Chapter 6.1 The role of microdialysis in drug discovery: focus on antipsychotic agents

Abstract Since its inception some two decades ago, microdialysis has rapidly assumed a crucial role as an interface between cellular models of drug actions in vitro and studies of their behavioural effects in vivo. Microdialysis provides invaluable information regarding the mechanisms of action of psychotropic agents and their influence upon endogenous modulators implicated in the aetiology and treatment of CNS disorders. In addition, measures of extracellular levels of specific neurotransmitters are complementary to behavioural parameters in the characterisation of experimental models of psychiatric and neurological diseases. Further, microdialysis can be used for quantification of levels of psychotropic agents themselves in specific brain regions. Though microdialysis techniques are increasingly being applied to a broad variety of cellular mediators, most studies have to date focussed on monoamines, acetylcholine and amino acids like glycine, glutamate and GABA; that is, neurotransmitters strongly implicated in the pathogenesis and control of depression, anxiety, schizophrenia and other psychiatric states. Recent years have seen substantial improvements in the sensitivity of systems for their detection, which now permit, for example, the simultaneous quantification of dopamine (DA), serotonin (5-HT) and noradrenaline (NA) levels in single dialysis samples; quantification of acetylcholine (ACh) levels in the absence of acetylcholinesterase inhibitors; and determination of glutamate and GABA levels concurrently with glycine and a miscellany of related amino acids. The present chapter provides an overview of how microdialysis can be applied to the discovery and evaluation of centrally active drugs. Furthermore, it specifically focuses on the application of novel microdialysis techniques to the characterisation of antipsychotic agents for the improved treatment of schizophrenia.