Dopamine dysfunction

My answer always is that no one has yet done a detailed neurobehavioral study of these individuals and the deficit that they may have. It may be very subtle in nature, and 1 am not sure that we have the methods available to detect and quantify those deficits. The fact that these people are not walking in with overt behavioral disturbances as the people with MPTP did. 1 think, is related to the fact that, one, they may not have the kind of neurotoxicity we are suspecting, and two, if they do, the kind of functional consequences that you may get from serotonergic dysfunction may be much more subtle than the kind of functional consequences you get with dopamine dysfunction, where it is very easy to recognize the parkinsonian patient... 

Because the evidence for cortical dopamine dysfunction in schizophrenia is indirect, the data can be interpreted in different ways. For example, the increase in DLPFC I) receptors could be seen as a primary phenomenon, and the alteration in WM performance in these patients could result from increased postsynaptic response to DA released in the DLPFC during task performance (Watanabe et al., 1997). According to this alternate hypothesis, WM impairment observed in these patients results from excessive D, receptor transmission (Amsten et al., 1994 Murphy et al., 1996a, b Cai and Arnsten, 1997 ... 

Jentsch JD, Redmond DE Jr, Elsworth JD, Taylor JR, Youngren KD, et al. 1997. Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration of phencyclidine. Science 277 953-955. 

Costall B, Marsden CD, Naylor RJ, Pycock CJ (1976) The relationship between striatal and mesolimbic dopamine dysfunction and the nature of circling responses following 6-hydroxydopamine and electrolytic lesions of the ascending dopamine systems of rat brain. Brain Res 773 87-113. 

As described in the previous sections, neuropathological studies demonstrated alterations in the levels of several synaptic proteins in the PFC, hippocampus, and cerebellum of patients with schizophrenia (13, 15, 53). These observations have lead to the hypothesis that the clinical symptoms of schizophrenia are manifestations of abnormal neural circuitry and dysfunctional communication between different brain regions (22, 51). These abnormalities affect multiple neurotransmitter systems. Although dopamine dysfunction in schizophrenia is widely accepted, a growing body of evidence suggests the involvement of glutamate, GABA, and other neurotransmitters in schizophrenia. 

Dysfunction of cortical-subcortical dopamine systems is associated with an impaired inhibitory control after chronic drug administration. 

Bellomo R. Chapman M, Finfer S, Hickhng K, Myburth J Low-dose dopamine in patients with early renal dysfunction a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Chnical Trials Group. Lancet 2000 356 2139-2143. 

Nath A, Jones M, Maragos W, Booze R, Mactutus C, BeU J, Hauser KF, Mattson M (2000) Neurotoxicity and dysfunction of dopamine systems associated with AIDS dementia. Psychopharmacol 14 222-227... 

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. 

The D2 antagonist activity of current antipsychotics led to the "dopamine hypothesis," which states that the pathophysiology of schizophrenia is due to excessive dopaminergic neurotransmission and dysfunctional D2 signaling [6]. This hypothesis has prevailed for nearly 60 years however, it falls short as a complete explanation due to the deficiencies current antipsychotics exhibit against negative and cognitive symptoms. 

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. 

After more than a decade of use, bupropion (24) is considered a safe and effective antidepressant, suitable for use as first-line treatment. In addition, it is approved for smoking cessation and seasonal affective disorder. It is also prescribed off-label to treat the sexual dysfunction induced by SSRIs. Bupropion is often referred to as an atypical antidepressant and has much lower affinity for the monoamine transporters compared with other monoamine reuptake inhibitors. The mechanism of action of bupropion is still uncertain but may be related to inhibition of dopamine and norepinephrine reuptake transporters as a result of active metabolites [71,72]. In a recently reported clinical trial, bupropion extended release (XL) had a sexual tolerability profile significantly better than that of escitalopram with similar re-... 

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. 

Another widely practiced strategy to treat sexual dysfunction is the addition of pro-noradrenergic or pro-dopaminergic medications such as dopamine agonists or psychostimulants. The addition of bupropion is also believed to be effective but its mechanism of action remains obscure. 

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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