This is an application for funding of a study examining the role of a2-containing GABAA receptors animal models of depression. It has been shown previously that mice which display reduced GABAergic inhibition (32 mice) display a phenotype reminiscent of depression. It is not known which GABAA receptor subtypes mediate antidepressant-like actions, while we have recently obtained preliminary data suggesting that 13-containing GABAA receptors mediate prodepressant-like actions. Whereas dopaminergic neurons in the ventral tegemental area express primarily a3-containing GABAA receptors, the GABAergic neurons in the nucleus accumbens primarily express a2-containing GABAA receptors. Using mice lacking the a2 subunit, we want to test the hypothesis that a2-containing GABAA receptors mediate an antidepressant-like action in the despair-based forced swim test, the conflict-based novelty-suppressed feeding test and the reward-based intracranial self-stimulation paradigm. The identification of the GABAA receptor subtype responsible for antidepressant-like effects would represent an important advance for understanding mood regulation and would provide a new avenue for the development of novel antidepressant agents. Depression and related mood disorders are among the greatest public health problems;severe forms of depression affect 2-5% of the U.S. population, and up to 20% of the population suffer from milder forms of the illness. Symptoms of depression include a reduced ability to experience reward (anhedonia), dysphoria, anxiety and despair, and a substantial number of patients do not respond satisfactorily to current treatment options. Identification of the a2-containing GABAA receptor as having antidepressant and in particular reward-enhancing functions would identify this receptor subtype as a target for the development of antidepressants with a novel mechanism of action.
Depression and related mood disorders are among the greatest public health problems;severe forms of depression affect 2-5% of the U.S. population, and up to 20% of the population suffer from milder forms of the illness. Symptoms of depression include a reduced ability to experience reward (anhedonia), dysphoria, anxiety and despair, and a substantial number of patients do not respond satisfactorily to current treatment options. Identification of the ?2-containing GABAA receptor as having antidepressant and in particular reward-enhancing functions would identify this receptor subtype as a target for the development of antidepressants with a novel mechanism of action.
| Engin, Elif; Liu, Jing; Rudolph, Uwe (2012) ?2-containing GABA(A) receptors: a target for the development of novel treatment strategies for CNS disorders. Pharmacol Ther 136:142-52 |
| Smith, Kiersten S; Rudolph, Uwe (2012) Anxiety and depression: mouse genetics and pharmacological approaches to the role of GABA(A) receptor subtypes. Neuropharmacology 62:54-62 |
| Vollenweider, Isabel; Smith, Kiersten S; Keist, Ruth et al. (2011) Antidepressant-like properties of *2-containing GABA(A) receptors. Behav Brain Res 217:77-80 |
| Rudolph, Uwe; Knoflach, Frederic (2011) Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes. Nat Rev Drug Discov 10:685-97 |
