Dopamine Receptors and the Treatment of Schizophrenia

Abstract

Schizophrenia is a most disabling psychiatric disorder characterized by a myriad of symptoms. While the delusions and hallucinations are the most iconic symptoms of schizophrenia, patients also exhibit negative and cognitive symptoms. It is thought that these symptoms arise, at least in part, through a cortical subcortical imbalance of dopamine function and pharmacological approaches that reduce dopaminergic neurotransmission through dopamine receptor blockade, and in particular through the D-2 receptor, have antipsychotic action in humans. However, D-2 antagonists are not optimally effective against the full spectrum of schizophrenia symptoms and induce side effects that limit their use. Research to enhance the therapeutic benefits of antipsychotics while diminishing their side effects has led to the development of atypical antipsychotics (D-2 antagonists with activity at other receptors) and, more recently, a new strategy using dopamine partial agonists to reduce dopaminergic neurotransmission has proven to be successful. This chapter reviews the pharmacological effects of typical and atypical antipsychotics on the different dopamine receptor subtypes, as well as on non-dopaminergic receptor targets, and on the prominent role of D-2 receptor blockade as the primary site of their action in brain. In addition, we discuss current theories on the mechanisms of antipsychotic action, including the role of combined action at the dopamine and serotonin receptors, transient dopamine D-2 blockade, preferential blockade of limbic D-2 receptors, or combined blockade of D-1 and D-2 receptors. Some critical clinical considerations with regard to the speed of onset action and the occurrence of relapse and supersensitivity psychosis on withdrawal are discussed with special relevance to their relationship to the dopamine system. While the D-2 receptor-based treatments seem to have dominated the field till now, drugs that reduce dopamine-mediated transmission through action at presynaptic sites and of drugs providing D-1 signaling augmentation in prefrontal cortex may provide novel therapeutic avenues for the treatment of schizophrenia.