Theoretical and practical applications of the intracerebroventricular route for CSF sampling and drug administration in CNS drug discovery research: a mini review.

Clinically, central nervous system (CNS) disorders account for more hospitalisations and prolonged care than almost all other diseases combined. In the preclinical setting, the intracerebroventricular (ICV) route for cerebrospinal fluid (CSF) sampling or dose administration in rodent models of human CNS disorders has potential to provide key insight on the pathobiology of these conditions. Low level neuroinflammation is present in >40% of patients with severe depression or schizophrenia and so comparative assessment of CSF composition between patients and rodent models of CNS disorders is potentially invaluable for hypothesis generation and for assessing rodent model validity. As molecules in the CSF have relatively low protein binding and are freely exchanged into the extracellular fluid of the brain parenchyma, supraspinal drug administration into the CSF can produce therapeutic drug concentrations in the brain. Direct administration of investigational agents into the CSF of the lateral ventricle of the brain enables intrinsic efficacy and adverse effect profiles to be evaluated without the confounding effects of drug metabolism, due to the low capacity of the CNS to metabolise exogenous compounds. It is our view that the ICV route for CSF sampling and for administration of novel drugs in development is under-utilised in preclinical research on CNS disorders. This is due to the high degree of technical skill and low margin for error associated with correct ICV guide cannula implantation in the rat. However, these technical challenges can be overcome by using standardised procedures and attention to detail during surgery and in the post-operative period.