Dopamine hypothesis neuroleptics

Although the serotonin hypothesis of schizophrenia was formulated at approximately the same time as the discovery of the first neuroleptics, it had no direct connection with the pharmacological propraties of these drugs. The situation is different in the case of the dopamine hypothesis because all known neuroleptics have some inhibitory action on dopaminergic neurons, even though they vary considerably with regard to other pharmacological effects. 

Despite a number of necessary refinements in later years, the dopamine hypothesis in its simple original version ( neuroleptics act via blockade of postsynaptic dopamine receptors ) is still consistent with many pharmacological and clinical observations, such as ... 

Another hypothesis (Crow, 1982) involves a division of schizophrenias into two types Type I corresponds to acute schizophrenia or schizophreniform disorder in which one observes more positive symptoms of hallucinations and delusions with a good prognosis and excellent response to neuroleptics... Type II represents chronic schizophrenia with affective flattening, poverty of speech and loss of drive, the so-called negative symptoms of schizophrenia. Type II patients respond less well to neuroleptics... (Snyder, 1982). Type I patients would fit into the dopamine hypothesis whereas a pathophysiological basis other than dopaminergic hyperactivity must be assumed for type II patients. However, as pointed out by Snyder (1982). "one should be cautious about drawing such a distinction. ... 

It may be concluded that despite the importance of the dopamine hypothesis of schizophrenia in serving to unify the mechanism of action of both typical and atypical neuroleptics, it is apparent that some serotonin receptor subtypes, and glutamate receptors of the NMDA subtype, may also play a crucial role. 

In addition to acute and chronic schizophrenia, the neuroleptics are sometimes used in the management of mania, delirium, and severe agitation, whatever the cause of these symptom complexes. It must be noted that unlike parkinsonism, where a definite dysfunction in the DA system has been established, for schizophrenia and other psychiatric diseases, no unequivocal evidence has yet been presented to prove that there is a disturbance of the DA system (e.g., dopaminergic overactivity or receptor hypersensitivity). In untreated schizophrenics the production of DA metabolites is normal. Conflicting results have been obtained in studies of the DA receptors in schizophrenics (11,12,13), but in the case of patients who have not received neuroleptics, the receptor density and affinity appear to be normal (13). The "dopamine hypothesis" in these disorders derives from the beneficial effects of drugs that block DA receptors. 

The dopamine hypothesis in schizophrenia is supported by three findings (1) All effective neuroleptic drugs are D2-dopamine receptor antagonists (2) functional abnormalities of mental functions related to dopamine alteration are found in schizophrenic patients and (3) drugs that increase dopaminergic activity induce psychosis in normal individuals or exacerbate symptoms in schizophrenic patients. 

Drugs that are successful in treating the disease act as dopamine receptor blockers and are known as antipsychot-ics or neuroleptics (e.g. chlorpromazine, haloperidol). Antipsychotic drags reduce some of the symptoms, especially the delusions and hallucinations. A side-effect of the drugs is that they can result in symptoms similar to those seen in patients with Parkinson s disease. This is not surprising, since the hypothesis to explain Parkinson s disease is too low a concentration of dopamine in a specific area of the brain (see below). 

The first intracellular effect mediated by dopamine receptors that has been reported was the stimulation of the production of cyclic AMP (cAMP) in target cells. This effect was originally described in the superior cervical ganglia and the cow retina (Kebabian and Greengard, 1971 Brown and Makman, 1972) and soon afterward, in the CNS, in rat striatum (Kebabian et al., 1972). Antipsychotic drugs were found to block this response (Clement-Cormier et al., 1974 Miller et al., 1974) and this was the first direct evidence supporting the hypothesis proposed by A. Carlsson in the 1960s that the therapeutic actions of neuroleptics result from their ability to block dopamine receptors. 

The discovery that the first antipsychotic drugs in the early 1950s, such as chlorpromazine, work in vitro by blocking dopamine receptors led to the hypothesis that schizophrenia was the result of excessive dopaminergic neurotransmission (54, 55). Supporting this hypothesis, dmgs that enhance dopamine action (e.g., cocaine, amphetamines, and L-DOPA) worsen the symptoms of schizophrenia. However, it is clear that 1) not all patients respond to neuroleptic treatment and 2) not all symptoms are reversed by the medication. 

Although much evidence supports the DA hypothesis of schizophrenia, there have been some viable concerns regarding the theory, such as the clinical efficacy of clozapine as related by Burki at al., 51 the time dependent effect of neuroleptics on dopamine turnover in psychiatric patients 32 and the lack of correlation between results obtained with neuroleptic agents in the H-haloperidol and 3H-dopamine binding systems. 47 48 Also, the dopamine blockade hypothesis may explain the effectiveness of the neuroleptic drugs, however, there is little evidence to support DA overactivity in schizophrenia. 53... 

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