Based on parameters from human and our monkey pharmacokinetic studies, we modeled a prevalent human METH exposure of daily multiple doses in socially housed vervet monkeys. METH doses were escalated over 33 weeks, with final dosages resulting in estimated peak plasma METH concentrations of 1-3 mu M, a range measured in human abusers. With larger METH doses, progressive increases

in abnormal behavior and decreases in social behavior were observed on ‘injection’ days. Anxiety increased on ‘no injection’ days while aggression decreased throughout the study. Thereafter, during 3 weeks abstinence, differences in baseline vs post-METH behaviors were not observed. Post-mortem JSH-23 concentration analysis of METH brains showed 20% lower striatal DA content while

autoradiography studies of precommissural striatum showed 35% lower [H-3]WIN35428 binding to the DA transporter. No statistically significant changes were detected for [H-3] dihydrotetrabenazine binding to the vesicular monoamine transporter (METH-lower by 10%) or for [H-3]SCH 23390 and [H-3]raclopride binding to DA D1 and D2 receptors, respectively. Selleckchem PRN1371 Collectively, this long-term, escalating dose METH exposure modeling a human abuse pattern, not associated with high-dose binges, resulted in dose-dependent behavioral effects and caused persistent changes in presynaptic striatal DA system integrity.”
“Variola virus, the causative agent of smallpox, encodes a soluble complement regulator named SPICE. Previously, SPICE has been shown to be much more potent in inactivating human

complement than the vaccinia virus complement control protein (VCP), although they differ only in 11 amino acid residues. In the present study, we have expressed SPICE, VCP, and mutants of VCP by substituting each or more of the 11 non-variant VCP residues with the corresponding residue of SPICE to identify hot spots that GNA12 impart functional advantage to SPICE over VCP. Our data indicate that (i) SPICE is similar to 90-fold more potent than VCP in inactivating human CA, and the residues Y98, Y103, K108 and K120 are predominantly responsible for its enhanced activity; (ii) SPICE is 5.4-fold more potent in inactivating human C4b, and residues Y98, Y103, K108, K120 and L193 mainly dictate this increase; (iii) the classical pathway decay-accelerating activity of activity is only twofold higher than that of VCP, and the 11 mutations in SPICE do not significantly affect this activity; (iv) SPICE possesses significantly greater binding ability to human CA compared to VCP, although its binding to human C4b is lower than that of VCP; (v) residue N144 is largely responsible for the increased binding of SPICE to human C3b; and (vi) the human specificity of SPICE is dictated primarily by residues Y98, Y103, K108, and K120 since these are enough to formulate VCP as potent as SPICE.