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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    546—Cocaine: Neural Mechanisms of Addiction IV

    Tuesday, November 12, 2013, 8:00 am - 12:00 noon

    546.22: Cellular mechanisms of enhanced cocaine self-administration in mhc class Ι deficient mice

    Location: Halls B-H

    Dept. of Psychology, Hmamatsu Univ. Sch., Shizuoka, Japan

    Abstract Body: Brain was thought to be an immune privilege region, however, it has been recently discovered that various immune proteins have important roles even in the brain. Particularly major histocompatibility complex class Ι (MHCΙ) is critically involved in the organization of neural circuits in development and learning and memory in adults. Given that cocaine abuse activates the immune system in peripheral organs, it is reasonable to hypothesize that cocaine modulates the expression of MHCΙ and changes the synaptic plasticity in brain regions contributing to cocaine addiction. Our previous experiment showed that mice with functionally deficient MHCΙ exhibited enhanced locomotor sensitization induced by repeated cocaine injection in comparison with their wild type. In self-administration paradigm, functional MHCI deficient mice showed much more addictive behavior such as enhanced locomotor activity and nose-poking than wild type mice after 10 days of cocaine administration and 10 days of abstinence followed by a 3-day reinstatement. This result showed a critical involvement of MHCΙ in cocaine addiction.
    To assess whether cocaine modified expression of MHCI in the brain, we compared the mRNAs of H2D and H2K by qPCR in brain regions such as the ventral tegmental area (VTA), accumbens (Acb), prefrontal cortex (PFC), amygdala (Amy) and hippocampus (Hip). Cocaine decreased H2D expression only in the VTA after the injection for 7 days followed by 10 days of abstinence. The decrease of H2D expression in the VTA was also observed in the mice exposed to self-administration paradigm. We also confirmed that H2D was expressed in dopaminergic neurons in the VTA by immunohistochemistry with membrane-nonpermeabilization method using several antibodys. Now we are investigating the role of MHCI in the cocaine addiction at a level of electrophysiological properties of dopaminergic neurons in the VTA. To confirm the reduction of H2D particularly in the VTA contributing to the process of cocaine addiction, we are also trying to manipulate the expression of H2D in the VTA using adeno-associated virus vector.

    Lay Language Summary: Our research indicates that major histocompatibility complex I (MHCI), a key player in adaptive immune responses, involved in the procession of cocaine addiction in the dopamine system. In our novel self-administration system, mice deficient for MHCI showed accelerated cocaine addiction. This is the first demonstration that MHCI critically contributes to the regulation of the dopamine system.
    Cocaine addiction is a psychiatric disorder that remains a serious public health problem worldwide. Because effective pharmacological drugs have not been identified, the current therapy largely depends on behavioral treatments. Thus, our further understanding of mechanisms behind the procession of cocaine addiction is important to identify novel targets for the pharmacological treatment. It has been recently discovered that MHCΙ is expressed in the brain that is used to be designated as an immune privilege region. In contrast to its role in the immune system, MHCΙ is critically involved in the organization of neural circuits and modulation of synaptic plasticity in the adult brains. This molecule is highly expressed in the ventral tegmental area (VTA) of the dopamine system, dysregulation of which is the principal pathogenesis of drug addiction. In this study, we demonstrated that MHCΙ in the VTA is critically involved in the procession of cocaine addiction. The dopamine system compromised in cocaine addiction is also affected in other psychiatric disorders such as schizophrenia, autism and attention deficit hyperactivity disorder (ADHD). Our further understanding of the molecular actions of MHCI in future may provide a clue for the etiology of other dopamine-related disorders.
    To assess the role of MHCI in the procession of cocaine addiction, we employed a self-administration paradigm, where mice administrate cocaine by themselves. This model mimics the human drug use much better than experimenter-administration model. In commonly used self-administration systems, the indwelling catheter needed to be implanted and maintained in small, fragile veins, which was found technically challenging. By employing an intracranial delivery system via microdialysis probes, we succeeded in ensuring daily 24-hr access to cocaine and in stable establishment of the large quantity of cocaine-addicted mice. In our self-administration paradigm, we allowed mice their access to cocaine for 10 days, followed by the abstinence period for the next 10 days. Then, we gave the reinstatement period, when we observed nose poking behavior of mice for access to cocaine. This behavior represents a good measure of cocaine-seeking behavior, and could not be assessed in the experimenter-administration model. In this paradigm, mice deficient for functional MHCI showed much more addictive behaviors, as indicated by increased nose poking by two fold as well as increased locomotor activity, compared to wild type mice. To evaluate the effects of cocaine on MHCI in the brain, we investigated the expression level of MHCI in brain regions involved in the process of cocaine addiction, including the VTA, after conducting the experimenter-administration paradigm. Repeated cocaine injection led to the decrease in the expression level of a subunit of MHCI, H2D, in the VTA but not in any other regions. The decrease of H2D expression in the VTA was also confirmed in mice from the self-administration paradigm.
    Altogether, our research showed suppressive effect of MHCI on the procession of cocaine addiction in mice lacking functional MHCI. Even in wild type mice, cocaine leads to lowering the level of H2D specifically in the VTA, which would accelerate cocaine addiction, as observed in mice deficient for MHCI. This result postulates MHCI as a novel target for therapy of cocaine addiction.