Schizophrenia has been associated with a dysfunction of brain dopamine (DA). This, so called, DA hypothesis has been refined as new insights into the pathophysiology of schizophrenia have emerged. Currently, dysfunction of prefrontocortical glutamatergic and GABAergic projections and dysfunction of serotonin (5-HT) systems are also thought to play a role in the pathophysiology of schizophrenia. Refinements of the DA hypothesis have lead to the emergence of new pharmacological targets for antipsychotic drug development. It was shown that effective antipsychotic drugs with a low liability for inducing extra-pyramidal side-effects have affinities for a range of neurotransmitter receptors in addition to DA receptors, suggesting that a combination of neurotransmitter receptor affinities may be favorable for treatment outcome.This review focuses on the interaction between DA and 5-HT, as most antipsychotics display affinity for 5-HT receptors. We will discuss DA/5-HT interactions at the level of receptors and G protein-coupled potassium channels and consequences for induction of depolarization blockade with specific attention to DA neurons in the ventral tegmental area (VTA) and the substantia nigra zona compacta (SN), neurons implicated in treatment efficacy and the side-effects of schizophrenia, respectively. Moreover, it has been reported that electrophysiological interactions between DA and 5-HT show subtle, but important, differences between the SN and the VTA which could explain (in part) the effectiveness and lower propensity to induce side-effects of the newer atypical antipsychotic drugs. In that respect the functional implications of DA/5-HT interactions for schizophrenia will be discussed.Key Words: Schizophrenia, antipsychotic drug, substantia nigra, ventral tegmental area. DOPAMINE AND SCHIZOPHRENIAThe mesocortical pathway, the mesolimbic pathway, the nigrostriatal pathway and the tuberoinfundibular pathway have all been postulated to be involved in the pathophysiology of schizophrenia and the propensity of antipsychotic drugs to induce side-effects [144]. Hypofunction of the mesocortical pathway and hyperfunction of the mesolimbic pathway [44,55,144] are thought to be responsible for the symptoms that can be observed (see also Sesack and Carr, 2002 [138])) and points to one of the many difficulties for effective treatment: increasing dopamine (DA) activity in the mesocortical pathway, while concomitantly decreasing DA activity in the mesolimbic pathway. The nigrostriatal and tuberoinfundibular pathways are involved in side-effects of antipsychotic drug treatment, such as extra-pyramidal side effects and hyperprolactinemia, respectively [10, 30] which are related to changes in firing activity of neurons in these pathways, especially the DA neurons. What lies at the root of this mesocortical mesolimbic dysfunction is unclear but loss of cholinergic interneurons in the striatum, hypoglutamatergia or "miswiring" of glutamatergic and _-amino butyric acid (GABA)-ergic projections from the prefrontal...

The classification of dopamine receptors proposed more than two decades ago remains valid today. Based on biochemical and pharmaceutical properties two main classes of dopamine receptors can be distinguished: D(1)-like (D(1), D(5)) and D(2)-like (D(2), D(3), and D(4)) dopamine receptors. Dopamine receptors belong to the class of G protein-coupled receptors and signal to a wide range of membrane bound and intracellular effectors such as ion channels, secondary messenger systems and enzymes. Although the pharmacological properties of ligands for D(1)-like and D(2)-like dopamine receptors are quite different, the number of selective ligands for each of the five receptors subtypes is rather small. Many drugs used to treat neurological and neuropsychiatric disorders like Parkinson's disease, restless leg syndrome and schizophrenia have affinities for dopamine receptors. Such medications are not without limitations so the development of novel (selective or aselective) dopamine receptor ligands is of the utmost importance for improved therapeutic approaches for these diseases. In that respect it is also important to understand how dopamine receptor ligands affect receptor signalling processes such as desensitization, receptor heterodimerization and agonist-receptor trafficking, issues which will be discussed in the present review. Furthermore, attention is paid to interactions of dopamine receptors with serotonin receptors since many drugs used to treat above mentioned disorders of the brain also possess affinities for serotonin receptors. Because of the enormity of this area we have tried to focus more specifically on interactions within the prefrontal cortex where it appears that the serotonergic modulation of dopaminergic function might be very relevant to schizophrenia.