Advancing Pharmacotherapy Development from Preclinical Animal Studies

Abstract

Animal models provide rapid, inexpensive assessments of an investigational drug's therapeutic potential. Ideally, they support the plausibility of therapeutic efficacy and provide a rationale for further investigation. Here, I discuss how the absence of clear effective-ineffective categories for alcohol use disorder (AUD) medications and biases in the clinical and preclinical literature affect the development of predictive preclinical alcohol dependence (AD) models. Invoking the analogical argument concept from the philosophy of science field, I discuss how models of excessive alcohol drinking support the plausibility of clinical pharmacotherapy effects. Even though these models are not likely be completely discriminative, they are sensitive to clinically effective medications and have revealed dozens of novel medication targets. In that context, I discuss recent preclinical work on GLP-1 receptor agonists, phosphodiesterase inhibitors, glucocorticoid receptor antagonists, nociception agonists and antagonists, and CRF1 antagonists. Clinically approved medications are available for each of these drug classes. I conclude by advocating a translational approach in which drugs are evaluated highly congruent preclinical models and human laboratory studies. Once translation is established, I suggest the burden is to develop hypothesis-based therapeutic interventions maximizing the impact of the confirmed pharmacotherapeutic effects in the context of additional variables falling outside the model.

The Interplay Between Subjective Response to Alcohol, Craving, and Alcohol Self‐Administration in the Human Laboratory

“…Craving for alcohol can also be captured through cue-or stress-induction paradigm (Plebani et al, 2012). Together, these models produce measures of craving for alcohol that are either alcohol-induced, cue-induced, or stress-induced, which in turn parallels nicely with the preclinical literature on alcohol/drug reinstatement (Egli, 2018). Recent studies examining the factor structure of responses to an alcohol challenge suggested that alcohol craving is distinct from other dimensions of SR, namely stimulation, sedation, and negative mood (Bujarski et al, 2015b, Ray et al, 2009.…”

The Endocrine System and Alcohol Drinking in Females

“… 5 , 8 , 13 , 92 Both glucocorticoid receptors and CRF Subscript 1 receptors are being pursued as potential targets for AUD pharmacotherapies, but preclinical data in support of these targets have been generated primarily in males. 98 Recent work in male and female mice found that a history of alcohol drinking and intermittent PS exposure produced sexually divergent and brain region differences in protein levels for glucocorticoid receptors and CRF Subscript 1 receptors. 95 Increased cortical glucocorticoid receptor levels and hippocampal CRF Subscript 1 receptor levels were only found in female mice.…”

The future of translational research on alcohol use disorder

“…AUD is also a heritable disorder, with a host of promising advances in understanding genetic causation and genetic predictors of treatment response 3,4 . While the past two decades have seen remarkable advances in our understanding of the neuroscience of addiction, 5,6 the translation of that knowledge to addiction therapeutics has been slower to materialize 7,8 . Efforts to improve this translation are timely in face of the BRAIN Initiative, which seeks to catalyze neuroscience discoveries to improve the treatment of neuropsychiatric disorders 9 .…”