal models

Animal models of RLS should be developed. It is hoped that a genetic model RLS could be developed, similar to what has been developed in narcolepsy. Iron deficiency might create an animal model. Finally, a spinal-cord transection model of periodic limb movements (PLMs) could be developed, although this is not necessarily a model of RLS.

F. PLMD

A dissociation clearly exists between RLS and PLMD. Not every patient with RLS has PLMD, and PLMD occurs in many other disorders. This leads to the following questions:

(1) Are PLMs the same in RLS as in other disorders, such as apnea, narcolepsy, uremia, and peripheral neuropathy? Current relevant results suggest that they are. The relationship between these other disorders and PLMs is not clear. Dyskinesias while awake do seem to be slight different compared with PLMs while sleeping, at least in duration of the electromyographic recording, which is longer while awake.

(2) How often do PLMs manifest as symptoms? Patients are clearly symptomatic from RLS. But are patients symptomatic from PLMs? Even if arousals occur during PLMs, it is not clear if PLMs are actually symptomatic. It is important to determine how often PLMs manifest as symptoms, separate from RLS.

(3)Why aren’t PLMs completely suppressed during rapid eye movement (REM) sleep?

G. Opiate sensitivity

The relationship between opiate sensitivity and sensory symptoms should be studied. Spinal opiate effects should also be studied. Are subtypes of opiates better than others, and can this help in understanding RLS symptoms?

H. Iron

Studies of iron should include anatomy of iron/dopamine; iron availability; iron transport; MRIs; and role of iron in other dopamine disorders.

I. Muscle tone

Muscle tone is relevant for many movement disorders. A lot more needs to be learned in the following categories: anatomy, physiology, spinal pathways; regulation; spinal pathways; cataplexy, compared with REM sleep; PD; and RLS and, PLMD. Other questions are as follows: Why is tone not suppressed in REM behavior disorder? During REM, how can there be movements occur when a -motor neurons are supposed to be suppressed? What is the possible relevance of muscle tone to sleep apnea? Can REM without atonia in animals (cats, rats) be corrected with same drugs used for REM behavior disorders, such as dopamine agonists?

J. Nerve tissue banks

Nerve tissue banks, which would include brain, spinal cord, peripheral nerve from patients with RLS and narcolepsy, would be extremely valuable. Brain banks already operate at the University of Maryland and at University of Miami. The International RLS Study Group started a brain bank. Issues of ownership need clarification.

K. The dopamine connection

What is the extent to which the dopamine connection is in common among the disorders? So far, the only thing in common is that the patients respond to drugs that act on dopamine. What else is in common: Drugs; time course; receptor agonists; targets; sensitization and desensitization? The role of dopamine should be studied in sleep, wakefulness, and alertness in RLS, PD, and narcolepsy.


_________________________________________________________________________

Dopamine (neurotransmitter which transmits signals between brain cells)



Dopamine is a neurotransmitter, a chemical used to carry messages between neurons. Dopamine is produced in several areas of the brain, including the substantia nigra.

Dopamine's effects are complex and poorly understood, but dopamine appears to play a role in signaling reward in the brain. For example, "pleasurable" events such as eating, drinking, and having sex are all associated with increased brain dopamine levels, while individuals experiencing depression or anxiety may have lowered brain dopamine levels. Many drugs of abuse which give "pleasurable" or "calming" highs, such as cocaine and nicotine, appear to work by mimicking dopamine in the brain.

Parkinson's disease destroys dopamine-producing neurons in the substantia nigra, and causes motor symptoms (dyskinesia, tremor, rigidity) as well as cognitive symptoms. The motor symptoms can be treated by drugs that increase brain dopamine levels.

Schizophrenia is a disorder associated with abnormally high levels of brain dopamine; symptoms may include disordered thought, hallucinations and social withdrawal. These symptoms may be ameliorated by drugs that decrease brain dopamine levels.

Parkinson's patients given too much dopaminergic medication may develop schizophrenia-like symptoms, while schizophrenic patients given too much anti-dopaminergic medication may develop motor problems reminiscent of Parkinson's disease. Apparently, the brain requires a very delicate balance of dopamine to function normally.

_________________________________________________________________________

The role of dopamine in learning, memory, and performance of a water escape task

Victor H. Denenberg, a, Douglas S. Kima, b and Richard D. Palmiter,

Department of Biochemistry, University of Washington, Seattle, WA Molecular and Cellular Biology Program, University of Washington, Howard Hughes Medical Institute, University of Washington,

2003.

Abstract

Dopamine-deficient (DD) mice have selective inactivation of the tyrosine hydroxylase gene in dopaminergic neurons, and they die of starvation and dehydration at 3–4 weeks of age.

Daily injections of -DOPA (50mg/kg, i.p.) starting ~2 weeks after birth allow these animals to eat and drink enough for survival and growth. They are hyperactive for 6–9h after receiving -DOPA and become hypoactive thereafter.

Because these animals can be tested in the presence or absence of DA, they were used to determine whether DA is necessary for learning to occur. DD mice were tested for learning to swim to an escape platform in a straight alley in the presence (30min after an -DOPA injection) or absence (22–24h after an -DOPA injection) of dopamine.

