Rodent models of attention-deficit hyperactivity disorder: An updated framework for model validation and therapeutic drug discovery

There are over twenty rodent models of Attention-Deficit Hyperactivity Disorder (ADHD), with most reflecting a recognized ADHD subtype. Of these, only five rat models (Neonatal 6-Hydroxydopamine, Spontaneously Hypertensive Rat, Prenatal Alcohol Exposure, Prenatal Nicotine Exposure, and Lphn3 Knockout) and three mouse models (Dopamine Transporter Knockout, Neurokinin-1 Receptor Knockout, and Prenatal Nicotine Exposure) have a sufficient number of publications to explore their suitability for modelling ADHD with respect to core features, executive dysfunction, and medication effects. An updated view is advanced specifying that an informative model encompasses elevated drug use risk as a means to assess ADHD/Substance Use Disorder (SUD) comorbidity, a common co-occurrence among patients. Based on the full range of symptoms and medication effects, it is concluded that the Spontaneously Hypertensive Rat (specifically the Charles River Laboratories substrain) has the most translational support at this stage to model ADHD/SUD comorbidity. The Lphn3 knockout rat model and the prenatal nicotine exposure mouse model are strong contenders if additional validation work is performed, as they have a high degree of construct validity pertaining to genetic and environmental etiologies of ADHD. Research using validated rodent models of ADHD is warranted because their study can provide insights for drug discovery geared toward the development of safer ADHD therapeutics, particularly for adolescent patients. • Few rat and mouse models of ADHD are appropriately validated. • Attention to core features, executive dysfunction, and medication effects is vital. • A view is advanced that ADHD models also should show elevated drug use risk. • SHR/NCrl rats have the most translational support to model ADHD/SUD comorbidity. • Lphn3 KO rats and prenatal nicotine exposed mice have the best construct validity.