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

    157—Drugs of Abuse: Toxicity and Structural Plasticity

    Sunday, November 10, 2013, 8:00 am - 12:00 noon

    157.09: Long-term effects of Methamphetamine abuse in an In vivo model of HIV-associated neurocognitive disorders

    Location: Halls B-H

    1Infectious and Inflammatory Dis. Ctr., 2Del E. Webb Neuroscience, Aging & Stem Cell Res. Ctr., Sanford-Burnham Med. Res. Inst., La Jolla, CA; 3Dept. of Mol. and Cell. Neurosci., The Scripps Res. Inst., La Jolla, CA; 4Dept. of Psychiatry, Univ. of California San Diego, San Diego, CA

    Abstract Body: Methamphetamine (METH) abuse is very common in HIV-1 positive individuals and is suspected to aggravate HIV-associated neurocognitive disorders (HAND). HIV-1/gp120 transgenic (gp120tg) mice express a soluble viral envelope in the brain and manifest several neuropathological features similar to those observed in the brains of AIDS patients, including decreased synaptic and dendritic density, as well as astrocytosis and increased numbers of activated microglia. METH is a psychostimulant that compromises several neurotransmitter systems, including the dopaminergic, glutaminergic, and serotonergic networks and it also affects the immune system. So far, the combined effects of HIV-1 and METH are incompletely understood.
    In this study, gp120tg mice were treated with an escalating METH binge regimen and the chronic effects thereof were analyzed after 5 months when the mice were about 10 months of age. Neuropathology was analyzed using immunofluorescence staining of MAP-2 and synaptophysin in cortex and hippocampus and quantitative deconvolution microscopy. METH treatment induced a significant reduction of MAP-2 and synaptophysin positive neuropil in gp120tg and WT brains. Electrophysiological studies in hippocampal slices revealed that only METH-exposed gp120tg animals displayed reduced post-tetanic potentiation, whereas both gp120 expression and METH treatment lead to reduced long-term potentiation. To understand the molecular basis of these alterations, we analyzed the expression of components of the GABAergic and glutaminergic neurotransmitter systems at RNA level using a quantitative RT-PCR array. METH and gp120 caused a significant down-regulation of numerous genes involved in both neurotransmission systems. Upon METH treatment, the only upregulated genes were CDK5 and BDNF, known to be involved in learning and synaptic plasticity and METH dependence, respectively. Behavioral tests showed that both gp120tg and WT animals treated with METH had impaired learning and memory.
    In summary, METH treatment and HIV-1/gp120 expression resulted in pre- and postsynaptic alterations in association with compromised learning and memory functions.

    Lay Language Summary: Our studies indicate that methamphetamine use for only a short period of time can cause lasting changes in brain functions, such as permanently harming learning and memory as it is necessary for every day life. These changes also exacerbate the neurological problems of HIV infection and NeuroAIDS.
    Methamphetamine abuse is very common among people infected with HIV-1 and appears to increase the risk of becoming infected with the virus. If untreated, infection with HIV-1 eventually leads to the development of AIDS and NeuroAIDS. Understanding how methamphetamine usage of addicted or HIV-infected individuals impairs their brain function is critical to addressing this continuing public-health challenge.
    Methamphetamine is a powerful and highly addictive stimulant that compromises several systems that the brain employs for communication between its nerve cells. Physicians have suspected that it aggravates disorders associated with HIV infection, including the impairment of cognitive functions and progression to dementia. The underlying mechanisms, however, have been unclear. Our new findings offer insights into how HIV-1 and methamphetamine alter brain functions particularly vital for learning and memory.
    In our study, we employed young adult mice that carry a component of the HIV-1 surface called gp120 in their brain, and share important features of brain injury with AIDS patients. We treated these mice and otherwise healthy control animals for 25 days with an escalating binge regimen of methamphetamine that was designed to mimic the pattern of methamphetamine use in humans. We then analyzed the chronic effects of methamphetamine after five months of drug abstinence, when the mice were about 10 months old. We studied behavior and examined different areas of the animals’ brains, in particular the cortex and the hippocampus, which are involved in functions such as decision-making and memory.
    Behavioral tests of the methamphetamine treated HIV-1 gp120 mice clearly showed an additive detrimental effect on the animals’ ability to learn and remember, while the effects of HIV gp120 or methamphetamine alone on the animals’ learning capability were comparable but milder.
    HIV-1 gp120 mice and healthy mice that were both on a binge regimen of methamphetamine showed a significant reduction in the number of nerve cells in cortex and hippocampus and they also possessed fewer connections between the nerve cells.
    Further analysis revealed that the expression of numerous factors vital to two key systems of nerve cell communication had been reduced in methamphetamine treated HIV-1 gp120 mice. Moreover, exposure to methamphetamine resulted in several more alterations of factors that are involved in memory and learning as well as in drug addiction.
    In summary, this study shows that the deleterious effects of methamphetamine abuse in the central nervous system further aggravate neurological problems caused by HIV infection. Our research identified several candidate factors that could lead to devise new drugs to help methamphetamine addicts and improve HIV+ patients’ lives, and was funded by the National Institute of Drug Abuse (NIDA).
    An alarming increase of methamphetamine users who have become infected with HIV has been noted in the past few years. Currently, over 40 million people worldwide are infected with HIV, and in the U. S. alone an estimated 50,000 new infections every year add to this number. Up to 40% of the HIV+ patients develop NeuroAIDS, and with the introduction of the highly active antiretroviral therapy in the 1990’s, HIV patients have a much longer life expectancy. Antiretroviral therapy has also helped to decrease the number of HIV-associated dementia cases, the worst form of NeuroAIDS. However, the overall incidence of HIV-associated neurological complications has increased in the aging community of people living with HIV, a trend that may be accelerated by drug abuse.