Dopamine antipsychotic action

Reserpine inhibits the synaptic vesicular storage of the monoamines dopamine, serotonin and noradrenaline. As a result they leak out into the cytoplasm where they are inactivated by monoamine oxidase this causes their long-lasting depletion. The resulting low levels of dopamine underlie the antipsychotic actions of reserpine (Chapter 11), whereas the reduced noradrenaline levels underlie its antihypertensive actions. Finally, the resulting low levels of serotonin and noradrenaline mean that reserpine also induces depression. These severe side effects mean that reserpine is no longer used clinically as a treatment for schizophrenia (Chapter 11). 

The antipsychotic effect is probably due to an antagonistic action at dopamine receptors. Aside from their main antipsychotic action, neuroleptics display additional actions owing to their antagonism at... 

At the time of the discovery of chlorpromazine. dopamine could not be assayed directly and its role as a neurotransmitter was unknown (Carlsson, 1987). Chlorpromazine exerts a large number of pharmacological effects, all of which could, in principle, be considered responsible for its clinical action. Thus, it was first assumed that the antipsychotic action of chlorpromazine and similar... 

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. 

Extension of this specificity principle to the clinical domain has resulted in the availability of increasingly well-aimed chemical bullets. If we wanted to block just one of the many serotonin receptors to see what would happen, we could probably do it But if we wanted to elevate mood in depression—or obsessive-compulsive disorder—would we expect the best result if we blocked just that one receptor And if we wanted to discourage auditory hallucinations in schizophrenia, would we want our drug to target only D2 dopamine receptors, even if we knew that the antipsychotic action of drugs correlated well with a drug s affinity for those receptors ... 

Serotonin 2A antagonism fortunately fails to reverse D2 antagonism in the mesolimbic system. If serotonin 2A antagonism reverses, at least in part, the effects of D2 antagonism in several dopamine pathways, then why does it not reverse the antipsychotic actions of D2 blockade in the mesolimbic dopamine pathway Evidently, the antagonism by serotonin of the effects of dopamine in this pathway is not robust enough to cause the reversal of D2 receptors by atypical antipsychotics or to mitigate the actions of atypical antipsychotics on positive symptoms of psychosis. 

In summary, for conventional antipsychotics dopamine blockade wins the tug-of-war in every dopamine pathway, resulting in antipsychotic actions for positive symptoms, but at a cost of worsened, or at least not improved, negative symptoms, production of EPS, tardive dyskinesia, and hyperprolactinemia. On the other hand, it appears that atypical antipsychotics let you have your cake and eat it too, that is, dopamine blockade wins the all important tug of war over dopamine release where it must win to treat disruptive positive symptoms, namely, in the mesolimbic dopamine... 

On the dopamine side of the equation, one of the most promising agents in late clinical development is aripiprazole, theoretically a presynaptic D2 autoreceptor agonist. This compound is postulated to exert its antipsychotic actions in a manner far different from serotonin-dopamine antagonism that is, it may shut off the presynaptic dopamine terminal and stop dopamine release in the mesolimbic dopamine pathway by stimulating presynaptic D2 receptors. The agents Cl-1007 and DAB-... 

Cannabinoid antagonists. Cannabinoid receptors are discussed in further detail in Chapter 13 on drug abuse. An antagonist to cannabinoid 1 (CB1) receptors, SR141716A, reduces the activity of mesolimbic dopamine neurons in animal models, suggesting possible antipsychotic actions in schizophrenia and leading to testing in schizophrenic patients. 

Amoxapine is a metabolite of the antipsychotic drug loxapine and retains some of its antipsychotic action and dopamine receptor antagonism. A combination of antidepressant and antipsychotic actions might make it a suitable drug for depression in psychotic patients. However, the dopamine antagonism may cause akathisia, parkinsonism, amenorrhea-galactorrhea syndrome, and perhaps tardive dyskinesia. 

The notion of a neurochemical balance is also introduced in some of these early accounts. Matthysse (1973) suggests that It may be that a system inhibited by, or inhibiting dopamine neurons is deficient in schizophrenia, and the dopamine blocking actions of antipsychotic drugs restores a balance (p. 204, italics added). 

The antipsychotic actions of neuroleptic drugs reflect blockade at dopamine and/or serotonin receptors. However, many of these agents also block cholinergic, adrenergic, and histamine receptors, causing a variety of side effects (Figure 13.3). 

In the in-vitro kinetic experiments, the rates of association (Kon) and dissociation (Kan) of various (labeled) antipsychotic compounds to dopamine D2 receptors were determined. Kapur and Seeman found that antipsychotics substantially differ (almost 1000-fold) in their Koff rate (whereas only 10-fold differences were found in the Kon rate), and that this value is highly correlated with their affinity to D2 receptors. These authors also demonstrated that Koff for clozapine, olanzapine and quetiapine was 1.386 min"1, 0.039 min"1, and 3.013 min"1, respectively, and assumed that the rate of how rapidly they left the receptor was an important mechanism in their atypical antipsychotic action. Indeed, this fully explained the lack of extrapyramidal symptoms (EPS) and hyperprolactinemia and the low risk for tardive dyskinesia [34—36]. In this regard, quetiapine (which has the lowest affinity to D2 receptors) seems to be the most atypical among all tested antipsychotics, followed by clozapine and olanzapine (nevertheless, olanzapine s Koff value is close to those of raclopride and chlorpromazine). 

The example of amisulpride (launched by Sanofi-Synthelabo in 1986) also supports the primary importance of dopamine D2 (as well as D3) but not 5-HT2A receptors in atypical antipsychotic action. This benzamide derivative displays high affinity only to D2 and D3 receptors (with some selectivity toward D3) [42], and in low doses (i.e., 50-100 mg day-1) it acts preferentially on negative [43] symptoms and at higher doses (400-800 mg day-1) on depressive symptoms [44] and cognitive impairment [45]. 

Has atypical antipsychotic properties (i.e., antipsychotic action without a high incidence of extrapyramidal symptoms), especially at low doses, but not a serotonin dopamine antagonist... 

Theoretically reduces dopamine output when dopamine concentrations are high, thus improving positive symptoms and mediating antipsychotic actions... 

The recent availability of aripiprazole, a partial agonist at D2 receptors, represents a further elaboration of the dopamine hypothesis of antipsychotic action. Based on extensive preclinical studies, it is proposed that aripiprazole works as a functional partial agonist in the hypodopaminergic state, and as a functional but weak dopamine antagonist in the hyperdopaminergic state. Aripiprazole is a rather... 

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. 

PET scans of the brain of untreated schizophrenics have revealed small increases in dopamine receptors. Dopamine receptor blockers should be avoided in parkinsonism. While most conventional antipsychotic drugs block receptors, this action is not an absolute requirement for antipsychotic action, since clozapine and newer drugs have a very low affinity for such receptors. The clinical potency of antipsychotic drugs does not correlate well with their beta adrenoceptorblocking actions. The effects of phencyclidine (PCP) closely parallel an acute schizophrenic episode, but PCP has no actions on brain dopamine receptors. The answer is (D). 

Some antipsychotics have dopamine antagonist actions, which wouid be expected to inhibit the efficacy of dopamine agonists such as bromocriptine. Carefui monitoring is required if combined use is considered necessary. 

---