tegmental area, further implicating its involvement in drug-induced changes of neural plasticity. The genes involved in LTP include specific ionotropic and metabotropic glutamatergic receptors, calcium signaling-related proteins such as calmodulin, calcium/calmodulin-dependent protein kinase, protein phosphotase, adenylate cyclase, protein kinase A and C, mitogen-activated protein kinase, and cAMP-response element binding protein (CREB). Among these, the most significantly affected genes are the N-methyl D-aspartate (NMDA) receptor 2B (GRIN2B), a subunit of the ionotropic glutamate receptor; protein phosphatase 3 catalytic subunit α isoform (PPP3CA), a part of the calcium-dependent phosphatase calcineurin; and calcium/calmodulin-dependent protein kinase type II Δ chain subunit (CAMK2D). In addition, the list of genes relevant to LTP whose expression is altered by long-term cocaine exposure includes protein phosphatase 1 catalytic subunit β and γ isoforms (PPP1CB and PPP1CC), calmodulin 2 (CALM2), CREB (CREB1), adenylate cyclase 1 (ADCY1), protein kinase C β1 (PRKCB1), and an N-ras oncogene with intrinsic GTPase activity (NRAS). Although we did not observe significant changes of the LTP pathway in the alcoholics, the phosphatidylinositol signaling system, which is closely related to the LTP pathway, was significantly altered by chronic exposure to both cocaine and alcohol. These findings of gene expression changes, together with other studies that have
