Dopamine blockade

Yokel, R.A., and Wise, R.A. Attenuation of intravenous amphetamine reinforcement by central dopamine blockade in rats. Psychopharmacology 48 311-318, 1976. 

The answer is d. (Hardman, p 414.) Antipsychotic agents, particularly prochlorperazine, are also useful as anti emetic agents, thought to be due to dopamine blockade at the stomach and at the chemoreceptor trigger zone of the medulla. 

Metoclopramide may be considered as a prototype 5-HT3 antagonist because its antiemetic efficacy both in animals and man could not be adequately explained by D2-dopamine blockade. In fact, metoclopramide was considerably weaker as a D2-antagonist than haloperidol or domperidone and yet it was effective against emesis induced by anticancer agents both in animals [43, 80] and cancer patients [135]. 

The second theory is that some atypicals work by balancing dopamine blockade with serotonin receptor blockade. We know that one of the roles of serotonin is to attenuate (or lessen) dopamine activity. Blocking serotonin action therefore may release just enough dopamine activity in the nigrostriatal pathway to avoid EPS without interfering with the antipsychotic effects in the mesolimbic area. 

Nevertheless, some dopamine-blockade side effects can still be found with the atypicals. Prolactin elevation still occurs, particularly with risperidone. The risk of... 

Neuroleptic malignant syndrome is a rare condition which can occur even after the single administration of antipsychotics. It manifests itself with hyperpyrexia, muscle rigidity, autonomic symptoms, clouding of consciousness and it has a mortality rate of over 10%. The aetiology is unknown but dopamine blockade may play a role. 

Wolkin, Adam, Faouzia Barouche, Alfred P. Wolf, John Rotrosen, Joanna S. Fowler, Chyng-Yann Shiue, et al. Dopamine Blockade and Clinical Response Evidence for Two Biological Subgroups of Schizophrenia. American Journal of Psychiatry 146 (1989) 905-908. The researchers discovered evidence for two different types of schizophrenia. 

These similarities are quite striking and support the theory that they work through a common mechanism of action (e.g., dopamine blockade). Furthermore, relevant differences are primarily related to their side effect profiles. 

The first generation antipsychotics, now known as typical drugs, were all D2 receptor blockers and, as such, very likely to produce Parkinsonian side effects. Because antipsychotic potency was associated with D2 receptor affinity, it was assumed that dopamine overactivity was the essential defect in schizophrenia and that a direct dopamine blockade was the definitive route to treatment. But these drugs affected both the target dopamine pathways of the mesolimbic projection and the uninvolved nigrostriatal projection. Unfortunately, that meant that movement disorders were the price that had to be paid for antipsychosis. 

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... 

Parkinsonism, dystonias, akathisia Dopamine blockade of basal ganglia All potent typical neuroleptics... 

It is also clear in retrospect that the reserpine-induced state was a state of dopamine blockade, characterised by sedation and inactivity, rather than a valid model of depression (Mendels Frazer 1974). Whether it commonly caused a true depressive state in humans has also been disputed. One review suggested that it did so in 6% of cases, but mostly in people who had a previous history of depression (Goodwin Bunney, Jr. 1971). The only controlled study of reserpine on mood found no true cases of depression, but several patients were noted to show signs of excessive tranquillisation or pseudodepression (Bernstein Kaufman 1960). 

Kendler KS, Weitzman RE, Rubin RT (1978) Lack of arginine vasopressin response to central dopamine blockade in normal adults. J Cline Endocrinol Metab 47 204-207. 

Steele TE. Adverse reactions suggesting amoxapine-induced dopamine blockade. Am J Psychiatry 1982 139(11) 1500—1. 

A new, so-called third generation of antipsychotics has recently been introduced, and at this time one drug, aripiprazole, is available and others are in the late stages of development. This new class of medications has a novel mechanism of action that, at least in theory, should deal with several of the limitations of other atypicals. It will be remembered that all antipsychotics preceding this class had the ability to block the dopamine receptor, and they did so in all four dopamine pathways. As discussed, this had both benefits and drawbacks dopamine blockade resulted in the improvement of positive symptoms (mesolimbic pathway) but had a limited benefit in negative symptom reduction (mesocortical... 

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 neuroleptics produce extrapyramidal side effects due to the blocking of dopamine receptors. In addition to producing a reduction in positive psychotic symptoms by blocking dopamine in the mesolimbic region, they unfortunately produce extrapyramidal symptoms by dopamine blockade in the basal ganglia. There are three types of acute extrapyramidal symptoms Parkinsonian side effects are those that resemble Parkinson s disease, with slowed movements, decreased facial expres-... 

EXTRAPYRAMIDAL EFFECTS (dopamine blockade in basal ganglia)... 

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... 

Dopamine blockade via neuroleptics or destruction of dopaminergic cells in Parkinsons disease... 

Postsynaptic dopamine blockade produces antipsychotic symptoms... 

Prochlorperazine may antagonize the therapeutic effect of bromocriptine on prolactin secretion it also may decrease the vasoconstricting effects of high-dose dopamine and may decrease effectiveness and increase toxicity of levodopa (by dopamine blockade). Prochlorperazine may inhibit metabolism and increase toxicity of phenytoin. 

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