There is a strong positive association between heavy drinking (i.e., alcoholism) and depression, and epidemiological studies suggest that this depression can negatively influence successful cessation of alcohol use. Therefore, there is a fundamental need to develop new antidepressants that effectively treat depression, and can be used in conjunction with alcohol and/or are quick acting. Ketamine, a glutamatergic NMDA receptor antagonist shows promise as quick acting antidepressant. Preliminary studies also indicate a possible similar effect with AMPA (2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl) propanoic acid). However, the efficacy of these drugs with alcohol-induced depression is unknown. Our central hypothesis is that ketamine and AMPA will both be effective in blocking and alleviating depression caused by long-term alcohol use through mediation of neurotrophic and synaptogenic pathways. Our rationale for these studies is that identification of the central mechanisms by which ketamine and AMPA act to induce behavioral changes will help establish a strong scientific framework for new cessation treatment protocols in human patients with alcoholism or other addiction-depression co-morbid conditions. Guided by our preliminary data, and knowledge of the field, this hypothesis will be tested by pursuing two specific aims: 1) Examine the antidepressant effects of ketamine and AMPA during alcohol use and in acute withdrawal. 2) Examine the underlying neurobiological mechanisms of ketamine and AMPA in alcohol-induced depression. Under the first aim, we will compare rats treated with various doses of ketamine or AMPA during or after chronic exposure to high doses of alcohol to assess the drugs' potential to block the formation, or alleviate alcohol-induced depression, respectively. Under the second aim, we will elucidate how effective doses of ketamine or AMPA may alter central neurotrophic and synaptogenic markers. This approach is innovative, in our opinion, because it departs from the status quo of using biogenic amine based antidepressants (e.g. serotonin reuptake inhibitors: SSRIs), which can negatively interact with alcohol and have a lag in effectiveness. The proposed research is significant, because it is the first step in a continuum of research that will set a foundation for understanding how ketamine and AMPA can be effectively used to aid in alcohol use cessation, and possibly other addiction-depression co-morbid conditions. Moreover, findings will lead to further studies using ketamine and AMPA in combination treatment, and provide direction in understanding the differential acute and long-term mechanistic actions of these drugs in depression associated with alcoholism.
The proposed research is relevant to public health because the discovery of how ketamine and AMPA affect alcohol-induced depression could ultimately provide a tool to aid in treatment of and help prevent relapse to alcoholism. Thus, the proposed research is relevant to NIAAA's request for proposals that study neurobiological mechanisms that contribute to alleviating alcohol dependence, and its mission to reduce alcohol related health issues.
