Central nervous system disorders neurotransmitters

Sibutramine 144 is the active enantiomer of the drug Meridia (Abbott Laboratories), which is a potent neurotransmitter reuptake inhibitor used for treating central nervous system disorders.Sepracor devised an asymmetric synthesis of the active enantiomer 144 that relies on the use of the oxathiazolidine oxide 137 as a chiral auxiliary. 

Complicated processes govern wakefulness, sleep, and the transitions leading to sleep initiation and maintenance. Although the neurophysiology of sleep is complex, certain neurotransmitters promote sleep and wakefulness in different areas of the central nervous system (CNS). Serotonin is thought to control non-REM sleep, whereas cholinergic and adrenergic transmitters mediate REM sleep. Dopamine, norepinephrine, hypocretin, substance P, and histamine all play a role in wakefulness. Perturbations of various neurotransmitters are responsible for some sleep disorders and explain why various treatment modalities are beneficial. 

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). 

Complexity of inhibition of PLP-dependent enzymes is highlighted by detailed investigations on the inhibition of y-aminobutyric acid aminotransferase (GABA-AT), the enzyme responsible for the degradation of y-aminobutyric acid (GABA), one of the major inhibitory neurotransmitters in the mammalian central nervous system. Inhibition of GAB A-AT results in an increased concentration of GABA in the brain and could have therapeutic applications in neurological disorders (epilepsy, Parkinson disease, and Alzheimer disease). 

The 5-HT3 receptors are found in both the peripheral nervous system and central nervous system (CNS), where they mediate last synaptic transmission at synapses (3). In the CNS, they are located predominantly at intemeurones, where they modulate the release of a range of neurotransmitters (4-9). There is some evidence that 5-HT3 receptors play roles in brain reward mechanisms and in neurological phenomena such as anxiety, psychosis, nociception, and cognitive function (10,11), and in the first few years following the discovery of these receptors, there was also much interest in the therapeutic potential of 5-HT3 receptor antagonists for antipsychotic, antinociceptive, and other psychiatric disorders (12-15). This potential has not yet been realized, but there is still active research in this area (16), and their current major therapeutic target is against emesis in cancer chemotherapy and irritable bowel syndrome (17,18). 

The amino acids GABA and glutamic acid (glutamate) (Figs. 4 and 5, respectively) are major inhibitory and excitatory neurotransmitters, respectively, in the central nervous system, and a requisite balance between the two operates in normal brain. Aberrations in the functions of one or both of these neurotransmitters have been implicated in the pathogenesis of several neurological and psychiatric disorders, which include depression (36-38). 

It was named Dopamine because it was a monoamine, and its synthetic precursor was 3,4-dihydroxyphenylalanine (L-DOPA). He was awarded Nobel Prize in 2000 along with Eric Kandel and Paul Greengard in Medicine for showing that dopamine is not just a precursor of noradrenaline and adrenaline, but also neurotransmitter as well. DO is a type of neurotransmitter naturally produced in by the human body. It is also a neurohormone released by the hypothalamus. It is a chemical messenger that is similar to adrenaline and affects the brain processes that control movement, emotional response, and the capacity to feel pleasure and pain. It is vital for performing balanced and controlled movements [172,173], In the extra-cellular fluid of the central nervous system, the basal DO concentration is very low (0.01-1 pM). Abnormal levels of DO have been linked with Parkinson s disease, Tourette s syndrome, Schizophrenia, attention deficit hyperactive disorder and generation of pituitary tumours [174-176],... 

Dopamine is a major catecholamine neurotransmitter in the central nervous system that has been implicated in the regulation of locomotor activity, emotion, cognition, and behavior reward and in neuroendocrine regulation [39]. Clinically, dopaminergic drugs (e.g., risperidone) that block or activate dopamine receptors are used to treat neurodegenerative, neuropsychiatric, and neurode-velopmental conditions such as Parkinson s, schizophrenia, bipolar disorder, and autism [40],... 

Catecholamine neurotransmitters in the central nervous system are synthesized in that location itself because they cannot cross the blood-brain barrier. However, dopa readily crosses the blood-brain barrier, promoting the catecholamine synthesis. Thus, in disorders involving deficiency of catecholamine synthesis, administration of dopa may have beneficial effects. In Parkinson s disease, in which deficiency of dopamine synthesis affects nerve transmission in the substantia nigra of the upper brain stem, administration of dopa leads to some symptomatic relief. Parkinsonism is a chronic, progressive disorder characterized by involuntary tremor, decreased motor power and control, postural instability, and muscular rigidity. 

The electroconvulsive therapy performed in the past is a far cry from the process used today in the treatment of major depressive disorder. In ECT a generalized central-nervous-system seizure is induced by means of an electric current. The objective is to achieve the full seizure threshold until the full therapeutic gains can be established. The exact process by which ECT works is unknown however, the shock results in an increase in different neurotransmitter responses at the cell membrane. Four to twelve treatments are generally given until therapeutic results are noted (Sachs, 1996). 

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