Antipsychotic drugs dopamine hypothesis

However, the dopamine hypothesis does not account for some important observations. If an abnormality of dopamine physiology were solely responsible for the pathogenesis of schizophrenia, antipsychotic drugs would do a much better job in treating patients. As it is, they are only partially effective for most and ineffective for some patients. Moreover, there is evidence that diminished glutamatergic activity also plays a role in... 

After dopamine was identified as a neurotransmitter in 1959, it was shown that its effects on electrical activity in central synapses and on production of the second messenger cAMP by adenylyl cyclase could be blocked by antipsychotic drugs such as chlorpromazine, haloperidol, and thiothixene. This evidence led to the conclusion in the early 1960s that these drugs should be considered dopamine-receptor antagonists and was responsible for the dopamine hypothesis of schizophrenia described earlier in this chapter. The antipsychotic action is now thought to be produced (at least in part) by their ability to block dopamine in the mesolimbic and mesocortical systems. 

These findings have been incorporated into the dopamine hypothesis of schizophrenia. However, additional factors complicate interpretation of dopamine receptor data. For example, dopamine receptors exist in both high- and low-affinity forms, and it is not known whether schizophrenia or the antipsychotic drugs alter the proportions of receptors in these two forms. The fact that aripiprazole shows partial agonism at D2 and 5-HT1A receptors in preclinical studies suggests that the proportions of several receptors in their various affinity states may prove clinically important. 

Serotonin-dopamine hypothesis. On the basis of the studies of both 5HT and DA in OCD, it seems possible that at least in some forms of OCD (e.g., OCD with a history of Tourette syndrome), both 5HT and DA transmitter systems may be involved in the pathophysiology of symptoms. It is not clear whether the primary abnormality is in 5HT function, DA function, or serotonin-dopaminergic balance. This hypothesis is supported by many preclinical data, which suggest that important anatomic and functional interactions exist between serotonergic and dopaminergic neurons. This will be discussed in detail in Chapter 11 in the sections on antipsychotic drugs that work simultaneously on DA and 5HT receptors. 

FIGURE 11 — 2. The dopamine receptor antagonist hypothesis of antipsychotic drug action for positive symptoms of psychosis in the mesolimbic dopamine pathway is shown here. Blockade of postsynaptic dopamine 2 receptors by a dopamine 2 antagonist acting in the mesolimbic dopamine pathway is hypothesized to mediate the antipsychotic efficacy of the antipsychotic drugs and their ability to diminish or block positive symptoms. 

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. 

It was later found that some effects of dopamine did not involve stimulation of adenylyl cyclase. Particularly, in the pituitary gland, dopamine was found to inhibit prolactin release without stimulating adenylyl cyclase activity and even by inhibiting it (Spano et al., 1978 De Camilli et al., 1979). Moreover, the antipsychotic drug sulpiride blocked the dopamine-induced release of prolactin in the pituitary gland but was unable to antagonize the dopamine response on adenylyl cyclase activity in the striatum (Trabucchi et al., 1975). These observations led to the hypothesis that the dopamine receptors exist as two... 

The dopamine hypothesis postnlates that there is an increased dopamine drive in the mesolimbic system, leading to the causation of positive symptoms and a decreased dopamine drive in the mesocortical system, leading to the cansation of negative symptoms. Antipsychotic drugs tar-... 

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. 

Keywords Major depressive disorder Biopolar disorder Schizophrenia Mood disorders Biogenic amine hypothesis Learned helplessness Antidepressant drugs Mood stabilizers Dopamine hypothesis Antipsychotic drugs... 

When these drugs were first used in clinical settings, the mechanism of action was unknown, although the medications were clearly quite successful in reducing psychotic symptoms. Later research determined that antipsychotic medications acted by producing a chemical blockade of dopamine D2 postsynaptic receptors and that their clinical potency correlated with their degree of dopamine blockade. This led to the dopamine hypothesis of schizophrenia (see chapter 9). 

The dopamine hypothesis is the most accepted explanation of the action of antipsychotic medications. Two core elements of the dopamine hypothesis are psychoses are induced by increased levels of dopaminergic activity, and most antipsychotic drugs block postsynaptic dopamine receptors. 

In 1967 after 6 years of studies, trials of L-dopa in patients with Parkinson s disease showed dramatic improvements in aU motor deficits. The hypothesis that dopamine is involved in the pathogenesis of psychosis, in particular schizophrenia, rests on the finding that most antipsychotic drugs are dopamine-receptor antagonists and that agents which cause excessive release of dopamine mimic schizophrenia-like states. In 1979, John Kebabian and Donald Caine (NIH, Bethesda, USA) found that dopamine exerts its effects by binding to two subtypes of receptors. 

Since the discovery of the role of dopamine (DA) as a neurotransmitter in 1958, and the observations that antipsychotic drugs arepostsynaptic DA-receptor antagonists, interest in a dopaminergic hypothesis for the pathophysiology of schizophrenia has existed. However, these theories may be more appropriately oriented toward the treatment of psychosis with antipsychotics. 

The dopamine hypothesis of schizophrenia posits that such symptoms arise because of a functional excess of dopaminergic activity in the CNS. The notion is based on the facts that drugs that activate DA receptors may cause psychotic symptoms and those that block DA receptors often have antipsychotic actions. However, drugs used for schizophrenia do not remedy all symptoms they are not curative, and some newer agents appear to be effective in many patients, even though they do NOT act as antagonists at brain DA receptors but may modify serotonin functions. 

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