An optimized procedure for robust volitional cocaine intake in mice.

Substance use disorder (SUD) is a behavioral disorder characterized by volitional drug consumption. Mouse models of SUD allow for the use of molecular, genetic, and circuit-level tools, providing enormous potential for defining the underlying mechanisms of this disorder. However, the relevance of results depends on the validity of the mouse models used. Self-administration models have long been the preferred preclinical model for SUD as they allow for volitional drug consumption, thus providing strong face validity. While previous work has defined the parameters that influence intravenous cocaine self-administration in other species-such as rats and primates-many of these parameters have not been explicitly assessed in mice. In a series of experiments, we showed that commonly used mouse models of self-administration, where behavior is maintained on a fixed-ratio schedule of reinforcement, show similar levels of responding in the presence and absence of drug delivery-demonstrating that it is impossible to determine when drug consumption is and is not volitional. To address these issues, we have developed a novel mouse self-administration procedure where animals do not need to be pretrained on sucrose and behavior is maintained on a variable-ratio schedule of reinforcement. This procedure increases rates of reinforcement behavior, increases levels of drug intake, and results in clearer delineation between drug-reinforced and saline conditions. Together, these data highlight a major issue with fixed-ratio models in mice that complicates subsequent analysis and provide a simple approach to minimize these confounds with variable-ratio schedules of reinforcement. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The pathology and changing epidemiology of dialysis-related cardiac beta-2 microglobulin amyloidosis.

Cardiac amyloidosis in the setting of systemic amyloidosis due to ß2-microglobulin can occur in the setting of long-term dialysis. It has been suggested that newer dialysis techniques may prevent or at least reduce the likelihood of this disorder occurring. Currently, the prevalence and incidence of dialysis-related cardiac ß2-microglobulin amyloidosis are unclear. The published literature regarding dialysis-related cardiac ß2-microglobulin amyloidosis (Aß2M) was reviewed, and a new case of this disorder is reported. The cumulative available data were analyzed for changing patient characteristics over time. Cardiac Aß2M was previously a common condition in patients who had undergone dialysis for 9 or more years with traditional low-flow dialysis membranes. Newer dialysis technologies reduce, but do not normalize, serum ß2-microglobulin levels in chronic dialysis patients. Newer dialysis technologies appear to reduce the risk of developing Aß2M compared with traditional low-flow dialysis membranes. New cases of documented dialysis-related cardiac Aß2M are uncommon. Analysis of the cases of dialysis-related cardiac Aß2M published over the last 3 decades reveals increasing dialysis intervals over time. Thus, new cases of this disorder are typically associated with remote prior dialysis with low-flow membranes. While initially, the majority of cases of dialysis-related cardiac Aß2M were reported from Europe and the United States, more recently, the majority of cases were reported from Japan, where there is a relatively large population of patients on very long-term dialysis. In addition, low-flow dialysis membranes continue to be used in many parts of the world, raising the potential for dialysis-related cardiac Aß2M to be more common in those countries. Dialysis-related osteoarticular Aß2M appears to continue to occur in the setting of chronic dialysis with the use of high-flow membranes. Dialysis-related cardiac Aß2M is currently uncommon and typically associated with the use of low-flow dialysis membranes. However, the condition could potentially occur in the setting of long-term dialysis even with the use of high-flow membranes. SUMMARY: Dialysis-related cardiac ß2-microglobulin amyloidosis frequently occurred in the past in patients who had undergone dialysis for nine or more years. Currently, the condition is uncommon and typically associated with remote prior dialysis with low-flow membranes. There is potential for this condition to continue to afflict patients receiving chronic dialysis with newer dialysis technologies.