Animal models of Schizophrenia
Schizophrenia is a complex neuropsychiatric disorder which impairs almost all aspects of a person's mental functions (thought, perception, behavior, emotion, and social interaction). In 2002, the overall cost of schizophrenia was estimated to be $62.7 billion just in the US. It is a brain disease that results from complex interactions among various genetic and environmental factors. Schizophrenia strikes individuals with susceptible genes in their early adulthood, and is usually "triggered" by psychosocial and environmental stress. Animal models play an important role in understanding the neurobiological causes of schizophrenia, as well as for developing effective pharmacotherapies against this illness. The commonly used models rely on the use of psychotomimetic drugs such as amphetamine or phencyclidine (PCP) or brain lesions to produce behavioral or neurochemical changes resembling those found in schizophrenia. Our lab is trying to develop multidimensional models of schizophrenia which captures the nature/nurture interaction, the central role of dopamine and glutamate in the mediation of this disease and the heterogeneous nature of this disease (positive, negative, affective, cognitive symptoms).
Psychopharmacology of Antipsychotic Drugs
Antipsychotic drugs are the primary drugs used to treat schizophrenia. Currently they are classified into two groups, typical and atypical, with atypical drugs offering reduced risk of extrapyramidal motor syndromes (EPS) such as involuntary movements, tremors and rigidity. A great deal of efforts has been devoted to understanding the neurobiological mechanisms of antipsychotic action at the molecular level. As a result, we now know that all antipsychotic drugs antagonize dopamine D2 receptors and this property may contribute to their anti-"psychotic" action. Actions on other receptor systems (5-HT1a, 5-HT2a, DA D1, adrenergic a1, a2) may contribute to the low EPS associated with the atypicals. However, what is less understood is how the neurobiological or brain level changes (e.g. blocking D2) translates into psychotic symptom improvement which occurs at essentially phenomenological or mind level. In other words, we know little about how antipsychotics work psychologically to control the extant delusions and hallucinations and to prevent formation of new delusions and hallucinations in schizophrenic patients. One focus of my work is to try to understand the psychopharmacological mechanisms of action of antipsychotics. We use a variety of animal behavioral models to mimic positive and negative symptoms of schizophrenia and to examine what are neural and psychological processes that antipsychotics act on to achieve their clinical effects. The models used in this lab include both unconditioned natural behaviors (e.g. social interaction, maternal behavior, locomotor activity), as well as conditioned behaviors (e.g. two-way conditioned avoidance response, Pavlovian fear conditioning). We use multiple behavioral and physiological measures such as active avoidance responding, 22 kHz and 50 kHz ultrasonic vocalizations, defecations and body temperature changes to help us understand the multifaceted effects of psychotropic drugs.
Comorbidity of Nicotine Use in Schizophrenia
Clinical observations suggest that there is a serious co-morbidity of nicotine use and schizophrenia. While the prevalence of cigarette smoking in the U.S. population is about 25 to 30%, the rate in the schizophrenic population can reach as high as 90% (Dalack et al., 1998). Schizophrenic patients also tend to be heavy smokers, defined as those who smoke more than one and a half packs a day (Lyon, 1999). They are also less likely to attempt quitting (Lasser et al., 2000) and have higher risk of developing smoking-related illnesses, such as lung cancer, cardiovascular disease and stroke (Hurt et al., 1996; Lichtermann et al., 2001). Exactly why schizophrenic patients smoke is not fully understood. In collaboration with Dr. Rick Bevins's lab, we are interested in developing suitable animal models of schizophrenia that show a high propensity to abuse nicotine so we can start to investigate the neurobiological and behavioral mechanisms underlying cigarette smoking in schizophrenia.
Functional Neuroanatomy of Maternal Behavior
Maternal behavior in rats is a highly motivated and well organized social behavior. It is not just a stereotyped, species-characteristic set of responses. Its activation recruits multiple behavioral systems including perceptual, emotional, memory, and motor systems. Multiple and interconnecting brain systems, coordinated by the action of the parturitional hormones, are thought to mediate this behavior. These neural systems include the final common pathway for the expression of the behavior, the medial preoptic area (MPOA), as well as limbic and cortical systems that influence the hypothalamic mechanisms. Our research seeks to understand how the limbic systems, especially the basolateral amygdala-nucleus accumbens system interacts with the medial preoptic area-periaqueductal gray pathway in the control of the expression and maintenance of this behavior. Currently we are especially interested in the role of serotonin receptors in this behavior and try to study it in the context of postpartum depresssion and psychosis.