Behavioral Evidence for Enhanced Intracellular Calcium Signaling in Cocaine Sensitization

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Bailes, Carrie Ann
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Chronic cocaine use causes cellular adaptations in the prefrontal cortex (PFC) that contribute to addiction and relapse. A better understanding of these cellular adaptations will promote the development of effective relapse pharmacotherapies. By enhancing dopamine receptor signaling, chronic cocaine disrupts multiple intracellular signaling cascades in the PFC, including calcium release from intracellular stores. However, the behavioral role for intracellular calcium signaling in addictive behaviors is unclear. Therefore, using cocaine sensitization to model aspects of addiction, we designed experiments to test the hypothesis that an elevated release of calcium from PFC stores contributes to cocaine sensitization. To establish behavioral sensitization, we administered daily cocaine (15mg/kg IP) to rats and assessed their locomotor responses. Following four days of cocaine injections, rats developed robust locomotor sensitization which appeared sensitive to pharmacological manipulation of calcium release from intracellular stores. PFC infusion of Thapsigargin (5-500μM) or Xestospongin C (3ng/0.5uL), inhibitors of Ca2+ re-entry into intracellular stores, augmented locomotor activity in sensitized animals but had no effect in non-sensitized animals. Moreover, pre-treatment with a D1 receptor antagonist during the establishment of sensitization did not prevent sensitization to cocaine or alter XeC sensitivity, suggesting that changes in Ca2+ signaling may not be dependent on D1 receptor activation. 2-APB (10ng/0.5uL), an inhibitor of InsP3 receptors on the ER, did not alter locomotor activity, suggesting the underlying adaptations are independent of InsP3 receptors. Taken together, these findings demonstrate that increases in intracellular calcium signaling within the PFC contribute to the expression of cocaine sensitization. These underlying cellular adaptations may represent mechanisms by which drugs of abuse induce PFC dysfunction and lead to addiction.
Addiction, Cocaine, Sensitization, Calcium