This chapter brings together the work of several leading laboratories, each an outstanding example of integrative approaches to complex diseases of the central nervous system. Cognitive dysfunction and negative symptoms associated with schizophrenia are believed to result from hypofunction of the mesocortical dopaminergic projections to prefrontal cortex (PFC). Noradrenergic targets for the augmentation of dopaminergic function in PFC show promise to improve cognitive deficits as well as negative symptoms. Serotonergic targets for the modulation of mesocortical dopaminergic neurotransmission include 5-HT2A and 5-HT1A receptors. The hallmark of Parkinson's disease is the destruction of nigrostriatal dopaminergic neurons. l-DOPA, a metabolic precursor of dopamine, is the standard of treatment. However, the ectopic release of dopamine (DA) from serotonin neurons and the clearance of extracellular DA by the norepinephrine transporter in areas enriched with noradrenergic terminals contribute to extracellular DA produced by l-DOPA and offer opportunities to improve l-DOPA therapy. The high-affinity transporters for monoamines are the primary targets for antidepressant drugs. However, many patients experience suboptimal therapeutic benefit or fail to respond to treatment. Organic cation transporters and plasma membrane monoamine transporter serve an important function in regulating monoamine neurotransmission and hold potential utility as targets for the development of therapeutic drugs. Improved therapeutic approaches will arise from not only understanding how monoamines influence one another within the central nervous system as an integrated whole but also addressing the pathophysiology of specific core symptoms or distinct syndromal dimensions (cognitive impairment, motor slowing, and negative affect) regardless of disease classification, for example, psychotic, affective, and neurodegenerative. © 2013 Elsevier Inc.

This research was supported by grants Instituto de Salud Carlos III PI10/00290 cofinanced by FEDER, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM, P91C) (to AB), and SAF 2012-35183 from the Ministerio de Economía y Competitividad (to FA). Structural funds of the Catalan Government (grant 2009SGR220) are also acknowledged. AB is supported by the Researcher Stabilization Program of the Health Department of the Generalitat de Catalunya. This work was supported by grants from “Centre National de la Recherche Scientifique,” the University of Bordeaux, the “Fondation de France,” the “Société française de Physiologie,” and the European community (COST action CM 1103) (PD). This work was supported in part from USPHS grants R01-MH064489 (LCD), R01-MH093320 (LCD & WK), and NARSAD (LCD).

Peer Reviewed