Studies of the ventral striatum and its connections are of key importance for understanding the neurobiology of drug abuse and mental disorders. Anatomical, physiological and pharmacological studies in these brain regions have been central in gaining insight into the mechanisms underlying motivation, reward, and goal-directed behaviors. The """"""""motive"""""""" or drug-reward circuit involves the orbital and medial prefrontal cortex (OMPFC), the ventral striatum (VS), the ventral pallidum/substantia nigra, pars reticulata (VP/SNr), and the medial dorsal N. of the thalamus (MD), which links the circuit back to cortex. The opiates and excitatory amino acids through their interactions with ventral striatal transmitters and receptors, are central to studies on goal-directed behaviors, drug addiction, and behavioral disorders. During the previous funding period we identified important components of this circuit in primates along with the histochemical organization of the ventral striatal shell/core sub-territories. Using retrograde tracer injections, we demonstrated the OMPFC and thalamic projections to the VS. Based on these studies, the region of the striatum that can be associated with goal directed behaviors appears to be extensive. Furthermore, we demonstrated an integrative network of connections via the midbrain. The next step is to link together these components. The experiments proposed here will test the hypothesis that the ventral cortical- basal ganglia-cortical pathways via the thalamus and substantia nigra are also governed by an integrative network of connections with information flowing from limbic to more associative cortical regions in a step-wise manner through the ventral striatum. The experiments will first use anterograde tracer injections to delineate the rostro-caudal extent of the OMPFC projection fields to the VS, their relationship to the VS shell/core sub-territories and to the distribution of the mu receptor and GluR1 sub-unit receptor subtype. These experiments will also examine the relationship between MD and midline thalamic projections to the shell/core regions, how these relate to OMPFC inputs, and the mu and GluR1 receptors. A final set of experiments will address the connections between the output pathways from specific shell/core regions to the VP/SNr to the MD nucleus. These studies will link together how the OMPFC and thalamic inputs to the VS are related to the shell and core sub-territories, and the mu and GluR1 receptors and follow the outputs via the VP/SNr to the MD.
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