MODEL OF SCHIZOPHRENIA--ROLE OF CORTICAL DOPAMINE
Principal Investigator: JANET FINLAY
Abstract: Postmortem studies indicate that the dopamine (DA) innervation of prefrontal cortex (PFC) is diminished in schizophrenic subjects. Furthermore, neurodevelopmental disruptions involving mesoprefrontal DA neurons are thought to contribute to the pathophysiology of schizophrenia and could, in part, account for the emergence of symptoms as the individual matures. To determine the potential functional consequences of this structural abnormality, I will examine whether partial loss of DA axons in the prefrontal cortex (PFC) sustained early in development (12 days of age) differentially affect function of PFC in the prepubertal and adult rat. First, we will examine the effect of partial loss of DA axons sustained early in development on local extracellular DA in PFC of the prepubertal and adult rat (Aim 1). Our recent studies indicate that 60% loss of DA axons in PFC sustained immediately prior to puberty (40 days of age), decreased basal and stress- evoked extracellular DA in PFC of the adult rat (68 days of age). Thus, moderate loss of DA fibers as recently observed in PFC of schizophrenic subjects, may be sufficient to impair the function of PFC. I will also examine the effects of partial loss of DA axons in PFC sustained early in development on the ability of the PFC to regulate the neurochemical activity of a subcortical target area, the mesoaccumbens DA projection (Aim 2). Previously, it has been suggested that diminished activity of mesoprefrontal DA neurons augments the activity of subcortical DA neurons and that both events contribute to the pathophysiology of schizophrenia. Our own studies indicate that partial loss of DA axons in PFC sustained immediately prior to puberty, increased stress-evoked DA release in the NAS shell of adult rats. Finally, we will examine the impact of partial loss of DA axons in PFC sustained early in development on behaviors thought to be modulated by mesoprefrontal and mesoaccumbens DA neurons in the prepubertal and adult rat (Aim 3). It has been suggested that dysfunction of mesoprefrontal and mesoaccumbens DA neurons together give rise to some of the behavioral symptoms of schizophrenia. Previously, we reported that partial loss of DA axons in PFC sustained immediately prior to puberty attenuated amphetamine-evoked DA release in the NAS core and amphetamine-induced motor behavior in adult rats. Together, the latter findings suggest that neurochemical interactions between mesocortical and mesoaccumbens DA neurons ultimately play a role in the expression of behavior. The present studies will correlate changes in the activity of mesoprefrontai and mesoaccumbens DA neurons with performance on a delayed response task, motor behavior, and the behavioral response to appetitive and aversive stimuli.
Funding Period: 1999-09-01 - 2005-05-31
more information: NIH RePORT
- Neonatal depletion of cortical dopamine: effects on dopamine turnover and motor behavior in juvenile and adult ratsP J Boyce
Department of Psychology, Western Washington University, 220 Miller Hall, MS 9089, Bellingham, WA 98225, USA
Brain Res Dev Brain Res 156:167-75. 2005....
- Desipramine attenuates working memory impairments induced by partial loss of catecholamines in the rat medial prefrontal cortexS M Clinton
Mental Health Research Institute and Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109, USA
Psychopharmacology (Berl) 183:404-12. 2006....
- Extracellular dopamine and norepinephrine in the developing rat prefrontal cortex: transient effects of early partial loss of dopaminePatricia J Boyce
Department of Psychology, Western Washington University, Bellingham, WA 98225 9089, United States
Brain Res Bull 79:104-110. 2009..The present data suggest that early partial loss of mesoprefrontal DA nerve terminals, resulting in a persistent decrease in tissue DA concentrations, is unlikely to result in persistent alterations in local DA release...