Drugs, dopamine antagonists/antipsychotic

The number of D, and D2 receptors can be modulated by antagonists 222 Dopamine D2-like receptors appear to mediate the actions of antipsychotic drugs 222... 

However, experimental studies of the 5-HT3 antagonists on dopamine autoreceptors may eventually offer new leads to the development of novel antipsychotic drugs. 

It also seems plausible that antipsychotic drugs competitively bind with dopamine receptors and block the action of dopamine on corresponding receptor sites, thus lowering psychotic activity. Central dopamine receptors are subdivided into Dj, D2, and according to some sources, Dj receptors. These receptors have a high affinity for dopamine, but they differ in sensitivity to neuroleptics of various chemical classes. For example, drugs of the phenothiazine series are nonselective competitive Dj and D2 antagonists. Unlike phenoth-iazines, antipsychotics of the butyrophenone series such as haloperidol display selective action only on D2 receptors. 

D2 receptor, albeit with different specificity. Older examples of dopamine antagonists are chlorpromazine, haloperidol and many derivatives of these prototype compounds. Newer antipsychotic drugs such as risperidone, olanzapine and quetiapine have retained this mechanism of action, although no longer exclusively. 

The large majority of antipsychotic drugs act mainly as dopamine receptor antagonists reducing the excess responsiveness to that neurotransmitter present in psychoses. It was found a decade ago that antagonists of serotonin H2 showed promising antipsychotic activity in several model systems. These dmgs would be better tolerated than their predecessor since they should be devoid of side effects... 

Antipsychotics also have been used in the treatment of anorexia nervosa. The apparent role of dopamine in feeding and satiety involves increased receptor activity, producing symptoms similar to those found in anorexia nervosa. Thus, it seems reasonable to use dopamine antagonists to alter these behaviors. It also seems appropriate to use the sedative side effects of these drugs to decrease anxiety associated with eating. 

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. 

Consistent with the role of both serotonin and dopamine in OCD, some OCD patients benefit from treatment with the new serotonin-dopamine antagonists (also known as atypical antipsychotics), especially when there is inadequate response to an SSRI. On the other hand, other patients have no therapeutic response to these new agents, and the condition of still others is even worsened by these drugs. The atypical antipsychotics and serotonin dopamine antagonism are discussed in Chapter 11. 

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. 

FIGURE 11-23. Here postsynaptic dopamine 2 receptors are being blocked by a serotonin-dopamine antagonist (SDA) atypical antipsychotic in the nigrostriatal dopamine pathway. This shows what would happen if only the dopamine 2 blocking action of an atypical antipsychotic were active— namely, the drug would only bind to postsynaptic D2 receptors and block them. However, see Figure 11-24. 

FIGURE 11—32. Conventional antipsychotic drugs are D2 antagonists and thus oppose dopamine s inhibitory role on prolactin secretion from pituitary lactotrophs. Therefore, drugs that block D2 receptors increase prolactin levels (red circle). 

Which of the following serotonin dopamine antagonists (SDAs) is not considered to be a first line atypical antipsychotic drug ... 

FIGURE 8-1 Effects of antipsychotic drugs on dopamine synapses. Antipsychotics act as postsynaptic receptor antagonists to block the effects of overactive dopamine transmission. 

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