Abstract
Inhibitors of Na+/Cl- dependent high affinity transporters for norepinephrine (NE), serotonin (5-HT), and/or dopamine (DA) represent frequently used drugs for treatment of psychological disorders such as depression, anxiety, obsessive-compulsive disorder, attention deficit hyperactivity disorder, and addiction. These transporters remove NE, 5-HT, and/or DA after neuronal excitation from the interstitial space close to the synapses. Thereby they terminate transmission and modulate neuronal behavioral circuits. Therapeutic failure and undesired central nervous system side effects of these drugs have been partially assigned to neurotransmitter removal by low affinity transport. Cloning and functional characterization of the polyspecific organic cation transporters OCT1 (SLC22A1), OCT2 (SLC22A2), OCT3 (SLC22A3) and the plasma membrane monoamine transporter PMAT (SLC29A4) revealed that every single transporter mediates low affinity uptake of NE, 5-HT, and DA. Whereas the organic transporters are all located in the blood brain barrier, OCT2, OCT3, and PMAT are expressed in neurons or in neurons and astrocytes within brain areas that are involved in behavioral regulation. Areas of expression include the dorsal raphe, medullary motoric nuclei, hypothalamic nuclei, and/or the nucleus accumbens. Current knowledge of the transport of monoamine neurotransmitters by the organic cation transporters, their interactions with psychotropic drugs, and their locations in the brain is reported in detail. In addition, animal experiments including behavior tests in wildtype and knockout animals are reported in which the impact of OCT2, OCT3, and/or PMAT on regulation of salt intake, depression, mood control, locomotion, and/or stress effect on addiction is suggested.
Highlights
Neuronal networks in the brain control complex cerebral functions such as learning, reasoning, mood control, motivation, and motoric coordination
Selective SERT inhibitors (SSRIs) and clomipramine are recommended for treatment of obsessive-compulsive disorder (OCD) (Pittenger and Bloch 2014)
Like human organic cation transporter 2 (hOCT2), the Km values for uptake of monoamine neurotransmitters by hOCT3 are orders of magnitude higher compared to human Na+/ClÀ stoichiometries of 1:1:1 (NET) (hNET), human DAT (hDAT), and human SERT (hSERT)
Summary
Neuronal networks in the brain control complex cerebral functions such as learning, reasoning, mood control, motivation, and motoric coordination. The secreted neurotransmitters are taken up by cognate transporters located extrasynaptically in neuronal terminals where they are packed into intracellular vesicles for future neuronal release This synaptic, “wiring-type” activation is accompanied by activation of receptors on more distant neurons occurring via neurotransmitters that diffuse out of the synaptic cleft. In vivo experiments in rodents are listed that shed light on the impact of these transporters during psychiatric disorders Discussing these data, the limitations of the employed methodological tools are outlined. This overview intends to serve as an introductory guide for the more specialized presentations in this volume In this overview, detailed data concerning sites of cerebral expression, neurotransmitter substrates, interacting psychotropic drugs, and partially selective inhibitors of organic cation transporters are compiled. It is apparent that the current data are rather fragmentary and that more investigations are warranted to obtain a better understanding of the roles of organic cation transporters in the brain during health and psychiatric disorders
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
