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

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.

List of scientific papers

I. Karlsson RM, Holmes A, Heilig M, Crawley JN (2005). Anxiolytic-like actions of centrally-administered neuropeptide Y, but not galanin, in C57BL/6J mice. Pharmacol Biochem Behav. 80(3): 427-36. Epub 2005 Jan 25
https://pubmed.ncbi.nlm.nih.gov/15740785

II. Karlsson RM, Choe JS, Cameron HA, Thorsell A, Crawley JN, Holmes A, Heilig M (2008). The neuropeptide Y Y1 receptor subtype is necessary for the anxiolytic-like effects of neuropeptide Y, but not the antidepressant-like effects of fluoxetine, in mice. Psychopharmacology (Berl). 195(4): 547-57. Epub 2007 Sep 22
https://pubmed.ncbi.nlm.nih.gov/17891380

III. Karlsson RM, Molander A, Holmes A, Tanaka K, Spanagel R, Heilig M (2008). Suppression of ethanol intake and lack of ethanol reward in mice with a deletion of the glutamate transporter GLAST (EAAT1). [Manuscript]

IV. Karlsson RM, Tanaka K, Heilig M, Holmes A (2008). Loss of glial glutamate and aspartate transporter (excitatory amino acid transporter 1) causes locomotor hyperactivity and exaggerated responses to psychotomimetics: rescue by haloperidol and metabotropic glutamate 2/3 agonist. Biol Psychiatry. 64(9): 810-4. Epub 2008 Jun 12
https://pubmed.ncbi.nlm.nih.gov/18550032

V. Karlsson RM, Tanaka K, Saksida LM, Bussey TJ, Heilig M, Holmes A (2008). Assessment of Glutamate Transporter GLAST (EAAT1)-Deficient Mice for Phenotypes Relevant to the Negative and Executive/Cognitive Symptoms of Schizophrenia. Neuropsychopharmacology. Dec 10: Epub ahead of print
https://pubmed.ncbi.nlm.nih.gov/19078949