By contrast, if the VHC were chemically stimulated with METH earlier than the VTA, then METH produces place aversion learning; or it fails to produce positive place reinforcement even following the application of the drug into the other two regions (VTA and NAc). This observation led us to the hypothesis that the ascending pathway in the hippocampus-VTA loop mediates positive reinforcement learning while the descending pathway mediates aversion related to the exposure of psychostimulants such as METH. Needless to say, dose response effect of METH applied into each nucleus of the hippocampus-VTA loop is worth

investigating perhaps Inhibitors,research,lifescience,medical by operant conditioning behavioral techniques such as intravenous or intracranial drug self administration. Concluding Remark In summary, compared to the top-down order of conditioning, the bottom-up order of conditioning the hippocampus-VTA loop produced METH-mediated place reinforcement learning. The top-down order of conditioning attenuated place learning or produced place aversion. Blocking the NMDA receptors reversed this Inhibitors,research,lifescience,medical effect, which is interesting in light with the electrophysiological findings by

Lisman and Grace (Lisman and Grace 2005). Because addiction is a learning process, we propose Inhibitors,research,lifescience,medical that disruption of the learning circuitry also disrupts learning. We assume that interfering with the natural flow of neural information during the process of novel stimulus entry to the CNS results in aberrant learning. Thus, the reinforcing properties of psychostimulants including METH can be Inhibitors,research,lifescience,medical attenuated when one begins stimulating from the top-down pathway, which is anatomically located downstream of the comparator region of the hippocampus-VTA loop (Lisman and Grace 2005). Addiction is a very complicated psychological disease that becomes Inhibitors,research,lifescience,medical more and more complicated as time progresses. We believe that research on addiction should try to all targets address this disease at its earliest phase (acquisition) rather than trying to find the solution at its full blown (expression) phase. On the basis of our current findings, we suggest that future investigations should focus

Drug_discovery on neural and behavioral correlates of the hippocampus-VTA loop with due emphasis given on the acquisition phase of reinforcement learning. The findings from such research projects would help us develop some target-specific (e.g., receptor or receptor subunit specific) therapeutics for addiction-related health problems and any other psychological disorders that emanate as a result of exposing the brain to psychoactive drugs. Acknowledgments The research project was supported by the diversity program in neuroscience at NIMH, The Ewing Halsell Distinguished Chair under the American Psychological Program, APA T32 MH18882 and by the MBRS program at University of Texas at San Antonio, NIH GM07717. Supporting Information Additional Supporting Information may be found in the online version of this article: Figure S1.