Elucidating the role of processes that have not been investigated extensively in studies of cellular responses to exposure to drugs of abuse may uncover novel therapeutic targets for the treatment of addictions. We propose to test critical components of our innovative concept that an inflammatory enzyme, i.e., 5-lipoxygenase (5-LOX), influences biochemical and structural adaptations involved in behavioral sensitization to cocaine. Important for conceptualization of the proposed project was our accidental preliminary observation that cocaine responses (i.e., behavioral sensitization) differ between control and 5-LOX-deficient (knockout) mice. Neuroadaptive changes underlying behavioral sensitization have been related to those responsible for addicitive behaviors. Glutamate receptor-mediated neuroplasticity, which includes the phosphorylation and surface expression of the AMPA glutamate receptor subunit GluR1, is one of these changes. Recent published data and our preliminary results demonstrated that GluR1 phosphorylation can be increased by 5-LOX deficiency/inhibition. Hence, we hypothesize that 5-LOX inhibition/deficiency will facilitate cocaine-induced behavioral sensitization and that this will be accompanied by enhancement of the cocaine treatment- associated increase in GluR1 phosphorylation and surface expression.
In AIM 1, we will use pharmacological 5-LOX inhibition (treatment with MK-886) and 5-LOX deficient transgenic (knockout) mice, to investigate the effects of 5-LOX inhibition/deficiency on cocaine-induced changes in GluR1 phosphorylation and GluR1 surface expression. Analyses will be performed in the nucleus accumbens (NAc) and prefrontal cortex (PFC) at different times after a single cocaine injection (time course studies).
AIM 2 will test whether pharmacological 5- LOX inhibition and 5-LOX knockout alter the development phase of behavioral cocaine sensitization, whereas AIM 3 will test how pharmacological 5-LOX inhibition and 5-LOX knockout affect behavioral and molecular (i.e., GluR1 phosphorylation and surface expression) responses of cocaine-sensitized mice to a cocaine challenge administered after 7 days of wash-out. Demonstrating the involvement of 5-LOX in mechanisms of addiction would point to an unexplored putative therapeutic target (e.g., drugs that affect 5-LOX) and would bring attention to a possible role for 5-LOX gene polymorphisms in drug abuse in general. High-risk, conceptually creative and innovative projects are needed to significantly accelerate progress in drug abuse and addiction research. This proposal is aimed at testing critical components of the innovative concept that an inflammatory enzyme, i.e., 5-lipoxygenase (5-LOX), influences biochemical and structural adaptations involved in behavioral sensitization to cocaine. Demonstrating the involvement of 5-LOX in mechanisms of addiction would point to a novel and unexplored putative therapeutic target (e.g., drugs that affect 5-LOX) and also, if confirmed, elucidation of the role of 5-LOX in cocaine's effects would bring attention to a possible role for 5-LOX gene polymorphism in drug abuse in general. The concept we propose is highly innovative and no significant prior work is available to support it. We believe that with limited funding we will be in a position to verify the key components of our concept and to obtain the necessary data to initiate more complex future translational studies.
| Manev, Hari; Chen, Hu; Dzitoyeva, Svetlana et al. (2011) Cyclooxygenases and 5-lipoxygenase in Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry 35:315-9 |
| Chen, Hu; Manev, Hari (2011) Effects of minocycline on cocaine sensitization and phosphorylation of GluR1 receptors in 5-lipoxygenase deficient mice. Neuropharmacology 60:1058-63 |
| Chen, Hu; Uz, Tolga; Manev, Hari (2009) Minocycline affects cocaine sensitization in mice. Neurosci Lett 452:258-61 |
| Manev, Radmila; Manev, Hari (2009) Minocycline, schizophrenia and GluR1 glutamate receptors. Prog Neuropsychopharmacol Biol Psychiatry 33:166; author reply 167 |
| Imbesi, Marta; Uz, Tolga; Manev, Radmila et al. (2008) Minocycline increases phosphorylation and membrane insertion of neuronal GluR1 receptors. Neurosci Lett 447:134-7 |
