Alcohol use disorder commonly occurs among patients with schizophrenia and contributes greatly to the morbidity of schizophrenia. Patients with schizophrenia tend to consume modest quantities of alcohol on a regular basis and are less likely to develop alcohol dependence than alcohol abuse, but even this modest use of alcohol dramatically worsens their symptoms and decreases their overall functioning. Green (co- investigator) and colleagues have suggested that such moderate alcohol use may, however, transiently ameliorate a brain reward circuit deficiency that underlies alcohol use disorder in these patients. Unfortunately, available treatments for co-occurring alcohol use disorder in schizophrenia are very limited. This revised R03 proposal seeks to begin a line of research toward the development of such an animal model of alcohol use disorder in schizophrenia, an animal that exhibits characteristics of schizophrenia, and like patients with schizophrenia, also drinks at least moderate amounts of alcohol. To develop this animal model, we propose to use, as a base, a rat with a neonatal ventral hippocampal lesion (the NVHL rat), a well-established animal model of schizophrenia, a rodent that as an adult exhibits requisite characteristics of schizophrenia, demonstrates abnormalities in its brain reward circuit, and, interestingly, has recently been shown to exhibit increased cocaine self-administration. Our preliminary data in a small group of adult NVHL rats also suggest that this rat will voluntarily drink at least moderate amounts of alcohol. This revised research proposal seeks to further probe the potential role of the NVHL rat as an animal model of schizophrenia and comorbid alcohol use disorder. Using free-access conditions, we will: (1) compare the amount and preference of alcohol drinking [and blood alcohol level] in NVHL rats versus sham-operated rats; and (2) compare the size, frequency and temporal distribution of alcohol drinking bouts in NVHL rats versus sham-operated rats. If NVHL rats can be differentiated from sham rats according to these measures, we plan to continue research with NVHL rats in subsequent studies to: (1) explore mechanisms mediating alcohol drinking in these animals (e.g., to address the question of whether alcohol use serves to transiently ameliorate a deficit in brain reward functioning); and (2) screen medications that might be able to decrease alcohol drinking in this rat. Ultimately, we expect to translate the findings from our studies with the NVHL rat into studies involving human subjects, with the long- term goal of this research to find novel medications to treat patients with schizophrenia and alcohol use disorder, and thus to improve the outcome of these patients. Alcohol use disorder occurs commonly among patients with schizophrenia and greatly worsens the overall functioning of these patients. This research seeks to develop an animal model of alcohol use disorder in schizophrenia, an animal model that exhibits schizophrenia-like characteristics as well as increased alcohol drinking. This animal model, when developed, will be used: (1) to elucidate the underlying basis of alcohol use disorder in patients with schizophrenia; and, (2) to develop novel medications to limit alcohol use in these patients. ? ? ? ?
