Neurotransmitters imbalance

Alterations in neurotransmitter uptake and metabolism in glial cells / Modification in the ratio and function of inhibitory circuits / Local neurotransmitter imbalances (e.g., glutamate, y-aminobutyric acid [GABA]), acetylcholine, norepinephrine, and serotonin)... 

Neurochemists continue to improve the methods they use to measure and analyze chemicals of the brain. They have also developed techniques to study how neurons transmit messages across synapses to other neurons, and how these messages affect the recipients. Synaptic transmission is critical in brain function, and neurotransmitter imbalances have been associated with disorders such as depression and schizophrenia as well as drug abuse. Although the cause or causes of these conditions are not necessarily as simple as too much or too little of a certain neurotransmitter, chemicals such as dopamine and serotonin are undoubtedly involved. Neurotransmitters have been excellent starting points for further, ongoing studies into these issues. 

As others before them, Emrich and colleagues (63) propose that a single neurochemical imbalance is not sufficient to explain many of the inconsistencies and contradictions in studies with various mood stabilizers. Instead, they speculate that several neurotransmitter imbalances relating to different brain areas should be anticipated. 

These reactions, which have provided a means of inhibiting the flavin-linked monoamine oxidases, enable us to end on a clinical note. The monoamine oxidases are responsible for the deamination of monoamines such as adrenaline, noradrenaline, dopamine, and serotonin, which act as neurotransmitters. Imbalances in the levels of monoamines cause various psychiatric and neurological disorders Parkinson s disease is associated with lowered levels of dopamine, and low levels of other monoamines are associated with depression. Inhibitors of monoamine oxidases may consequently be used to treat Parkinson s disease and depression. The flavin moiety is covalently bound to the enzyme by the thiol group of a cysteine residue (equation 9.17). The acetylenic suicide inhibitor N,N-dimethyl-propargylamine inactivates monoamine oxidases by alkylating the flavin on N-5.25 A likely mechanism for the reaction is the Michael addition of the N-5 of the reduced flavin to the acetylenic carbon 2... 

The parameter B2 is chosen for this project in order to gain some insight into possible consequences of varying the capability of the acetylcholinesterase to hydrolyze the neurotransmitter. Imbalances in this capability give rise to devastating diseases such as Alzheimer s and Parkinson s. The enzyme activity is included in the grouped parameter B2, which includes the maximum reaction velocity in reaction 2. The parameter B2 itself includes the enzyme activity together with three constants for the enzyme system, namely the concentration of acetylcholinesterase in compartment (II), the volume V2 of compartment (II), and the flow rate q. 

FIGURE 10-1 Schematic representation of the neurotransmitter imbalance in Parkinson disease. Normally, a balance exists between dopamine and acetylcholine in the basal ganglia. In Parkinson disease, decreased dopaminergic influence results in increased acetylcholine influence. 

Danger signals can come from both foreign material (infectious agents) and endogenous sources (damaged cells or tissues, altered molecules, neurotransmitter imbalances). 

The proposed neurotransmitter imbalance in major depression is best characterized by ... 

Psychosis is caused by a dopamine (neurotransmitter) imbalance in the brain. Antipsychotic medications (dopamine antagonists) block the D2 dopamine receptors, reducing the psychotic symptoms. Some antipsychotic medications block the chemoreceptor trigger zone and vomiting (emetic) center, producing an antiemetic effect. Blocking dopamine causes the side effects of Parkinsonism (see 15.24 Parkinsonism Medication). Psychosis is treated with antipsychotic medications. Categories of antipsychotic are ... 

While I m not an Ayurvedic practitioner myself, I appreciate Ayurveda s integration of body, mind, and spirit and its vision of health as balance and harmony. I also find Ayurveda s system of categorizing different constitutional types very useful in understanding depression, particularly since, as we ve seen, the imbalances associated with each type resemble the neurotransmitter imbalances I described in Step One. Learning your Ayurvedic type is your first step toward crafting antidepression strategies specifically tailored to suit your own personal body, mind, and spirit. 

