Orthogonality Effects in Relativistic Models of Nucleon Knockout Reactions

We study the effect of wave function orthogonality in the relativistic treatment of the nucleon removal reactions (gamma, p) and (e, e' p). The continuum wave function describing the outgoing nucleon is made orthogonal to the relevant bound states using the Gram-Schmidt procedure. This procedure has the advantage of preserving the asymptotic character of the continuum wave function and hence the elastic observables are unaffected. The orthogonality effects are found to be negligible for (e, e' p) reactions for missing momenta up to 700 MeV/c. This holds true for both parallel and perpendicular kinematics. By contrast the orthogonalization of the wave functions appears to have a more pronounced effect in the case of (gamma, p) reactions. We find that the orthogonality effect can be significant in this case particularly for large angles. Polarization of the outgoing protons and photon asymmetry show more sensitivity than the cross sections. If the orthogonality condition is imposed solely on this one hole state the effects are usually smaller.Comment: LaTeX, 7 postscript figure

Neuropharmacological and neurobiological relevance of in vivo 1H-MRS of GABA and glutamate for preclinical drug discovery in mental disorders

Proton magnetic resonance spectroscopy (1H-magnetic resonance spectroscopy (MRS)) is a translational modality with great appeal for neuroscience since the two major excitatory and inhibitory neurotransmitters, glutamate, and GABA, can be noninvasively quantified in vivo and have served to explore disease state and effects of drug treatment. Yet, if 1H-MRS shall serve for decision making in preclinical pharmaceutical drug discovery, it has to meet stringent requirements. In particular, 1H-MRS needs to reliably report neurobiologically relevant but rather small changes in neurometabolite levels upon pharmacological interventions and to faithfully appraise target engagement in the associated molecular pathways at pharmacologically relevant doses. Here, we thoroughly addressed these matters with a three-pronged approach. Firstly, we determined the sensitivity and reproducibility of 1H-MRS in rat at 9.4 Tesla for detecting changes in GABA and glutamate levels in the striatum and the prefrontal cortex, respectively. Secondly, we evaluated the neuropharmacological and neurobiological relevance of the MRS readouts by pharmacological interventions with five well-characterized drugs (vigabatrin, 3-mercaptopropionate, tiagabine, methionine sulfoximine, and riluzole), which target key nodes in GABAergic and glutamatergic neurotransmission. Finally, we corroborated the MRS findings with ex vivo biochemical analyses of drug exposure and neurometabolite concentrations. For all five interventions tested, 1H-MRS provided distinct drug dose-effect relationships in GABA and glutamate over preclinically relevant dose ranges and changes as low as 6% in glutamate and 12% in GABA were reliably detected from 16 mm3 volumes-of-interest. Taken together, these findings demonstrate the value and limitation of quantitative 1H-MRS of glutamate and GABA for preclinical pharmaceutical research in mental disorders