Phospholipase Cγ in Distinct Regions of the Ventral Tegmental Area Differentially Modulates Mood-Related Behaviors

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Abstract
Neurotrophic factor signaling pathways modulate cellular and behavioral responses to drugs of abuse. In addition, chronic exposure to morphine increases expression of phospholipase Cγ1 (PLCγ1) (a protein involved in neurotrophic signaling) in the ventral tegmental area (VTA), a neural substrate for many drugs of abuse. Using viral-mediated gene transfer to locally alter the activity of PLCγ1, we show that overexpression of PLCγ1 in rostral portions of the VTA (R-VTA) results in increased morphine place preference, whereas PLCγ1 overexpression in the caudal VTA (C-VTA) results in avoidance of morphine-paired compartments. In addition, overexpression of PLCγ1 in R-VTA causes increased preference for sucrose and increased anxiety-like behavior but does not affect responses to stress or nociceptive stimuli. In contrast, overexpression of PLCγ1 in C-VTA decreases preference for sucrose and increases sensitivity to stress and nociceptive stimuli, although there was a tendency for increased anxiety-like behavior as seen for the R-VTA. These results show that levels of PLCγ1 in the VTA regulate responsiveness to drugs of abuse, natural rewards, and aversive stimuli and point to the possibility that distinct topographical regions within the VTA mediate generally positive versus negative responses to emotional stimuli. Moreover, these data also support a role for drug-induced elevations in PLCγ1 expression in the VTA in mediating long-term adaptations to drugs of abuse and aversive stimuli.