Another class of therapeutic agents is used for the treatment of certain genetic diseases or other enzymatic disorders caused by the dysfunction or absence of one particular enzyme. This often leads to an unwanted accumulation or imbalance of metaboUtes in the organism. Eor example, some anticonvulsive agents are inhibitors for y-aminobutyric acid aminotransferase [9037-67-6]. An imbalance of two neurotransmitters, glutamate and y-aminobutyric acid, is responsible for the symptoms. Inhibition of the enzyme leads to an increase of its substrate y-aminobutyric acid, decreasing the imbalance and subsequently relieving the symptoms of the disease. 

Depression, we are told over and over again, is a brain disease, a chemical imbalance that can be adjusted by antidepressant medication. In an informational brochure issued to inform the public about depression, the US National Institute for Mental Health tells people that depressive illnesses are disorders of the brain and adds that important neurotransmitters - chemicals that brain cells use to communicate - appear to be out of balance . This view is so widespread that it was even proffered by the editors of PLoS [Public Library of Science] Medicine in their summary that accompanied our article. Depression, they wrote, is a serious medical illness caused by imbalances in the brain chemicals that regulate mood , and they went on to say that antidepressants are supposed to work by correcting these imbalances. 

After neurotransmitter molecules have influenced the firing of a receiving neuron (more technically called a postsynaptic neuron), some of them are destroyed by enzymes in the synaptic cleft (the synapse), some are reabsorbed by the sending presynaptic neuron in a process that is called reuptake , and the rest remain in the space between the two neurons. The chemical-imbalance hypothesis is that there is not enough serotonin, norepinephrine and/or dopamine in the synapses of the brain. This is more specifically termed the monoamine theory of depression, because both serotonin and norepinephrine belong to the class of neurotransmitters called monoamines. 

Iproniazid and imipramine seemed to work as antidepressants, but how did they achieve their effects It would be another decade before the chemical-imbalance theory was launched. In 1965, Joseph Schildkraut at the National Institute of Mental Health in Washington, DC, published a groundbreaking paper in which he argued that depression was caused by a deficiency of the neurotransmitter norepinephrine in the gaps between neurons in the brain.8 Two years later Alec Coppen, a physician at West Park Hospital in Surrey, published another version of the chemical-imbalance theory. His version differed from Schildkraut s in that it put most of the blame on a different neurotransmitter, emphasizing serotonin rather than norepinephrine as the neurotransmitter that was lacking.9... 

What was the scientific basis for these chemical-imbalance theories As I noted above, norepinephrine and serotonin are now known to be neurotransmitters - chemicals that transmit nerve impulses from one neuron to another. But in the 1950s knowledge of neurotransmission was sketchy at best. The presence of norepinephrine in the nervous system was not demonstrated until 1954, and evidence that dopamine functions as a neurotransmitter was not reported until 1958. As late as i960 the idea that neurotransmission is largely chemical in nature, though advocated by a group of largely British scientists, was not yet widely accepted.10... 

Here then is the logic behind the first version of the chemical-imbalance theory. Iproniazid is a monamine oxidase inhibitor - it inhibits the oxidation of norepinephrine and serotonin in the synapses, thereby leaving more of these neurotransmitters available in the brain. When depressed people take iproniazid, they get better. Therefore insufficient norepinephrine and/or serotonin causes depression.12... 

There was a problem with this first version of the biochemical theory of depression. Iproniazid was not the only drug that had been reported to be effective as an antidepressant. Imipramine, the drug that had been tested by the Swiss psychiatrist Roland Kuhn, seemed to have similar effects. But imipramine is not an MAOI it does not inhibit the destruction of neurotransmitters in the synapse. So if antidepressants worked by inhibiting monoamine oxidase, why was imipramine effective How could its apparent effectiveness be reconciled with the chemical-imbalance theory ... 

Axelrod s discovery provided an answer to the question of why imipramine might alleviate depression, even if it did not inhibit the destruction of neurotransmitters in the brain. With the problem of imipramine solved, the chemical-imbalance theory seemed to work. Two different types of drugs relieve depression, the theory went,... 

