Long-term analgesic effects of inescapable shock and learned helplessness.

Although exposure to inescapable shocks induced analgesia in rats, the analgesia was not manifest 24 hours later. A brief reexposure to shock, however, restored the analgesia. This reexposure to shock had an analgesic effect only if the rats had been shocked 24 hours previously. Further, long-term analgesic effects depended on the controllability of the original shocks and not on shock exposure per se. Implications of these results for learned helplessness and stress-induced analgesia are discussed.

Exploration of the African green monkey as a preclinical pharmacokinetic model: oral pharmacokinetic parameters and drug-drug interactions.

African green monkeys (vervets) have been proposed as an alternate species that might allow improved access and provide high-quality pharmacokinetic results comparable with other primates. However, no oral data are available in vervets to evaluate cross-species predictive performance. Therefore, this study was conducted to evaluate the use of the vervet to predict human oral pharmacokinetics and drug interactions. Oral pharmacokinetic studies were conducted in the vervet for eight compounds: phenytoin, moxifloxacin, erythromycin, lidocaine, propranolol, ciprofloxacin, metroprolol, and prednisolone. To assess drug-drug interactions, co-administration experiments were conducted with ketoconazole and either propranolol or erythromycin. In general, the vervet provided similar predictivity for human oral exposure as cynomolgus or rhesus monkeys. In all non-human primates, human exposure to phenytoin would be over-predicted, and erythromycin, lidocaine, and propranolol under-predicted, with good predictivity for the other compounds studied. Furthermore, in the vervet, ketoconazole co-administration resulted in a six-fold increase in exposure to erythromycin, demonstrating proof of concept for drug-drug interaction screening. These data support further exploration of the vervet as an alternate primate species for use in preclinical pharmacokinetic screening.

Salvaging the self in a world without soul: William James's The Principles of psychology.

This article explores William James's transformation of the religious soul into the secular self in The Principles of Psychology. Although James's views on the self are familiar to many historians of psychology, the article places his treatment of the self within the broader social and cultural context of a secularizing, industrializing society. There were palpable tensions and anxieties that accompanied the cultural shift, and these are particularly transparent in James's Principles. James attempted the project of secularizing the soul in order to promote a natural science of the mind but with marked ambivalence for the project, because it left out some of the moral and metaphysical questions of great interest to him.

Eponymy, obscurity, Twitmyer, and Pavlov.

The discovery of the conditioned reflex is generally credited to Ivan P. Pavlov. So closely is Pavlov associated with this phenomenon that it is commonly referred to as the Pavlovian conditioned reflex. Edwin B. Twitmyer independently discovered the conditioned reflex at approximately the same time and reported the finding in 1904 at the meeting of the American Psychological Association. Unlike Pavlov's, Twitmyer's data had little impact on psychology. There have been various hypotheses to explain the failure of the field to recognize Twitmyer's discovery. These explanations are criticized and modified to reflect an emphasis on Twitmyer's and Pavlov's respective social and intellectual contexts.

Regulation of cell morphology and cytochrome P450 expression in human hepatocytes by extracellular matrix and cell-cell interactions.

The influence of extracellular matrix conditions and plating density on cell cytoarchitecture and the constitutive and chemically induced expression of cytochrome P450 3A4 (CYP3A4) was examined in primary cultures of human hepatocytes. Constitutive and drug-induced microsomal CYP3A4 expression occurred equally well in human hepatocyte cultures maintained on either a complex or simple substratum (Matrigel vs collagen, type I), or in a sandwich configuration (i.e., between two layers of extracellular matrix), despite the markedly different morphological properties exhibited by each condition. However, a density-dependent decrease in both the constitutive and induced levels of CYP3A4 was observed in hepatocytes maintained on a simple collagen substratum as plating density was reduced from 100% to 25%. Marked alterations in cell shape and cytoarchitecture were noted concomitant with decreases in the expression and localization of intercellular gap junctions and E-cadherin-mediated cell adhesions. In addition, the intracellular distribution of microtubules and microfilaments was altered substantially and the expression of immunoreactive actin and beta-tubulin increased as cell density was decreased. These effects were reversed to some extent by overlaying monolayers with extracellular matrix or by co-culturing with another cell type. Efforts to maintain normal cell shape and cytoskeletal distribution in hepatocytes at low cell density with a Matrigel substratum failed to restore normal basal levels of CYP3A4 expression or responsiveness to rifampicin (RIF). Likewise, E-cadherin and Cx-32 expression was again reduced, even though the distribution and expression of cytoskeletal elements returned to normal levels. These results suggest that cell-cell contacts, but not the extracellular matrix configuration or composition, play a critical role in determining normal responsiveness to chemical modulators in human hepatocytes.