The specific aim of the proposed studies is to determine if changes in the subunit composition of AMPA receptors in the ventral tegmental area (VTA) underlie changes in behavioral sensitivity to opiates of particular interest is further characterization of our previous finding that intermittent administration of morphine (a regimen that causes behavioral sensitization) upregulates expression of VTA GluR1. Increased GluR1 expression is known to make AMPA receptors permeable to Ca2+; changes in the excitability of VTA dopamine cells could explain neurobiological adaptations that accompany repeated morphine treatment. Proposed is a multidisciplinary approach to the study of VTA GluR1 in two phases: (i) to determine if altered VTA GluR1 is correlated with morphine sensitization, and (ii) to determine if altered VTA GluR1 causes changes in behavioral responses to morphine. First, to extend our preliminary finding that chronic treatment with the D1 antagonist SCH 23390 (a drug known to block sensitization) downregulates VTA GluR1, it will be determined if this action is common to other treatments that block sensitization (NMDA and AMPA antagonists, amygdala and frontal cortex lesions). Second, it will be determined if directly altering VTA GluR1-by increasing its expression through the use of an engineered viral vector, or by decreasing its expression with antisense oligonucleotides-alters morphine's locomotor stimulating or rewarding effects. These studies may help to establish that altered composition of AMPA receptors on VTA dopamine cells underlies behavioral adaptation to opiates.
