DRUGS OF ABUSE AND STRESS INCREASE THE EXPRESSION OF GLUR1 AND NMDAR1GLUTAMATE-RECEPTOR SUBUNITS IN THE RAT VENTRAL TEGMENTAL AREA - COMMON ADAPTATIONS AMONG CROSS-SENSITIZING AGENTS

Behavioral and electrophysiological evidence suggests that glutamaterg ic neurotransmission plays an important role in some of the long-term effects of cocaine and other drugs of abuse on brain function. We ther efore examined the effect of repeated cocaine treatment on glutamate r eceptor subunit expression in central dopamine (DA) pathways implicate d in many of cocaine's behavioral actions. By immunoblotting procedure s using subunit-specific antibodies, we found that repeated, but not a cute, cocaine treatment increased the levels of immunoreactivity of Gl uR1 (an AMPA receptor subunit) and NMDAR1 (an NMDA receptor subunit) i n the ventral tegmental area (VTA), a nucleus containing mesolimbic DA neurons. In contrast, chronic cocaine treatment did not alter levels of GluR2 (an AMPA receptor subunit), NMDA2A/B (NMDA receptor subunits) , or GluR6/7 (kainate receptor subunits) in this brain region. Moreove r, GluR1 and NMDAR1 levels were not regulated in other regions of the mesolimbic or nigrostriatal DA pathways, including the substantia nigr a. Because several drugs of abuse and stress can elicit common and cro ss-sensitizing effects on mesolimbic DA function, we next examined whe ther repeated morphine and stress treatments would regulate these prot eins similarly in the VTA. Although morphine delivered by subcutaneous pellet implantation had no significant effect on subunit levels, morp hine delivered intermittently by subcutaneous injections of escalating doses elevated GluR1 levels in the VTA. Repeated restraint stress als o increased GluR1 levels in the VTA, whereas an unpredictable stress p aradigm (2 stressors/d under variable conditions) increased both GluR1 and NMDAR1 levels in this brain region. Unlike cocaine, morphine, and stress, repeated treatment with other psychotropic drugs (haloperidol , raclopride, sertraline, and desipramine) that lack reinforcing or se nsitizing properties did not regulate GluR1 or NMDAR1 subunit levels i n the VTA. increased glutamate receptor subunit expression in the VTA may represent an important molecular mechanism by which drugs of abuse and stress exert common, long-term effects on mesolimbic DA function.