Variables In Dopamine Upon Schizophrenia Biology Essay

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Dopamine [4-(2-aminoethyl) benzene-1,2-diol)] is a catecholamine monoamine neurotransmitter (Neve, 2009, p. 24) formed in the brain's dopamine neurons from the amino acid precursor L‑tyrosine; it is then stored in vesicles within the nerve terminals, releasing the dopamine into the synaptic cleft. It is synthesized primarily in the adrenal gland medulla first by the hydroxylation of the amino acid L-tyrosine to L‑3,4‑dihydroxyphenylalanine (L-DOPA) via the enzyme tyrosine 3-monooxygenase (tyrosine hydroxylase) and then by the decarboxylation of L‑DOPA by aromatic L-amino acid decarboxylase (Myers, 2007, p.105).

This release is controlled by a variety of factors, including the firing rate-the impulse-dependent release (von Bohlen & Halback, 2006, p. 64)-of the dopamine nerve cell and the release and subsequent synthesis-modulating presynaptic dopamine receptors; because presynaptic dopamine receptors are sensitive to the cell's own neurotransmitter, they are called dopamine autoreceptors. The role of these autoreceptors is to monitor extracellular dopamine concentrations, modulating the impulse-dependent release rate and also to control dopamine synthesis (Powis & Bunn, 1995, p. 330). Once released the dopamine acts at postsynaptic receptors to influence behavior. These autoreceptors are found at dendrites and soma (von Bohlen & Halback, 2006, p. 66).

Binding to the postsynaptic receptors induces a change in the configuration of these receptors which then causes membrane permeability to ions and initiates a complex change of intracellular postsynaptic events (von Bohlen & Halback, 2006, p. 64). The outcome is an activation or inhibition of the postsynaptic neuron (Stahl, 2008, p. 346). The actions of dopamine in the synapse are terminated primarily by the re-uptake of neurotransmitter into the presynaptic terminal by means of an active dopamine transporter, where it is stored and can be reused (Eshlemann & Janowsky, 2003, p. 439).

The dopamine transporter is a glycoprotein of 619 amino acids that show a 12-span transmembrane design (von Bohlen & Halback, 2006, p. 64). The purpose of the transporter is to collect extracellular dopamine and place into the presynaptic terminal to regulate its life-cycle. This uptake process depends upon sodium and chlorine ions; its efficiency can be measured at 80% (von Bohlen & Halback, 2006, p. 64). Dopamine is either returned to synaptic vesicles for rerelease or degraded by monoamine oxidase (MAO) and aldehyde dehydrogenase to dihydroxiphenylacetic acid (Kuhar, et al., 1990, p. 18). Alternatively, it can be metabolized by catechol-0-methyltransferase to form 3-methoxytryptamine (von Bohlen & Halback, 2006, p. 64). The transport mechanism is not located in an active area, but rather in a perisynaptic area, implying that dopamine diffuses away from the intersynaptic cleft (Memo et al., 1986, p. 19).

Although it was first thought that dopamine occurred only as an intermediate product formed in the biosynthesis of two other catecholamine neurotransmitters, norepinephrine and epinephrine, dopamine is now recognized as a neurotransmitter in its own right. Several distinct dopamine neuronal systems have been identified in the brain (Memo et al., 1986, p. 22). These include systems within the hypothalamus and the pituitary gland; systems within the midbrain that project to a variety of cortical and limbic regions and basal ganglia; the retinal system; and the olfactory system. The midbrain dopamine neurons which project to a variety of forebrain structures are critically involved in normal behavioral attention and arousal; abnormalities in the normal functioning of these systems have been implicated in a variety of disorders.

Dopamine receptors are classified into two groups: D1 and D2. The following table depicts the properties of dopaminergic receptors. [1] Per Neve (2009, p. 24) these receptors belong to the class of G protein-coupled receptors. The G proteins interact with dopamine to send secondary messager cascades (Steiner & Tseng, 2010, p. 448).

Type

Amino Acid Sequence

Location on the Human Chromosome

Agonists

Antagonists

D1 family

D1 (1A)

446

Sq-34-35

A-G8930

CY-208-245

Dihydrexidine

Hydroxybenzazepine

Halobenzazepine

Thioxanthene

D5 (1B)

477

4p-15.1-3

Hydroxybenzazepine

Halobenzazepine

D2 family

D2L (2Aα)

443

11q-22-23

Aminotetraline

Benzamide

D2S (2Aβ)

414

11q

Ergoline

Benzamide

D3 (2B)

400

3q-13.1

(+)-7-OH-DPAT

S-14297

D4 (2C)

387+

11p-15.5

Ergoline

(+)-Aporphine

Clozapine

Dopaminergic hyperactivity leads to an accumulation of the neurotransmitter in the synaptic cleft (von Bohlen & Halback, 2006, p. 70). This hyperactivity results in an increased sensitivity to stress associated with a predominace of noradrenergic over dopaminergic hyperactivity (Yui et al., 2000, pp. 343-349). The excitatory feedback loop from the thalamus to the striatum, originating from the centromedian-parafascicular complex and the midline thalamic nuclei can lead to dopaminergic hyperactivity dysregulating sensorimotor and limbic circuits within the basal ganglia leading to thalamic hyperactivity, which would lead to extensive stimulation of the cortex (Visser-Vandewalle, 2007, p. 218).

