Update in the methodology of the chronic stress paradigm: internal control matters

To date, the reliability of induction of a depressive-like state using chronic stress models is confronted by many methodological limitations. We believe that the modifications to the stress paradigm in mice proposed herein allow some of these limitations to be overcome. Here, we discuss a variant of the standard stress paradigm, which results in anhedonia. This anhedonic state was defined by a decrease in sucrose preference that was not exhibited by all animals. As such, we propose the use of non-anhedonic, stressed mice as an internal control in experimental mouse models of depression. The application of an internal control for the effects of stress, along with optimized behavioural testing, can enable the analysis of biological correlates of stress-induced anhedonia versus the consequences of stress alone in a chronic-stress depression model. This is illustrated, for instance, by distinct physiological and molecular profiles in anhedonic and non-anhedonic groups subjected to stress. These results argue for the use of a subgroup of individuals who are negative for the induction of a depressive phenotype during experimental paradigms of depression as an internal control, for more refined modeling of this disorder in animals.     

Effects of age on sympathetic innervation of the myenteric plexus and gastrointestinal smooth muscle of Fischer 344 rats

Loss of myenteric neurons with age is well documented, however little is known about age-related changes of the sympathetic innervation of the myenteric plexus and gastrointestinal smooth muscle. The goal of the present study, therefore, was to evaluate the influence of age on the sympathetic innervation of the myenteric plexus throughout the gastrointestinal tract. Ad libitum fed virgin male Fischer 344 rats at 3, 15–16, 24, and 27–28 months of age were sampled. Whole mounts of the stomach, small intestine, and large intestine were processed with an antibody to tyrosine hydroxylase (TH). Additionally, some specimens labeled for TH were stained for NADPH-diaphorase to selectively label the nitrergic subpopulation of neurons in the myenteric plexus. Age-related changes in the TH-positive axons occurred as early as 15–16 months and became more pronounced by 27–28 months. Changes included markedly swollen axons and terminals and a decrease in the intensity of TH staining in some of the surviving processes. Similarly, swollen NADPH-diaphorase-positive axons were found in the myenteric ganglia and secondary plexus between ganglia in the whole mounts of rats 15–28 months of age, but swollen nitrergic axons and dystrophic TH-positive axons were never present in the same ganglion or connective. Therefore, in the aged rat, deterioration of the sympathetic innervation of the myenteric plexus could be one possible mechanism for the age-related decline in gastrointestinal motor function evidenced in the elderly.     

Timing of carcinogenicity studies and predictability of genotoxicity for tumorigenicity in anti-HIV drug development

The timing of carcinogenicity studies in parallel with the clinical development of anti-human immunodeficiency virus (HIV) drugs has been flexible for most cases in the past. This includes postponement of the initiation of the studies and submission of final audited reports to the US Food and Drug Administration (FDA) for a new drug application (NDA) approval. We address this regulatory practice for anti-HIV drugs for which, in the past, there had been no effective treatment. We also examine the correlation of genotoxicity data with carcinogenicity data for the varied subclasses of anti-HIV drugs. We suggest that this regulatory policy regarding the timing of carcinogenicity testing does not compromise the safety standards of FDA's drug evaluation and the approval process. The policy does facilitate availability of these agents to meet the medical needs of the target population. Our analysis on the profile of carcinogenicity findings of anti-HIV drugs shows trends of class effects. Additionally, both carcinogenicity and genotoxicity data show significant correlations, which provide useful insights into issues involving these 2 important areas of toxicological investigations.