Antipsychotic drugs dopamine receptor blockade

Most older typical antipsychotic drugs, with the exception of thioridazine, have a strong antiemetic effect. This action is due to dopamine-receptor blockade, both centrally (in the chemoreceptor trigger zone of the medulla) and peripherally (on receptors in the stomach). Some drugs, such as prochlorperazine and benzquinamide, are promoted solely as antiemetics. 

Consequently, antipsychotic drugs all share a basic mechanism of action that involves dopamine receptor blockade. It is apparent, however, that they are not all equal in their ability to affect specific sub-types of dopamine receptors, and that their effectiveness and side effects are related to their affinity and preference for certain receptors. As indicated earlier, other neurotransmitters may also be involved in the pathogenesis of psychosis, and differences in specific antipsychotic medications may be related to their ability to directly or indirectly affect these other transmitters as well as block dopamine influence. Future studies will continue to clarify how current antipsychotics exert their beneficial effects and how new agents can be developed to be more selective in their effects on dopamine and other neurotransmitter pathways. 

The predominant mechanism by which currently available antipsychotic medications interfere with dopamine activity is by blockade of dopamine receptors on neurons innervated by dopamine nerve terminals. Of the five types of dopamine receptors, all antipsychotics share in common the fact that they block the dopamine type 2 receptor, also known as the D2 receptor, to a varying degree. Some of the atypical antipsychotics also block other dopamine receptors (see Table 13.5). The role of blockade of Dl, D3, D4, and other dopamine receptors in the therapentic effects of antipsychotic drugs remains unclear. Aripiprazole is an exception to this in that it is a partial agonist at the D2 receptor. 

Of the drugs used for treating parkinsonism, the anticholinergics are the only class that can provide benefit in the treatment of the drug-induced parkinsonism seen with antipsychotic therapy. This is because the blockade of dopamine receptors by the antipsychotics leads to increased activity of the striatal neurons. Blockade of the muscarinic receptors reduces this excitatory activity. 

The blockade of dopamine receptors by antipsychotic drugs is an immediate effect that can be detected even after a single dose, whereas the therapeutic action of these drugs becomes apparent only after several days or weeks of treatment. 

FIGURE 10—11. Several different causes of dopamine deficiency may result in negative and cognitive symptoms. In schizophrenia itself, there may be a primary dopamine (DA) deficiency or a DA deficiency secondary to blockade of postsynaptic D2 dopamine receptor by an antipsychotic drug. If serotonin is hyperactive, this may also cause a relative DA deficiency by inhibiting DA release. Either primary or secondary DA deficiency in this pathway may cause cognitive blunting, social isolation, indifference, apathy, and anhedonia. 

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—7. This figure represents an icon of a conventional antipsychotic drug. Such drugs generally have at least four actions blockade of dopamine 2 receptors (D2) blockade of muscarinic-cholinergic receptors (Ml) blockade of alpha 1 adrenergic receptors (alpha 1) and blockade of histamine receptors (antihistaminic actions [HI ). 

The ratio between the blockade of serotonin receptors and dopamine receptors differs for various classes of antipsychotic drugs. True or False. 

Antipsychotic drugs used to successfully treat schizophrenia block central dopamine receptors to some extent (Fig. 8-1).19,23 These drugs share some structural similarity to dopamine, which allows them to bind to the postsynaptic receptor, but they do not activate it. This action effectively blocks the receptor from the effects of the released endogenous neurotransmitter (see Fig. 8-1). Any increased activity at central dopamine synapses is therefore negated by a postsynaptic receptor blockade. 

While there is extensive experimental evidence showing that all clinically effective neuroleptic drugs block dopamine receptors, and a general agreement that blockade of the D2 receptors in the mesocortical regions is particularly important for antipsychotic activity, only with the advent of... 

---