Home Investigators Robert O. Messing, M.D. Research
Scientific Research PDF Print E-mail
My laboratory is engaged in discovering protein targets to modify behaviors related to substance abuse and co-morbid conditions, such as anxiety and pain. Current projects include:

Protein kinase C (PKC)ε:
We found that PKCε null mice show: (1) supersensitivity to drugs that activate GABAA receptors; (2) decreased acute tolerance to ethanol and decreased ethanol self-administration; (3) decreased anxiety; and (4) decreased hyperalgesia associated with inflammation or alcoholic polyneuropathy.We are now investigating mechanisms by which PKCε modulates GABAA receptors, are mapping brain regions where PKCε regulates anxiety and alcohol-related behaviors, and are identifying PKCε substrates in DRG neurons that mediate PKCε-dependent hyperalgesia.

PKCδ:
We have generated PKCδ: null mice and found that they are very resistant to intoxication by ethanol and show increased anxiety-like behavior. These findings are associated with reduced responses to drugs that act as agonists at extra-synaptic GABAA receptors. We are investigating how PKCδ regulates these receptors and whether this interaction contributes to the behavioral phenotypes we observe in PKCδ null mice.

PKCζ:
This PKC isozyme exists in two forms: the full length enzyme that is widely expressed outside of the nervous system, and a short form termed PKMζ that arises from an internal promoter and is expressed mainly in the brain. PKMζ has recently been shown to be crucial for the maintenance of spatial and gustatory memories. It may play important roles in persistence of habits, fear, and addictive behaviors. We have generated knockout mice that lack both PKCζ and PKMζ and are testing them for anxiety and addiction-related behaviors. We are also performing studies in rats to determine if inhibiting PKMζ in specific limbic brain regions reduces drug self-administration or prevents relapse to drug seeking.

PKC substrates:
The catalytic domains of the PKC family are very similar and, as a result, in vitro studies have identified very few PKC isozyme-specific substrates. In collaboration with Kevan Shokat’s laboratory at UCSF, we have generated PKCε, PKCδ, and PKCζ variants with mutations in their ATP binding domains to confer sensitivity to inhibitors that are inactive at native kinases. We are expressing these mutant kinases in cells and generating knock-in mice to identify PKC isozyme-specific substrates in neural tissues.

N-type calcium channels:
We previously found that ethanol inhibits N-type calcium channels and chronic ethanol exposure increases N-type channel density in the brain. We recently found that mice lacking N-type channels show reduced sensitivity to the hypnotic effect of ethanol, altered ethanol reward and reduced ethanol preference compared with wild type mice. We are currently investigating whether novel small molecule N-type channel antagonists reduce ethanol intoxication and decrease drinking in rodents. We are also examining whether levetiracetam, an anticonvulsant that is an N-type channel antagonist, reduces drinking in humans.