Comparative psychology and the grand challenge of drug discovery in psychiatry and neurodegeneration.

Drug discovery for brain disorders is undergoing a period of upheaval. Faced with an empty drug pipeline and numerous failures of potential new drugs in clinical trials, many large pharmaceutical companies have been shrinking or even closing down their research divisions that focus on central nervous system (CNS) disorders. In this paper, we argue that many of the difficulties facing CNS drug discovery stem from a lack of robustness in pre-clinical (i.e., non-human animal) testing. There are two main sources for this lack of robustness. First, there is the lack of replicability of many results from the pre-clinical stage, which we argue is driven by a combination of publication bias and inappropriate selection of statistical and experimental designs. Second, there is the frequent failure to translate results in non-human animals to parallel results in humans in the clinic. This limitation can only be overcome by developing new behavioral tests for non-human animals that have predictive, construct, and etiological validity. Here, we present these translational difficulties as a "grand challenge" to researchers from comparative cognition, who are well positioned to provide new methods for testing behavior and cognition in non-human animals. These new experimental protocols will need to be both statistically robust and target behavioral and cognitive processes that allow for better connection with human CNS disorders. Our hope is that this downturn in industrial research may represent an opportunity to develop new protocols that will re-kindle the search for more effective and safer drugs for CNS disorders.

Scalar timing varies with response magnitude in classical conditioning of the nictitating membrane response of the rabbit (Oryctolagus cuniculus).

The present experiment was aimed at characterizing the timing of conditioned nictitating membrane (NM) movements as function of the interstimulus interval (ISI) in delay conditioning for rabbits (Oryctolagus cuniculus). Onset latency and peak latency were approximately, but not strictly, scalar for all but the smallest movements (<.10 mm). That is, both the mean and standard deviation of the timing measures increased in proportion to the ISI, but their coefficients of variation (standard deviation/mean) tended to be larger for shorter ISIs. For all ISIs, the absolute timing of the NM movements covaried with magnitude. The smaller movements (approximately, .11-.50 mm) were highly variable, and their peaks tended to occur well after the time of US delivery. The larger movements (>.50 mm) were less variable, and their peaks were better aligned with the time of US delivery. These results are discussed with respect to their implications for current models of timing in eyeblink conditioning.