Neurotransmitters dysfunction

The treatment of non-motor symptoms should be based on whether they are worse during an off state or if they could be related to other neurotransmitter dysfunction. 

Although the role of neurotransmitter dysfunction in schizophrenia remains an exciting and important avenue of exploration, we are only aware of one study of neurotransmitters in COS. Jacobsen and colleagues (1997a) measured cerebrospinal fluid (CSF) levels of HVA and 5-HIAA, metabolites of dopamine and serotonin, respectively. While the concentrations of these monoamine metabolites were similar to that seen in adults with schizophrenia, they did not change significantly with treatment. 

Current concepts of how and why neurotransmitter dysfunction may contribute to schizophrenia stem from decades of experience with modulatory neurotransmitters such as dopamine or serotonin. However, there are several major differences involved in viewing schizophrenia from a glutamatergic, rather than a dopaminergic, perspective. 

Many depressed patients show evidence of abnormal hormone levels, especially adrenocortical hormones, which are adversely influenced by neurotransmitter dysfunction in the limbic system and hypothalamus. 

Alzheimer s disease is the best known age-related disorder for which the primary symptom is dementia. Advances have been made in understanding the etiology of AD, but much remains to be discovered. Clearly, there are documented neuropathological changes in the brain. For example, there is a broad spectrum of neurotransmitter dysfunction, where acetylcholine (ACh), serotonin [5-hydro3 rypta-mine (5-HT)], norepinephrine, dopamine (DA), and glutamate levels are reduced (28-31). Understandably, therapies that affect... 

To date, two types of major depression have been postulated. The first is often referred to as endogenous or melancholic depression. In this type of major depression, symptoms of depressed mood are related directly to internal biologic factors such as neurotransmitter dysfunction (Kaplan Sadock, 1990 Tierney et al., 1997). Electroconvulsive therapy (ECT), referred to historically as shock treatments, is often considered an endogenous treatment. Here, direct (biologic) stimulation of the neurotransmission process is the treatment strategy. Similar to ECT, antidepressant medications also are successful in lifting endogenous depression, with the major difference that they affect the neurochemical pathways chemically rather than electrically (Maxmen Ward, 1995). 

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. 

The objective of these studies is to find a neurochemical marker for depression. For obvious reasons, the majority has looked for changes that might affect monoamine function and so the following sections concentrate on these neurotransmitters. (Evidence suggesting that a dysfunction of the gluocorticoid hormonal system could be involved is discussed later.) Most techniques compare depressed and non-depressed (control) subjects and measure ... 

The exact cause of attention-deficit hyperactivity disorder is unknown, but dysfunction in neurotransmitters norepinephrine and dopamine has been implicated as a key component. 

Unlike many chemicals in the brain, neurotransmitters are not homogeneously distributed, but concentrated in certain regions. For example, almost two-thirds of the dopamine in the brain is found in the bilateral nigrostriatal (mesostriatal) tract (pathway), where the neuronal cell bodies are located in the substantia nigra and the axons terminate in the corpus striatum. When over 85% of these dopaminergic neurons are lost, the characteristic motor dysfunction of Parkinson s disease is seen. 

Neurochemical theories for the affective disorders propose that there is a link between dysfunctional monoaminergic synapses within the central nervous system (CNS) and mood problems. The original focus was the neurotransmitter noradrenaline, or NA (note noradrenaline is called norepinephrine, or NE, in American texts). Schildkraut (1965) suggested that depression was associated with an absolute or relative deficiency of NA, while mania was associated with a functional excess of NA. Subsequently, another monoamine neurotransmitter 5-hydroxytryptamine (5-HT), or serotonin, was put forward in a rival indoleamine theory (Chapter 2). However, it was soon recognised that both proposals could be reconciled with the available clinical biochemical and pharmacological evidence (Luchins, 1976 Green and Costain, 1979). 

There is evidence for the contribution of serotonin dysfunction to mania, and in the mechanism of action of mood stabilizers [19], however, specific data on the serotonergic system and mania are fewer and variable. Moreover, altered functioning of other neurotransmitters in mania such as norepinephrine, dopamine, acetylcholine, and GABA, and their interaction with serotonin, are also likely to be involved in the pathogenesis of mood disorders. Differences in these neurotransmitter systems possibly underlie differences in the pathogenesis of depressive and manic episodes. 

Traditionally, most affective disorders have been treated with compounds that resemble the neurotransmitters that are deficient or in excess in specific brain regions. The aberrant levels of neurotransmitters (or their receptors), such as norepinephrine, dopamine, acetylcholine, and serotonin, have correlated with behavioral symptoms of schizophrenia, depression, anxiety, sleep disorders, motor dysfunctions, attention difficulties, and cognitive disorders. Most drugs discovered for these disorders resulted from screening compounds directly in rodent behavioral models that mimic the behavior of the disease. In these cases, the molecular target" or mechanism of action was assumed to be the deficiency or excess of a neurotransmitter. 

The main risk factor appears to be a genetic susceptibility to the illness. The majority of narcolepsy patients, particularly those with cataplexy, have a genetic marker known as HLA-DQB1 0602. Recent evidence indicates that the key dysfunction in narcolepsy is diminished activity of a newly discovered neurotransmitter known as hypocretin. This new evidence has led to the development of a new diagnostic test for narcolepsy and may ultimately lead to new treatments that act directly on hypocretin systems in the brain. 

Acetylcholine is the primary neurotransmitter in the parasympathetic division of the autonomic nervous system, which mainly innervates the gastrointestinal tract, eyes, heart, respiratory tract, and secretory glands. Although its receptors are crucial for maintaining all normal functions of the body, an extremely small number of illnesses can be explained by the dysfunction of cholinergic regions of the peripheral autonomic system. 

The neurochemistry of schizophrenia has been considered in a variety of ways by numerous investigators and most have, as here, focussed on the role of abnormalities and/or dysfunction of brain neurotransmitter systems in the disease. Implicit in a book on the neurochemistry of consciousness is the assumption that this chapter will address the neurochemical basis of the disturbance (s) of consciousness that occurs in schizophrenia. Consciousness in its particular and generally-understood meaning is not obviously distorted in schizophrenia, although schizophrenic patients clearly have a different, or abnormal experience of the external world—their conscious awareness is disturbed. 

One of the few studies directly identifying an abnormality in dopamine neurotransmitter in schizophrenia demonstrated a lateralised, left hemisphere, elevation in the amygdala (Reynolds, 1983), which added to the evidence for the view of schizophrenia as a left temporal lobe disorder. This elevation is not, however, interpreted as a primary pathology it seems likely that it reflects a dysfunction or dehcit in the neuronal systems controlling dopaminergic activity, and a correlation with diminished levels of a marker for GABA support this interpretation (Reynolds et ah, 1990). 

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