CREB, alcohol, and anxiety
By Kerry Grens
Another quality of the rats interested Subhash Pandey of the University of Illinois at Chicago. "When they drink alcohol," Pandey says, "their anxiety disappears." Pandey wanted to find out what was responsible. He turned to CREB and one of its targets, neuropeptide Y (NPY), a potent, endogenous anxiolytic compound.
Heilig, when he was a postdoc with George Koob at the Scripps Research Institute, had shown that NPY acts in opposition to corticotropin releasing factor, also known as corticotropin releasing hormone (CRH).2 "NPY is an antistress system that basically antagonizes the effects of CRH," Heilig says. NPY is also important in alcohol-drinking behaviors: NPY-deficient mice drink more alcohol, and mice with an overexpression of NPY drink less.3
? Mark Goddard
Because of the amygdala's role in anxiety, Pandey looked at CREB levels there; he found lower levels in the central and medial amygdala among rats that prefer drinking more alcohol. "Decreases in CREB in the amygdala increase anxiety," Noronha says, "and when you have increased anxiety you have increased alcohol consumption and a propensity for addiction."
When P rats were given alcohol, the activated form of CREB increased. "If that is the case," Pandey conjectures, "these animals are drinking to elevate CREB function," and induce the anxiolytic effects of NPY. Pandey went one step upstream of CREB and looked at protein kinase A (PKA), which regulates CREB activity. He infused a PKA activator or NPY straight into the amygdala, which decreased alcohol consumption and anxiety in P rats. When he blocked PKA, he saw the opposite effect.4 "When we block PKA, they have less CREB phosphorylation, less NPY expression, and they become more anxious and drink more alcohol," Pandey says. The results supported Pandey's hypothesis.
It's unclear whether alcoholics have similar low levels of NPY as P rats, but that could be resolved soon. David Goldman's group at NIAAA is just one of a number of groups collaborating to explore NPY - including measuring serum protein levels in patients with alcoholism, and gene-expression studies in postmortem samples. "We've found new functional variation in NPY," Goldman says. The NPY locus his team has identified accounts for variation in RNA expression and protein levels in vivo, he says. "This new functional genetic variation we're exploring for its linkage to anxiety and addictions." He expects to publish his findings later this year.