Neuropeptide Y (NPY) and glutamate transporter (GLAST) in behavioral models of psychiatric disorders

Abstract

For many psychiatric disorders there are still unmet needs for treatment. Using genetically modified mice provide means to study the systems that underlie these disorders as well as identifying potential novel targets for treatment. In this thesis we focused on mouse models of two different systems, using behavioral measures to study their relationship with anxiety, depression, alcoholism and schizophrenia.

In the first part we investigated the anti anxiety-like effects of neuropeptide Y (NPY) in mice. Administration of NPY into the lateral ventricle produced an anxiolytic-like behavior in regular C57BL/6J mice which was not evident in mice lacking the NPY Y1 receptor, confirming that the anxiolytic-like response of NPY is dependent on the NPY Y1 receptor. In addition, the NPY Y1 receptor mutant mice showed a depressant-like behavior on two different paradigms. Both the antidepressant effect of fluoxetine, and its action to stimulate hippocampal neurogenesis were intact in the NPY Y1 receptor mutant mice.

Increased levels of glutamate, which could potentially be caused by a deficiency in glutamate transporters has been implicated in a wide variety of psychiatric disorders. In the second part of this work we started with examining the glutamate aspartate transporter (GLAST) mutant mice for behavioral stress responses and alcohol addiction. Lack of GLAST did not alter anxiety-like behavior or the anxiety-related response to stress, and quite contrary to what was predicted, GLAST mutant mice demonstrated a decrease of alcohol consumption and conditioned place preference for alcohol. Furthermore, in an examination of the consequences of this gene deletion in schizophrenia-like behavior the GLAST mutants exhibited phenotypic features associated with the positive, negative and cognitive symptoms of schizophrenia.