College of Pharmacy and Pharmaceutical Sciences

• Behavioral genetics of addiction
• Neurodevelopmental models of psychiatric disorders
• Genetic models of psychiatric disorders
• Epigenetic mechanisms in psychiatric disorders
• Attention deficit hyperactivity disorder
• Dopamine transporter knockout mice
• The behavioral and neural consequences of social isolation
• The role of cell adhesion molecules in addiction

The causes of addiction and other psychiatric disorders involve a complex interplay between genetic predisposition and the environment, in particular early life experiences. An important aspect of developing new drug treatments for psychiatric disorders is to identify these causes and to incorporate them into valid animal models. Dr. Hall has spent his career developing animal models of psychiatric disorders, focusing initially upon the study of early life experiences, in particular deprivation of social play, and later upon genetic models. Current research in the laboratory focuses on several aspects of such models.

1. Genetic contributions to addiction liability:  Dr. Hall researched alcoholism and drug addiction models for 20 years at the National Institute on Alcoholism and Alcohol Abuse (NIAAA) and the National Institute on Drug Abuse (NIDA).  In particular his work at NIDA focused on genetic contributions to addiction using genetically modified mouse models.  These studies were extensive, beginning with genes that were the major targets of addictive drugs, but later moving on to novel genes identified in genome wide association studies for addiction. Among the many important contributions of this work was the demonstration that deletion of the µ opioid receptor affects ethanol consumption, as well as the reinforcing effects of a number of addictive drugs. By contrast, to eliminate the reinforcing effects of cocaine, deletion of both the dopamine and serotonin transporters was necessary, apparently due to alterations in the roles of the serotonin and norepinephrine transporters in cocaine effects. Current work focuses on the mechanisms underlying increases ethanol drinking (escalation) during the development of alcoholism in animal models.

2. Lethal and toxic effects of modified amphetamines (e.g. “bath salts”). Another aspect of Dr. Hall’s research into the mechanisms of drugs of abuse investigates the lethal and toxic effects of synthetic psychoactive cathinones (SPCs; so-called “bath salts”). Current research investigates the lethal and toxic effects SPCs in mice.

3. DAT KO mouse as an animal model of attention deficit hyperactivity disorder (ADHD). In a series of studies with collaborators George R. Uhl, Ichiro Sora, and other colleagues, Dr. Hall found that dopamine transporter knockout (DAT KO) have ADHD-like deficits: hyperactivity, impaired pre-attentional processes, impaired learning, and impaired executive function. These deficits are reversed by drugs that treat ADHD (the same drugs cause deficits in mice without DAT mutations). This research has suggested that stimulants may act to treat ADHD by acting at the norepinephrine transporter in the prefrontal cortex. In the DAT KO model this reverses imbalances of brain function that resemble similar alterations in patients with ADHD. Current work investigates the effects of DAT KO in models of attention and a potential non-stimulant, approach to ADHD-treatment.

4. Neurodevelopmental effects of social isolation: implications for psychiatric disorders. Dr. Hall’s PhD work, with Professor Trevor Robbins, helped to develop isolation-rearing as an animal model of schizophrenia that has greater validity than most other models. This work included the demonstration of a hyperdopaminergic state resulting from isolation rearing, as well as sensorimotor-gating deficits similar to those observed in schizophrenia patients that are reversed by antipsychotic drugs. Subsequent work showed that these effects are not limited to dopamine antagonists, but that the isolation-rearing model can be used to identify antipsychotic medications acting through a variety of mechanisms. Consequently, this model came to be used extensively by pharmaceutical companies in the evaluation of potential antipsychotic treatments. Current work investigates sex differences in the effects of early isolation and the mechanisms by which social play produces these effects.