The role of protein kinase A and stress in ethanol-induced locomotor sensitization Public Deposited

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  • March 22, 2019
  • Fee, Jon R.
    • Affiliation: College of Arts and Sciences, Department of Psychology and Neuroscience
  • There is a growing body of literature dedicated to elucidating the mechanisms involved in behavioral sensitization. The following studies examined the ability of alterations in PKA signaling (via genetic knockout) and CRF signaling (via pharmacological blockade) to modulate ethanol-induced locomotor sensitization and restraint stress-induced crosssensitization. Experiment 1 utilized the RIIβ knockout model to determine if alterations in PKA signaling affect locomotor activation in response to ethanol as well as the development of ethanol-induced locomotor sensitization. RIIβ-/- mice consistently showed significantly greater ethanol-induced locomotor activity relative to RIIβ+/+ mice. RIIβ-/- mice also showed increased sensitivity to ethanol-induced locomotor sensitization, an effect that may be dependent on genetic background and/or testing paradigm. Importantly, increased locomotor activity by RIIβ-/- mice was specific to ethanol injections, absent following saline injections, and not associated with altered blood ethanol levels. Experiment 2 attempted to discern a few of the mechanisms underlying the restraint stress-induced cross-sensitized response to ethanol in mice. Chronic exposure to restraint stress (2hrs for 10 days) induced a cross-sensitized response to ethanol in two commercially available inbred strains of mice, C57BL/6J and DBA/2J. The RIIβ knockout mouse model was also utilized to test if enhanced sensitivity to stress might be a factor contributing to the previously observed heightened sensitivity to ethanol-induced locomotor sensitization in these mice. RIIβ-/- and RIIβ+/+ showed no differences in the effect of stress on ethanolinduced locomotor activity. Finally, pretreatment with CRF Receptor 1 antagonist, CP- 154,526, prior to restraint stress sessions in male DBA/2J mice failed to block the acquisition of a cross-sensitized response to ethanol. Experiment 3 used a CRF Receptor 1 antagonist, CP-154,526, in an attempt to block the acquisition and expression of ethanol-induced locomotor sensitization in male DBA/2J mice. Pretreatment with CP-154,526 was ineffective in blocking the acquisition of a sensitized response to ethanol. In contrast, pretreatment with CP-154,526 effectively blocked expression of a sensitized response in DBA/2J mice that had been previously sensitized to the locomotor stimulating effects of ethanol. These effects were not attributable to alterations in blood ethanol levels, and ethanol naïve DBA/2J mice when pretreated with CP-154,526 show no such reductions in locomotor activity in response to ethanol. These experiments suggest a role for both PKA and CRF signaling in the mechanisms underlying ethanol-induced locomotor sensitization. Additionally, the ability of chronic restraint stress to elicit a cross-sensitized response to ethanol in mice is demonstrated. Ultimately, it remains unclear if alterations in PKA or CRF signaling are involved in the mechanisms associated with restraint stress-induced cross sensitization.
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  • Thiele, Todd
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