But that was only one half of the logic behind the chemical-imbalance theory. The other half came from studies of reserpine, a drug that was extracted from Rauvolfia serpentina or the Indian snakeroot plant, which had historically been used to treat snakebite, hypertension, insomnia and insanity. In studies of animals, reserpine was reported to induce sedation and to decrease brain levels of norepinephrine, serotonin and dopamine. Clinical reports indicated that some people became severely depressed when taking reserpine.14 Putting these two findings together, it seemed likely that reserpine made people depressed because it decreased neurotransmitter levels. 

When the reserpine studies are added to the antidepressant studies, the logic behind the chemical-imbalance theory begins to look compelling. Drugs like reserpine that decrease monoamine neurotransmitters make people depressed. Drugs that increase these neurotransmitters by one means or another relieve their depression. Hence, depression is due to a monoamine deficiency. 

When the chemical-imbalance theory was introduced more than 40 years ago, the main evidence in favour of it was the contention that antidepressants, which were thought to increase the availability of serotonin and/or other neurotransmitters in the brain, seemed to be effective in the treatment of depression. As Alec Coppen wrote in 1967, one of the most cogent reasons for believing that there is a biochemical basis for depression or mania is the astonishing success of physical methods of treatment of these conditions. 26 The situation has not changed very much since then. People still cite the supposed effectiveness of antidepressants as fundamental support for the chemical-imbalance hypothesis. This theory, they say, is supported by the indisputable therapeutic efficacy of these drugs .27... 

Different types of antidepressants are supposed to affect different neurotransmitters. Some are supposed to affect only serotonin, others are supposed to affect both serotonin and norepinephrine, and still others are supposed to affect norepinephrine and dopamine. But there is a relatively new antidepressant that has a completely different mode of action. It is a most unlikely medication, and the evidence for its effectiveness puts the last nail in the coffin of the chemical-imbalance theory of depression. 

The biochemical theory of depression is in a state of crisis. The data just do not fit the theory. The neurotransmitter depletion studies that I described earlier in this chapter show that lowering serotonin or norepinephrine levels does not make most people depressed. When administered as antidepressants, drugs that increase, decrease or have no effect on serotonin all relieve depression to about the same degree. And the effect of anti-depressants, which was the basis for proposing the chemical-imbalance theory in the first place, turns out to be largely a placebo effect. 

An imbalance of amino acids in the blood often alters the rate of transport of these compounds into the brain, thereby affecting levels of neurotransmitters and rates of protein synthesis 670... 

One model of an ionic mechanism of action of Li+ in affective disorders has been proposed, in which the receptors for Li+ are ion channels and cation coenzyme receptor sites, and in which the presence of intracellular Li+ in excitable cells results in the displacement of exogenous Na+ and/or other intracellular cations [13]. It has been suggested that this could lead to a decrease in the release of neurotransmitters alternatively it may be that this intracellular Li+ is altering a preexisting, disease-related electrolyte imbalance [14]. A number of observations of such imbalances in affective disorders have been made depression is associated with elevated levels of intracellular Na+ [15] retention of Li+ is observed in manic-depressive patients prior to an episode of mania [ 16] and Na+/K+ activity is defective during both mania and depression [17]. 

The importance of brain circuitry is that it reminds us that these chemical neurotransmitters are not released willy-nilly throughout the brain. This is why the term chemical imbalance is so unsatisfactory. The brain is not a large water bottle into which these chemicals are poured and maintained in some precise balance. For that reason, there is no simple test to check a neurotransmitter level like the dipstick on your car s oil reservoir. Instead, your brain is a delicate instrument with predefined but ever-adapting pathways of communication. 

Imbalanced Neurotransmission. Most brain regions are innervated by axonal projections secreting multiple neurotransmitters. When the system is healthy, the activity of the two (or more) neurotransmitters is held in a delicate balance. Some illnesses result from an imbalance in transmission of multiple neuro-... 

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