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.