My primary research interests are directed at the neurobiology of alcoholism. A growing body of literature shows that central neuropeptides, including those involved in the integrating emotional and appetitive behaviors, regulate neurobiological responses to ethanol. The overarching goal of the research conducted in my laboratory is to discover the roles that central neuropeptides play in modulating excessive binge-like ethanol consumption, and how changes in these neuropeptide pathways contribute to the transition to ethanol dependence. To this end, we employ mouse models of binge drinking to:
- Determine the roles that central neuropeptides play in modulating ethanol consumption, binge-like ethanol drinking, and the reinforcing properties of ethanol.
- Indentify the central neurochemical pathways that modulate the effects of psychological stress on excessive ethanol drinking.
- Determine how neuropeptides interact with each other and with intracellular signaling mechanisms (such as cAMP-dependent protein kinase A; PKA) in the modulation of excessive ethanol consumption.
Discovered that binge-like ethanol consumption and other neurobiological responses to ethanol are modulated by neuropeptide Y (NPY) signaling:
- A history of binge-like ethanol intake blunts NPY levels in the extended amygdala, and increases NPY-induced inhibition of GABAergic transmission in the central amygdala.
- Y1 receptor agonists, and Y2R antagonists, protect against excessive binge-like ethanol intake when administered centrally.
- NPY signaling protects against elevated levels of anxiety-like behavior stemming from ethanol withdrawal.
- NPY Y2 receptor signaling in the core region of the nucleus accumbens facilitates the expression of sensitization to the locomotor stimulant effects of ethanol stemming from repeated ethanol administrations.
Discovered that binge-like ethanol consumption is modulated by the hypothalamic melanocortin (MC) system:
- MC receptor agonists reduce, and MC receptor antagonists increase, ethanol consumption, respectively.
- MC receptor agonists modulate ethanol consumption via the MC-4 receptor.
- The endogenous MC receptor antagonist, agouti-related protein (AgRP), modulates ethanol consumption and the reinforcing properties of ethanol, and promotes binge-like ethanol drinking in mice.
Discovered that binge-like ethanol consumption and other neurobiological responses to ethanol are modulated by corticotropin releasing factor (CRF) signaling:
- A history of binge-like ethanol intake increases CRF levels in the central amygdala and blunts CRF-induced excitation of GABAergic transmission in the central amygdala.
- CRF-1 receptor antagonists protect against binge-like ethanol drinking when administered peripherally or directly into the central amygdala.
- The delayed increase of ethanol drinking by mice exposed to psychological stress is modulated by CRF-1 receptor signaling.
- CRF-1 receptor signaling modulates the expression of sensitization to the locomotor stimulant effects of ethanol stemming from repeated ethanol administrations.
Discovered that the RIIβ subunit of PKA modulates neurobiological responses to ethanol:
- Deletion of the RIIβ subunit of PKA in mice is associated with increased consumption of ethanol and reduced sensitivity to the sedative properties of this drug.
- Mice lacking the RIIβ subunit of PKA show increased sensitivity to the locomotor stimulant effects of ethanol and behavioral sensitization stemming from repeated ethanol injections.
Discovered that binge-like ethanol drinking using “drinking in the dark” (DID) procedures augments subsequent voluntary ethanol intake.
- Increases of subsequent voluntary ethanol consumption become more robust following repeated episodes of binge-like ethanol drinking, consistent with a dependence-like state.
Current Research Projects
Melanocortin Neuropeptides and Ethanol Intake. Supported by the National Institute on Alcohol Abuse and Alcoholism (R01-AA015148); Thiele (PI).
The Role of Neuropeptide Y in Ethanol Intake and Sensitivity. Supported by the National Institute on Alcohol Abuse and Alcoholism (R01-AA013573); Thiele (PI).
Current Mentored Research Projects
Ethanol-Induced Locomotor Sensitization: NPY Signaling and Chromatin Remodeling. (F31-AA019839), Gretchen Sprow (PI), Todd Thiele (Mentor).
Histone methylation: a role in excessive ethanol intake and self-administration. (F32 – AA021611); Jennifer Rinker, PhD (PI), Todd Thiele (Mentor).