Global quantitative analysis of phosphorylation underlying phencyclidine signaling and sensorimotor gating in the prefrontal cortex.

Prepulse inhibition (PPI) is an example of sensorimotor gating and deficits in PPI have been demonstrated in schizophrenia patients. Phencyclidine (PCP) suppression of PPI in animals has been studied to elucidate the pathological elements of schizophrenia. However, the molecular mechanisms underlying PCP treatment or PPI in the brain are still poorly understood. In this study, quantitative phosphoproteomic analysis was performed on the prefrontal cortex from rats that were subjected to PPI after being systemically injected with PCP or saline. PCP downregulated phosphorylation events were significantly enriched in proteins associated with long-term potentiation (LTP). Importantly, this data set identifies functionally novel phosphorylation sites on known LTP-associated signaling molecules. In addition, mutagenesis of a significantly altered phosphorylation site on xCT (SLC7A11), the light chain of system xc-, the cystine/glutamate antiporter, suggests that PCP also regulates the activity of this protein. Finally, new insights were also derived on PPI signaling independent of PCP treatment. This is the first quantitative phosphorylation proteomic analysis providing new molecular insights into sensorimotor gating.

SU-E-T-11: LINAC Dose Profiling Using Cherenkov Emission Imaging.

PURPOSE: To demonstrate the potential for fast 3D dose profile imaging of a LINAC beam using images of the induced Cherenkov radiation in a water tank. A specialized time-gated imaging system was developed as a prototype to quantify and compare with Monte Carlo, to illustrate the concept. METHODS: Images were acquired from a water tank during irradiation from a 6 MV Varian-2100C linear accelerator beam using a time-gated CCD-based imaging system. The camera was placed normal to the tank wall to minimize parallax reflections, and resultant images were produced by evaluating the median of each pixel in a stack of 2000 images taken at a rate of 60 Hz with an exposure time of 10 ms. Experimental data was compared to images obtained from GEANT4 simulations of the optical setup. RESULTS: Examination of the scored quantities for dose and generated Cherenkov photons indicates that there is a strong similarity, which can be explained by considering the electron energy losses per unit path length. However, due to the complex convolution of the Cherenkov emission directionality and camera lens angular field of view, this relationship is distorted. These errors can be calibrated using the GEANT4 simulations to more accurately reflect the intrinsic dose in the water volume. CONCLUSIONS: This work demonstrates dose profiling using the induced Cherenkov radiation signal for the first time. These preliminary results serve as a proof of concept of imaging at one azimuthal angle. Analogous to SPECT, the technique could easily be translated to multiple angles yielding full dose reconstructions following filtered back projection. Further refinement of this technology could be the first step in a paradigm shift towards an alternative method for fast radiation field analysis. Advantages would include increased speed, as well as the ability to profile dynamic beam shapes within transparent solid anthropomorphic phantoms. This work has been financially supported by NIH grant R01CA109558.

Possible mechanism of hypothermia induced by intracerebroventricular injection of orphanin FQ/nociceptin.

Orphanin/nociceptin (OFQ/N), a 17-amino-acid peptide, is an endogenous peptide, the receptor for which is similar to mu-, delta- and kappa-opioid receptors ( approximately 65% homology). Reports indicate that OFQ/N can block the antinociception induced by mu-, delta- and kappa-opioid agonists in the rat and in the mouse, indicating that there is a functional interaction between opioid receptors and OFQ/N receptors in the nervous system. It is well known that activation of the mu- and kappa-opioid receptors results in hyperthermia and hypothermia, respectively, in Sprague-Dawley rats. The present studies were designed to examine effects of OFQ/N on body temperature (Tb) and explore whether the mechanism of T(b) change induced by OFQ/N involved the opioid system. The results show that (1) i.c.v. injection of a high dose of OFQ/N (9-18 micro g) produces hypothermia in adult rats; (2) OFQ/N (1.8 micro g, i.c.v., t=+30 s after morphine) can decrease morphine-induced hyperthermia; (3) neither the opioid receptor antagonist, naloxone (10 mg/kg, s.c., t=-15 s before OFQ/N) nor the kappa-opioid receptor antagonist nor-BNI (1 micro g/5 microl, i.c.v., t=-30 s before OFQ/N) reduces the hypothermia induced by i.c.v. injection of OFQ/N at dose of 18 micro g (P>0.05); (4) 60 micro g/5 microl AS oligo (i.c.v. treatment on days 1, 3 and 5) against OFQ/N receptors significantly reduces the hypothermia induced by i.c.v. injection of 9 micro g OFQ/N (P<0.01). These results suggest that the hypothermia induced by i.c.v. injection of a high dose of OFQ/N (9 or 18 micro g) is mediated, at least partially, by its own receptor, independent or downstream of opioid receptors in the rat brain and that OFQ/N probably acts as a physiological antagonist to reduce morphine-induced hyperthermia.