The groups were split 24h later and retested 30min or 22–24h after their last -DOPA injection. In the initial test, DD mice without dopamine showed no evidence of learning, whereas those with dopamine had a learning curve similar in slope to controls but significantly slower.

A retest after 24h showed that DD mice can learn and remember in the absence of dopamine, leading to the inference that the lack of dopamine results in a performance/motivational decrement that masks their learning competence for this relatively simple task.



http://dwb.unl.edu/Teacher/NSF/C10/C10Links/www.pharmcentral.com/dopamine.htm

_________________________________________________________________________

J Pineal Res. 2004 Apr;36(3):177-85.


Circadian rhythms of dopamine, glutamate and GABA in the striatum and nucleus accumbens of the awake rat: modulation by light.

Castaneda TR, de Prado BM, Prieto D, Mora F.

Department of Physiology, Faculty of Medicine, Universidad Complutense, Madrid, Spain.

Using microdialysis, we investigated the circadian rhythms of the extracellular concentrations of dopamine, glutamate and gamma-aminobutyric acid (GABA) in the striatum and nucleus accumbens of the awake rat. Wistar rats were maintained in a 12 hr dark:12 hr light (12:12) cycle for 2 wk before the experiment began. The neurotransmitter levels were measured every 30 min for 30 hr in control (maintaining the 12:12 cycle) or in experimental conditions under a 24-h light period (continuous light) or under a 24-h dark interval (continuous dark). The dopamine metabolites, DOPAC and HVA, and the main serotonin metabolite, 5-HIAA, were measured along with arginine and glutamine under all conditions. In 12:12 conditions, a circadian rhythm of dopamine, glutamate and GABA was found in both the striatum and nucleus accumbens. Again under 12:12 conditions, DOPAC, HVA, 5-HIAA, and arginine, but not glutamine, fluctuated in a circadian rhythm. In the striatum under constant light conditions, there was a circadian rhythm of dopamine, glutamate, GABA, DOPAC and HVA, but not 5-HIAA. By contrast, when the rats were kept under continuous dark, dopamine and its metabolites, DOPAC and HVA (but not glutamate and GABA), did not fluctuate in a circadian rhythm. In the nucleus accumbens, under both constant light or dark conditions, no changes were found in the circadian rhythm in any of the neurotransmitters and metabolites studied. These findings show that in the striatum, dopamine but not glutamate and GABA, seem to be influenced by light. In the nucleus accumbens, however, the three neurotransmitters had a circadian rhythm, which was independent of light.


Neuropharmacology. 1991 Jun;30(6):575-8.


Release of dopamine is reduced by diazepam more in the nucleus accumbens than in the caudate nucleus of conscious rats.

Invernizzi R, Pozzi L, Samanin R.

Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italia.

The effects of 1-20 mg/kg diazepam were studied on the extracellular concentrations of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens and striatum of conscious rats, using intracerebral microdialysis. Five, but not 1 mg/kg diazepam significantly reduced extracellular DA, DOPAC and HVA in the nucleus accumbens. Twenty mg/kg diazepam significantly reduced extracellular DA, DOPAC and HVA in the striatum. A significant effect on striatal DOPAC, but not on DA and HVA, was seen with 10 mg/kg diazepam, while no changes were found with 5 mg/kg diazepam. The results suggest that diazepam reduces the release and metabolism of DA in the nucleus accumbens more than in the striatum.

________________________________________________________________________


Greater Availability of Brain Dopamine Transporters
in Major Depression Shown by
[(99m)Tc]TRODAT-1 SPECT Imaging
by
Brunswick DJ, Amsterdam JD,
Mozley PD, Newberg A.
Am J Psychiatry. 2003 Oct;160(10):1836-41

ABSTRACT
OBJECTIVE: Studies of laboratory animals have shown that administration of antidepressants of all pharmacological classes produces changes in dopamine transporter binding affinity. These observations suggest that dopamine transporter function may play a critical role in the pathophysiology of depression. The present study was an examination of the availability of brain dopamine transporter sites in patients with major depression and in healthy comparison subjects. METHOD: Single photon emission computed tomographic (SPECT) brain scans were acquired for 15 drug-free depressed patients and 46 age- and gender-matched healthy comparison subjects by using [(99m)Tc]TRODAT-1, a selective dopamine transporter imaging agent. Specific regions of interest in the basal ganglia and supratentorial areas of the brain were examined. Specific uptake values of dopamine transporter [(99m)Tc]TRODAT-1 binding affinity were calculated from the SPECT scan data, and the values for the patients and healthy subjects were compared. RESULTS: The specific uptake values of [(99m)Tc]TRODAT-1 binding were significantly higher in the right anterior putamen (23%), right posterior putamen (36%), left posterior putamen (18%), and left caudate nucleus (12%) of the patients than in the comparison subjects. These differences persisted when the data were further analyzed according to gender and age. CONCLUSIONS: Dopamine transporter affinity may be higher than normal in the basal ganglia of depressed patients. These findings suggest that dopamine function may be altered in depression and may also be a mechanism of antidepressant activity.
















Enter supporting content here

Visitors since 8/2004.