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The Journal of Neuroscience, August 20, 2003, 23(20):7569-7576

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

Carlos A. Bolaños,¹ Linda I. Perrotti,¹ Scott Edwards,¹ Amelia J. Eisch,¹ Michel Barrot,¹ Valerie G. Olson,¹ David S. Russell,² Rachael L. Neve,³ and Eric J. Nestler¹

¹Department of Psychiatry and Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, ²Departments of Psychiatry and Neurology, Yale University School of Medicine, New Haven, Connecticut 06508, and ³McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478

Neurotrophic factor signaling pathways modulate cellular and behavioral responses to drugs of abuse. In addition, chronic exposure to morphine increases expression of phospholipase C1 (PLC1) (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 PLC1, we show that overexpression of PLC1 in rostral portions of the VTA (R-VTA) results in increased morphine place preference, whereas PLC1 overexpression in the caudal VTA (C-VTA) results in avoidance of morphine-paired compartments. In addition, overexpression of PLC1 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 PLC1 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 PLC1 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 PLC1 expression in the VTA in mediating long-term adaptations to drugs of abuse and aversive stimuli.

Key words: growth factors; neural plasticity; viral-mediated gene transfer; drug addiction; morphine; stress; depression

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Received Jan. 14, 2003; revised May. 1, 2003; accepted May. 1, 2003.

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