Christine Konradi - US grants

DESCRIPTION (provided by applicant): The adolescent brain is still developing and highly vulnerable to chemical influences. From a neurobiological perspective, children and adolescents are not small adults, and they are more vulnerable to the adverse effects of drugs, chemicals, or diseases. Any chemical impact on a brain that is still developing and pruning neuronal connections can affect this process and alter the course of what should have been the adult destiny of the brain. By virtue of the ongoing developmental processes, adolescent drug exposure can have far more serious consequences than adult drug exposure. In a behavioral and a molecular analysis, we will test the hypothesis that binge-administration of cocaine during adolescence affects the biology and function of the prefrontal cortex (PFC) in adulthood. The PFC is critical for cognitive processing during early development and into adulthood. Dopamine plays an important role in the development of the PFC and of these cognitive abilities. An artificial alteration of dopamine levels by chemicals such as cocaine during adolescence could have a profound effect on cognitive processing in adulthood. In two specific aims we plan to address the potential long-term effect of cocaine exposure during adolescence on (1) a PFC-specific test, the attentional set-shifting task, and (2) on adult gene expression patterns in two areas of the PFC. Both specific aims will be carried out ten days after finishing the cocaine binge-paradigm, and in adulthood three and six weeks after the end of cocaine administration. Molecular analysis will also be carried out during cocaine administration. We expect to see altered PFC function and biology long after cocaine administration has seized. If this paradigm proves to be predictive of adolescent cocaine administration, we will, in future proposals, investigate the consequences of adolescent cocaine administration on other behaviors and brain areas relevant to drug abuse.

[unreadable] DESCRIPTION (provided by applicant): Project Summary: Antipsychotic drugs (APDs) are used to treat schizophrenia and they have the potential to ameliorate the clinical symptoms. Because APDs do take time to exhibit their full therapeutic potential, it has been suggested that molecular changes, i.e. altered gene and protein expression, are an important element of their mechanism of action. These findings and hypotheses imply that (a) treatment with APDs reinstates a process or anatomic substrate that is disturbed in schizophrenia, and (b) that gene expression changes are involved in the reinstatement. An analysis of gene expression changes in the relevant anatomical structures after treatment with APDs could therefore provide valuable information about the disease, the mechanism of action of both conventional and atypical APDs, and it could provide leads in the search for novel treatment strategies. High amongst the relevant anatomical substrates in schizophrenia are limbic structures, particularly the hippocampus and the amygdala. It has been shown consistently that schizophrenia is accompanied by reductions in the hippocampus-amygdala complex. This reduction is correlated with poorer information processing in the disorder. The abnormalities have also been observed in drug-naive patients, indicating that they are not caused by the treatment. The present proposal will investigate gene expression patterns in the hippocampus and the amygdala of rats after chronic treatment with the APDs, haloperidol and clozapine. Both drugs will be used at three different concentrations in independent groups of rats, and analyzed in a manner to further our understanding of the molecular properties that unite these drugs, as well as properties that separate them. Furthermore, we will establish a gene expression profile in both anatomic structures that has predictive value for APD exposure. This profile can serve as an assay for future drug-discovery purposes. Relevance: Using recently developed, powerful molecular tools, we propose to investigate how APDs act in brain areas that are altered in schizophrenia. The information gained can be used to (a) understand some of the underlying pathophysiology in schizophrenia, (b) develop more useful assays to scan novel drugs for antipsychotic properties, and (c) develop novel approaches to the treatment of schizophrenia. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Bipolar disorder (BPD) affects approximately 3% of the population in the US, and is among the 10 leading causes of disability in the developed world. The etiology of the disease is unknown and treatment options are either based on empirical observations from serendipitous discoveries of mood stabilizing effects of certain substances, or on cross-over trials with psychoactive medications used in other psychiatric disorders. Not surprisingly, these treatment options are wanting in many cases, and they come with unpleasant side effects. Finding organic abnormalities in BPD can promote our understanding of the etiology of the disease, and help us define better-targeted therapeutic approaches. One particular hypothesis about BPD is mitochondrial dysfunction. We have previously shown that mRNA levels of genes of the mitochondrial electron transport chain (mtETC) are reduced in the hippocampus of BPD patients, and examined primary lymphocytes to extend our findings. The lymphocytes were subjected to low-glucose stress, with the result that lymphocytes from normal controls up-regulated mtETC levels in response to low-glucose stress, while lymphocytes from BPD patients failed to respond. These experiments showed for the first time that cells have a distinct molecular reaction to energy stress, and that this response is missing in BPD. We would now like to establish transformed lymphoblastoid cell lines for further experimental manipulations, since for an in-depth examination of the hypothesis of mitochondrial dysfunction in BPD tissue we will need to increase the number and viability of lymphocytes per study participant. We have tried to use cell lines commercially available for genomic analysis, but found unacceptable batch effects in gene expression patterns due to the fact that lymphoblastoid cell lines from controls and patients are often collected at different times and locations, and little attention is paid to the number of passages the lines are subjected to. Therefore, we need to collect our own cell lines to examine if immortalization under tightly controlled conditions can be accomplished in a manner that retains gene expression patterns, at least over a limited number of passages. We have established a collaboration with the Department of Psychiatry at Vanderbilt Medical School through which we can recruit study participants, and we have chosen the R21 funding route to establish a model system in which we can examine mitochondrial function in BPD. If the outcome is positive, we will employ this system in the future for a more extensive analysis. PUBLIC HEALTH RELEVANCE: The causes of bipolar disorder are unknown, and treatment options are not well targeted. We have found cellular abnormalities in BPD patients that involve mitochondrial function. We are trying to replicated and extend these findings, since they open new treatment approaches for BPD, and since they can improve our understanding of the organic mechanisms leading to the clinical symptoms observed in BPD.