Dopamine Receptor Blockade: Antipsychotic Drugs

Excessive neurotransmission of dopamine is associated with schizophrenia, a clinical condition

marked by seriously disordered thought. Antipsychotics, also called neuroleptics, are a class of
compounds with a high affinity for several subtypes of dopamine receptors. The chemical
structure of the various antipsychotics allows them to bind to dopamine receptors without
triggering the postsynaptic response that the binding of dopamine normally would. Because of
their ability to block dopamine receptors without causing the opening of ion channels and setting
off an action potential, neuroleptics can be administered to schizophrenic patients to help reduce
excess levels of dopamine, and to thus help alleviate the positive symptoms of the disorder.
There are approximately thirty antipsychotic drugs presently available in North America.
Developed in the 1950's, the "typical antipsychotic drugs" include the phenotiazines (e.g.
chloropromazine), the thioanthenes (e.g. chlorprothixene), the butyrophenones (e.g. haloperidol),
the diphenypbutylpiperidines (e.g. pimozide), and the dihydroindolones (e.g. molindone). These
drugs illustrate a high affinity for the D2 family of dopamine receptors and it is at these sites that
they are thought to exert their therapeutic action. Because D2 dopamine receptors are present not
only on the post-synaptic membrane, but on the cell bodies, dendrites and nerve terminals of
presynaptic cells as well, antipsychotic compounds can interfere with dopaminergic
neurotransmission at various sites in both the pre- and postsynaptic cell. Some neuroleptics
interfere with the release of DA at the presynaptic terminal, while others block postsynaptic
dopamine receptors so that postsynaptic cells cannot recognize dopamine.
Using typical antipsychotic drugs to interfere with dopaminergic neurotransmission in the limbic
system and in the cerebral cortex (areas involved in the control of motivated and emotional
behavior and in facilitating organized thought) can be helpful in alleviating the positive
symptoms of schizophrenia. The inhibition of dopamine transmission in other pathways,
however, can result in a wide range of highly undesirable side effects. Unfortunately, when
typical antipsychotics are administered, all D2 receptors are blocked, including those in areas of
the brain involved in the fine tuning of motor movement (namely, the basal ganglia and
cerebellum). As a result, when these drugs are administered to schizophrenic patients, many
experience the motor dysfunction characteristic of Parkinson's disease: tremors, akinesia (a
slowing of voluntary movements), spasticity and rigidity, and a kathesia (discomfort and a
feeling of restlessness in the legs). The use of typical antipsychotics may also interfere with
normal endocrine function, and can exert anticholinergic, antiadrenergic, antihistaminic and
antiserotonergic actions.
A second class of neuroleptics, known as "atypical antipsychotics," exert the same therapeutic
effects of the traditional antipsychotics without producing the undesirable side effects of the
older, typical antipsychotics. The atypical antipsychotics illustrate a lower affinity for D2
receptors, yet readily bind with D3 and D4 dopamine receptors. Since the expression of D3 and

D4 is restricted to the neurons of the limbic system and cerebral cortex only, the action of these
newer antipsychotics is confined to areas involved in the pathology of schizophrenia.