Neurotoxin Modeling of Brain Disorders — Life-long Outcomes in Behavioral Teratology

Trevor Archer, Danilo Garcia, Archer, Trevor, Garcia, Danilo

Attention-deficit/hyperactivity disorder (ADHD) pathophysiology persists in an obscure manner with complex interactions between symptoms, staging, interventions, genes, and environments. Only on the basis of increasing incidence of the disorder, the need for understanding is greater than ever. The notion of an imbalance between central inhibitory/excitatory neurotransmitters is considered to exert an essential role. In this chapter, we first review how the default mode network functions and dysfunction in individuals diagnosed with ADHD. We also present and briefly review some of the animal models used to examine the neurobiological aspects of ADHD. There is much evidence indicating that compounds/interventions that antagonize/block glutamic acid receptors and/or block the glutamate signal during the "brain growth spurt" or in the adult animal may induce functional and biomarker deficits. Additionally, we present evidence suggesting that animals treated with glutamate blockers at the period of the "brain growth spurt" fail to perform the exploratory activity, observed invariably with control mice, that is associated with introduction to a novel environment (the test cages). Later, when the control animals show less locomotor and rearing activity, i.e., interest in the test cages, the MK-801, ketamine and ethanol treated mice showed successively greater levels of locomotion and rearing (interest), i.e., they fail to "habituate" effectively, implying a cognitive dysfunction. These disturbances of glutamate signaling during a critical period of brain development may contribute to the ADHD pathophysiology. As a final addition, we have briefly identified new research venues in the interaction between ADHD, molecular studies, and personality research.