Yousef Tizabi - US grants

Nicotine, the primary psychoactive gent in tobacco, interacts with specific neurotransmitter systems including the noradrenergic system. Noradrenergic neurotransmission is mediated by several receptor subtypes including alpha2-adrenoceptors. Nicotine-alpha2-adrenoceptors interactions may not only be responsible for some of the beneficial effects of nicotine, but may also be involved in nicotine dependence and nicotine withdrawal symptoms. Indeed, smoking cessation may be facilitated by clonidine, an alpha2-adrenoceptor agonist. However, clonidine's adverse effects preclude its use as a first-line treatment in smoking cessation. Various subtypes of alpha-2 adrenoceptors with distinct central distribution have been identified. Chronic nicotine administration results in increased density of cortical alpha2-adrenoceptors. However, it is not know whether alpha2-adrenoceptors in other discrete brain regions are also affected by nicotine. More importantly, no information is available on interactions between nicotine and specific alpha2-adrenoceptor subtype(s). This information is critical in identifying specific alpha2-adrenoceptor subtypes as potential targets for the development of novel agents in treatment of nicotine dependence and/or withdrawal. Thus, we propose to establish the specificity, time-course, duration, and dose-response relationship between nicotine administration/withdrawal and central alpha 2-adrenoceptors. Furthermore, since gender differences in the effects of nicotine and clonidine have been observed, both male and females will be studied. Nicotine will be administered to rats by osmotic mini-pumps. Autoradiography will be used to quantify alpha2-adreneceptor subtypes plasma levels of nicotine and cotinine (a major nicotine metabolite) will be determined by gas chromatography/mass spectrography and will be correlated with receptor binding data. These studies will significantly enhance our understanding of nicotine-alpha2-adrenoceptor interactions in the brain and will set the stage for further characterization of this interaction which may lead to novel pharmacotherapy in smoking cessation.

ABSTRACT Novel Interventions in Alcohol-Induced Depression 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.