Dopaminergic hypoactivity results in motor dysfunction (von Bohlen & Halback, 2006, p. 70): the basal ganglia has an important role in movement. Antagonism of presynaptic D2 receptors increases the release of norephinephrine, while antagonism of postsynaptic D2 receptors results in select vascular relaxation (Brent, 2005, p. 307).

Schizophrenia

Schizophrenia was first classified as a separate mental disorder by Kraepelin in 1890 (Kraepelin, 1911). Historically, however, as compared to other psychopathological states, description, classification and causation has been vague. In 1952, the first edition of the Diagnostic and Statistical Manual of Mental Disorders was published by the American Psychiatric Association in an effort to standardize diagnosis and etiology (Wilson, 1993, p. 400).

From a psychological perspective, no single personality type has been consistently found in premorbid histories of schizophrenics (Cancro, 1985, p. 635). One of the core research studies used to identify a genetic role in the causation of an illness is the family or consanguinity method. This method compares the prevalence rate of a patient's disorder with their relatives vis-à-vis the general population. This, along with twin studies, provided equivocal results (Cancro, 1985, pp. 635-637).

No specific somatic manifestations exist in schizophrenia; however, in its early stages, patients report multiple symptoms, including headache, rheumatic pains in the shoulders, back pain, weakness and indigestion (Weiner, 1985, p. 691). A patient experiencing an acute schizoid reaction regularly presents dilated pupils, moist palms and moderate tachycardia (Weiner, 1985, p. 691). Pneumoencephaographic data, however, showed evidence for ventricular enlargement in a statistically significant percentage of schizophrenics (Cancro, 1985, p. 639). Over the years, the immune systems, plasma factors, and blood flow studies had been conducted on schizophrenics with the result of nonspecific findings (Cancro, 1985, p. 639). However, studies of dopamine levels have been promising. Dopamine levels in schizophrenic brains postmortem are higher in the caudate nucleus and the nucleus accumbens. It has been repeatedly shown that schizophrenic's post-mortem brains had an increase in the number of D2 type dopamine receptor binding sites (Cancro, 1985, p. 639).

Discussion concerning the etiology of schizophrenia is complicated by a central conceptual issue: what are the theories supposed to explain about the disease. These theories are frequently stated in terms of single causes which become manifest only through their interaction with other systems. A single factor will not account for all of the etiological variance. Correlations are mistaken for causal explanations. If it were to become evident that chemical production, reception or metabolism were the nexus for schizophrenia, a functional explanation would become the underlying premise for the condition to exist. Disturbances in attention are a prominent feature of schizophrenia. On the basis of reaction time experiments, schizophrenics tend to be affected or distracted by irrelevant aspects in the context of the stimulus (Weiner, 1985, p. 664). They may have some difficulty in maintaining a state of readinesss to make a response to a stimulus and in organizing their response in time, which is "an inability to maintain a major set" (Weiner, 1985, p. 664). The etiological theory most subscribed to is that schizophrenia is a physical disease due to a structural or functional defects in some organ system. Having observed that schizophrenics have low stress tolerance, the adrenocortical hormones were investigated, with abnormal levels found, only to later emerge as covariants of the patient's behavior and the degree of disruption of psychological functioning (Weiner, 1985, p. 669). A similar conclusion can be drawn about the findings that 30% of schizophrenics have an abnormal dexamethasone suppression test (Weiner, 1985, p. 669).

