Schizophrenia, dopamine

While the obvious value of in vivo animal models is clear, there also are instances—especially in cases of inflammatory arthritis, behavior, and tumor growth—where they have failed to be predictive of useful clinical activity in humans [51], For example, leukotriene (LTB4) antagonists showed activity in animal models of inflammatory arthritis yet failed to be useful in rheumatoid arthritis [52]. Similarly, dopamine D4 antagonists showed activity in animal behavior models previously predictive of dopamine D2 antagonists in schizophrenia. However, testing of dopamine D4 antagonists showed no efficacy in humans [53]. 

Neuroleptics or antipsychotics suppress the positive symptoms of schizophrenia such as combativeness, hallucinations and formal thought disorder. Some also alleviate the negative symptoms such as affective blunting, withdrawal and seclusiveness. Neuroleptics also produce a state of apathy and emotional indifference. Most neuroleptics block dopamine D2-receptors but some, like clozapine, also block dopamine D4-receptors or serotonin 5-hydroxytryptamine2A-receptors. 

Disulfiram produces a variety of adverse effects, which commonly include drowsiness, lethargy, and fatigue (Chick 1999). Other more serious adverse effects, such as optic neuritis, peripheral neuropathy, and hepatotoxicity, are rare. Psychiatric effects of disulfiram are also uncommon. They probably occur only at higher dosages of the drug and may result from the inhibition by disulfiram of a variety of enzymes in addition to ALDH. Included among the enzymes inhibited by disulfiram is dopamine P-hydroxylase, inhibition of which increases dopamine levels, which in turn can exacerbate psychotic symptoms in patients with schizophrenia and occasionally may result in psychotic or depressive symptoms in patients without schizophrenia. 

The localisation of a particular peptide to a particular brain area and possibly associated with a particular transmitter (e.g. CCK with dopamine in mesolimbic pathways) has often prompted a prediction of function (e.g. CCK may have a role in schizophrenia). Animal studies in which the peptide has been injected into the appropriate brain area or tested on slices taken from the brain area have sometimes been taken to confirm such hypotheses. These approaches have lined up the peptides for a whole range of potential roles, some of which are listed in Table 12.4. Whether these predictions are realities will depend on the availability of chemical agents and their evaluation, not only in animals but also in humans. 

Bristow, LJ, Kramer, MS, Kulagowski, J, Patel, S, Ragan, Cl and Seabrook, GR (1997) Schizophrenia and L745,870, a novel dopamine D4 receptor antagonist. Trends Pharmacol. Sci. 18 186-188. 

Knoble, MB and Weinberger, DR (1997) Dopamine, the prefrontal cortex and schizophrenia. J. 

Pilowsky, LS, Costa, DC and Eli, PJ (1992) Clozapine single photon emission tomography and the D2 dopamine receptor blockade hypothesis of schizophrenia. Lancet 340 199-202. 

Now the use of molecular psychiatry of ascorbic acid in schizophrenia by Linus Pauling and others, where there seems to be some relationship to dopamine neurons, and finding that dopamine-dopaminergie neurons or receptors are present in twice the normal amount, makes this an intriguing... 

A number of azetidine-based compounds have been disclosed in patent applications from Aventis Pharma for CBi-modulated treatment of diseases such as obesity, Parkinson s disease, schizophrenia, respiratory and neurological diseases [330-334]. Compound (556) was specifically claimed for use in two formulation patent applications [330, 331] for a stable semi-solid composition and oral emulsion composition, respectively. The optional coadministration of an agent that activates norepinephrinergic and se-rotoninergic neurotransmission (for example, sibutramine) or dopaminergic neurotransmission was also claimed for the treatment of obesity. The optional use of a dopamine agonist (for example, levodopa) was claimed... 

Aripiprazole was formulated in the early 1980s to function as a potential dopamine modulator, with both antagonist and agonist activity at the D2 receptor. It is the first D2 partial agonist available for the treatment of schizophrenia and is sometimes referred to as a third-generation antipsychotic. This novel mechanism is... 

Xing, Q. el al. (2006a). The relationship between the therapeutic response to risperidone and the dopamine D2 receptor polymorphism in Chinese schizophrenia patients. Int. J. Neuropsy-chopharmacol., 10, 631-7. 

Kaiser, R., Konneker, M., Henneken, M. et al. (2000). Dopamine D4 receptor 48-bp repeat polymorphism no association with response to antipsychotic treatment, but association with catatonic schizophrenia. Mol. Psychiatry, 5, 418-24. 

Malhotra, A. K., Goldman, D., Buchanan, R.W. et al. (1998). The dopamine D-3 receptor (DRD3) Ser-9Gly polymorphism and schizophrenia a haplotype relative risk study and association with clozapine response. Mol. Psychiatry, 3, 72-5. 

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