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The serine/threonine kinase, glycogen synthase kinase 3beta (GSK3beta), is abundant in CNS and is neuron specific. GSK3beta plays a pivotal role in the regulation of numerous cellular functions. GSK3beta phosphorylates and thereby regulates many metabolic, signaling, and structural proteins which can influence cell survival. Increased GSK3beta correlates with increased cell death, whereas reduced GSK3beta expression correlates with increased cell survival. We report that the GSK3beta inhibitor Chir025 is neuroprotective in vitro and in vivo. First, Chir025 reduced cultured hippocampal neuron death following glutamate exposure by 15-20% versus vehicle-treated controls. Second, Chir025 significantly reduced cultured cortical neuron death following oxygen-glucose deprivation (OGD) by approximately 50%. Third, Chir025 reduced infarct size following focal cerebral ischemia by nearly 20%. There were no significant differences in the number of TUNEL-positive neurons or in caspase-3 and -9 activities between Chir025- and vehicle-treated rats, although Chir025 elevated cytosolic Bcl-2 expression. These data show that Chir025-mediated inhibition of GSK3beta is neuroprotective and that the mechanism is probably not anti-apoptotic.

The Drosophila protein Rop shows similarity with the Sec1p protein of S. cerevisiae. Sec1p has an essential role in secretion, whereas most related proteins from higher organisms are hypothesized to function in neurotransmitter release. We show that, like the latter proteins, Rop is expressed in the nervous system, but it is expressed in other tissues as well, many of which are actively engaged in secretion. We have isolated mutations in the Rop gene and find that the extracellular accumulation of a number of normally secreted cellular products fails to occur in null mutant animals, which subsequently die at a late embryonic stage. Electrophysiological recordings on temperature-sensitive Rop mutants show that reductions in Rop activity result in a loss of the normal synaptic response to a light stimulus. These data suggest that a member of the Sec1p class of proteins has an in vivo function in both general secretion and synaptic transmission.

s / Drug and Alcohol Dependence 140 (2014) e2–e85 e81 Opioids with lower brain uptake are less recognizable in rat drug discrimination tests and thus potentially less subject to abuse Stephen D. Harrison1, H. Gursahani1, J. Pfeiffer1, K. Gogas1, J. Riggs1, T. Riley1, D. Gauvin2, S. Doberstein1 1 Nektar Therapeutics, San Francisco, CA, United States 2 MPI Research, Inc., Mattawan, MI, United States Aims: Prescription opioids are the mainstay of analgesic therapy, although their abuse is rising to epidemic proportions. A solution to this problemwould be to separate opioid analgesia from abuse potential. Drugs that are readily recognized as opioids are considered more prone to abuse. We have tested whether lowering the rate of brain entry of an opioidwillmake it less recognizable in rat drug discrimination assays. Methods: Various mu-opioid agonists were assessed for different properties: (1) potency by receptor binding and elicitedfunction in vitro; (2) brain-uptake rate relative to an antipyrine control compound by in situ brain perfusion; (3) potential to be recognized as a mu-opioid agonist by rats trained to recognize oxycodone in the drug discrimination assay. Correlations between these parameters were made to establish underlying relationships between them. Results: The rate of brain uptake and potency of mu-opioid agonists both correlate inversely with the minimum discriminable dose (MDD) in the rat drug discrimination assay. The highest MDD was observed for opioids with dramatically reduced brain uptake rates (between 0.01 and 0.1 relative to antipyrine) compared to commercially used opioids (brain uptake rates between 0.5 and 10 relative to antipyrine). Conclusions: Opioid agonists that have a high potency against the mu-opioid receptor and which have a high rate of entry into the brain are more likely to be recognized as a mu-opioid agonists. A low MDD is considered to be reflective of potential abuse liability and consequently opioids with low brain entry rates, and thus higher MDD values, may have less abuse potential. Consequently it may be possible to maintain analgesic efficacy and yet reduce the potential for the abuse, by reducing brain entry rate. Mu-opioid agonists with an engineered reduction in brain uptake rate offer a potential approach to achieving this goal. Financial support: Nektar Therapeutics. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.239 Differences in cannabis withdrawal symptoms between individuals with and without attention deficit hyperactivity disorder Karen Hartwell1,2, E. Chauchard3,4, D.A. Gorelick3, Aimee McRae-Clark1 1 Department of Psychiatry, MUSC, Charleston, SC, United States 2 Ralph H. Johnson VAMC, Charleston, SC, United States 3 Intramural Research Program, NIDA, Bethesda, MD, United States 4 Toulouse University Octogone-CERPP, Toulouse