Role of the ventral tegmental area, cannabinoid receptors and GABA neurons in motor activity

Illicit abuse of psychoactive substances, including marijuana, continues to be a serious problem in our society and therefore cultivating a more thorough understanding of the neuroanatomical and neurochemical substrates underlying drug abuse is needed. Characterizing specific brain nuclei that are integral components of brain reward circuits, such as the ventral tegmental area (VTA), may offer important insights into modulation of behaviors associated with drug abuse. The VTA includes DA-containing and GABA-containing neurons which provide important forebrain control over the limbic system. The present series of studies explored these VTA neurons from two perspectives: First, we explored the VTA as a potential site of action for cannabinoid receptors (CB1R) and provide the first detailed analysis of the distribution of CB1R throughout the various subnuclei and across the rostrocaudal extent of the VTA. We demonstrated that CB1R populations have postsynaptic localization in the VTA, and a rostrocaudal gradient of expression in the interfascicular nucleus, which expressed the highest level of CB1R in the VTA subnuclei. Second, we explored the prospect that specific ablation of a subset of VTA neurons, those GABA-containing neurons that posses -opioid receptors, play an important role in the generation of motor behavior. Ablation of GABA neurons following intra-VTA administration of the selective toxin dermorphin-saporin was associated with elevated spontaneous locomotor activity at day 7 that normalized to basal levels by day 14 after treatment. Despite this normalization motor hyperactivity induced by the well-characterized psychostimulant cocaine was significantly elevated in keeping with the hypothesis that loss of GABAergic innervation in the VTA sensitizes to the neurochemical actions of cocaine. Collectively, our results demonstrate a new localization of CB1R in the VTA and the behavioral impact of GABA-containing neuron ablation in the VTA. These data add to growing evidence of the impact of psychoactive substances on neuroanatomical substrates, such as the VTA.