For a number of years now, the plausible hypothesis is that dopamine interactions can explain schizophrenia. This is based primarily upon reverse engineering, based upon the brain's reaction to antipsychotic drugs and projecting their impact upon dopamine levels; this is the model's underlying weakness; this model does not eliminate all of the extraneous variables such as other chemical reactions, genetics, environment,

A number of articles have been published concerning increased levels of enzymes in the blood of acutely psychotic patients, including creatine phosphokinase (CPK), aldolase, and platelet MAO-B (Akasaki, et al., 1993, pp. 843-846; Gosling, et al., 1972, pp. 351-355; Matthysse & Lipinski, 1975, pp. 551-565; Meltzer, 1973, pp. 589-593). What is interesting here is that CPK is derived from muscle, not from the brain. In acute psychosis, there are many kinds of anatomic changes in the subterminal motor nerve endings in skeletal muscle and in the muscle itself. In the vastus lateralis or gastrocnemius muscles of 57% of observed psychotic patients, myofibrillar changes occurred, including their degeneration (Weiner, 1985, p. 674). Another hypothesis is that pathogenesis of schizophrenia is the result of abnormal metabolism; these products are described as having psychomimetic properties (Weiner, 1985, p. 675). The underlying hypothesis is that metabolic disturbance is the result of methylated dopamine. Agents that increase or mobilize effective amounts of catecholamines in the brain increase psychotic symptoms; L-DOPA, the precursor to dopamine, norepinephrine and epinephrine may do so. But dopamine may not be the only culprit. Norepinephrine, widely distributed throughout the limbic, paramedian thalamic and hypothalamic structures of the brain, play a major role in many behaviors, including feeding, aggression, movement, memory and the sleep-wake cycle. As such, it may act as a neuromodulator rather than that of a neurotransmitter (Castro-Alamancos and Calcagnotto, 2001, pp. 1489-1497; Harik, 1984, pp. 699-707; Hu, et al., 2009, pp. 160-173). Tassin found that stimulation of cortical alpha-1 adrenergic receptors inhibits cortical dopamine transmission at D1 receptors (Tassin, 1992, pp. 135-162).

The psychological abnormalities and cognitive difficulties in schizophrenia precede and outlive the psychosis. The hypothesis of dopamine dysregulation is the best explanation for the psychotic episode in schizophrenia; the pathophysiology of other psychological and cognitive abnormalities in schizophrenia remains unclear. A combination of susceptibility genes (Brzustowica, et al., 2000, pp. 678-682) and other factors contributes to schizophrenia, and the net result dysregulates the dopamine neurotransmission system, leading to high release of dopamine, more D2 receptors, and an apparent predominance of monomer forms of D2 (Kapur & Mamo, 2003, pp. 1081-1090). This dopamine dysregulation leads to the psychotic episode.

Abnormal synchronization of neural activity between distal brain regions has been proposed to underlie schizophrenia. A study investigated whether abnormal synchronization occurs between the medial prefrontal cortex and the hippocampus , two brain regions implicated in schizophrenia, using the maternal immune activation model. It is induced through a single injection of the synthetic immune system activator polyriboinosinic-polyribocytidylic acid, a synthetic analog of double-stranded RNA, a molecular pattern associated with viral infection, in pregnant rats. It was based on epidemiological evidence of increased risk of schizophrenia in adulthood after prenatal exposure to infection (Dickerson, et al., 2010, p. 12424). EEG coherence and neuronal phase-locking to underlying EEG were measured. EEG coherence correlated with decreased prepulse inhibition of startle, a measure of sensory gating and a characteristic of schizoid behavior. Changes in the synchronization of neuronal firing to the underlying EEG were evident in the theta and low-gamma frequencies. Produced was a fundamental disruption in long-range neuronal synchrony in the brains of the adult offspring that models the disruption of synchrony observed in schizophrenia (Dickerson, et al., 2010, p. 12431).

In 2003 a study was performed of an initial subset of calcineurin-related genes. Transmission disequilibrium studies detected association with the PPP3CC gene, which encodes calcineurin γ catalytic subunit, located at 8p21.3 as a potential schizophrenia susceptible gene (Gerber, et al., 2003, p. 8997). In a follow-on study, confirmation of 1,140 cases supported the previous genetic association of altered calcineurin signaling with schizophrenia pathogenesis (Yamada, et al., 2006, p. 2819). This was reinforced by a similar study conducted in 2008 (Mathieu, et al., 2008, p. 1186). Another 2008 study posited that schizophrenia was a genetic disorder and has identified a specific gene as a precursor to schizophrenia (Takao, et al., 2008, p. 11).

Further research needs to uncover underlying mechanisms that predispose the brain to the dysregulation of the dopamine system (Bertolino, et al., 2000, pp. 125-132) and to further consider and eliminate outlying variables, plus developing a heuristic psychological/biochemical approach to schizophrenia (Howes & Kapur, 2009, p. 22; Kapur, 2003, pp. 13-23). Until then, the dopamine hypothesis remains a path to the origin and treatment of clinical signs and symptoms of psychosis in schizophrenia.

In conclusion, much of the preceding suggests the dopamine, acting singularly, may not cause schizoid symptoms. All extraneous variables must be identified and either systematically eliminated, or incorporated into a more global model to explain the biochemistry of schizophrenia.

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