A single link to the first track to allow the export script to build the search page
  • 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

    157.12: Methamphetamine causes degeneration of dopamine cell bodies and fibers of the nigrostriatal pathway evidenced by silver staining

    Location: Halls B-H

    N. GRANADO, S. ARES-SANTOS, I. ESPADAS, *C. VICARIO-ABEJON, R. MARTÕNEZ-MURILLO, R. MORATALLA;
    Cajal Institute, CSIC, Madrid, Spain

    Abstract Body: Methamphetamine is a widely consumed illicit drug with high abuse potential. Recent epidemiological studies showed that methamphetamine abuse increases the risk for developing Parkinson’s disease. Studies in animals have shown that this drug produces dopaminergic neurotoxicity in the nigrostriatal pathway. We examined the effect of repeated low and medium doses versus single high dose of methamphetamine on degeneration of the dopaminergic system, including terminals in the striatum and cell bodies in the SNpc. Mice were given methamphetamine using one of three protocols: three i.p. injections of 5 or 10 mg/kg at 3 hour intervals or a single 30 mg/kg injection. The integrity of dopaminergic fibres and cell bodies were assessed 1 and 3 days after methamphetamine by TH immunohistochemistry and silver staining. All three administration protocols induced significant hyperthermia and loss of striatal dopaminergic fibers. The 3x10 protocol yielded the highest effect, followed by the 3x5 and 1x30. Some degenerating axons could be followed from the striatum to the SNpc. All three protocols induced similar significant degeneration of dopaminergic neurons in the SNpc, evidenced by the presence of amino-cupric-silver stained dopaminergic neurons. Both necrosis and apoptosis were apparent in degenerating neurons. Silver staining was also observed in striatal neurons after methamphetamine. By using D1-Tmt/D2-GFP BAC transgenic mice, we observed that striatal degenerating neurons were equally distributed between direct and indirect projection pathway neurons and interneurons. These data provide direct evidence that methamphetamine administration to mice causes destruction of striatal neurons and dopaminergic fibers, along with significant irreversible degeneration of cell bodies in the SNpc.

    Lay Language Summary: Our research shows that methamphetamine, an illicit drug abused by 14-50 million people worldwide, can cause irreversible loss of dopaminergic neurons in the substantia nigra, a small region of the brain associated with motor planning and movement. Since loss of this specific population of nerve cells is the main cause of Parkinson’s Disease, our results offer a plausible explanation for the finding that methamphetamine abusers have a significantly higher risk of developing Parkinson’s Disease.
    As methamphetamine popularity increases worldwide, it is important to understand the detrimental long-term consequences, apart from addiction, that the consumption of this drug may have, especially those related to the irreversible neurodegenerative Parkinson’s Disease. Establishing whether methamphetamine produces persistent loss of dopamine nerve cells in the substantia nigra is vital, since lost dopamine nerve cells are not replaced, and the loss of a small proportion of them may predispose methamphetamine abusers to Parkinson’s Disease.
    It has been clear for some time that methamphetamine causes persistent loss of dopamine fibers, the long projections by which nerve cells located in the substantia nigra communicate with nerve cells in another brain region, the striatum, to produce movement. Our study addresses a long-standing question in the field: whether methamphetamine destroys not just the fibers, but also the nerve cell bodies in the substantia nigra, causing permanent damage. Our study is the first to provide conclusive evidence that methamphetamine kills dopamine neurons in the substantia nigra.
    We studied the effect of a single high dose or multiple low doses of methamphetamine on dopaminergic neurotoxicity. The integrity of dopaminergic fibers and cell bodies was evaluated 3 and 12 hours and 1, 3, 7 and 30 days after methamphetamine administration, using a marker to identify dopaminergic neurons and amino-cupric-silver staining to identify degenerating cell bodies and fibers. Strikingly, both treatment protocols resulted in a progressive death of the dopaminergic neurons in the substantia nigra, with 7-15% of these neurons degenerating 1 and 3 days post-methamphetamine, with further small loss of neurons at 7 and 30 days. The total loss of dopamine neurons was 20-25% at 7 or 30 days. Thus, this is the first demonstration of irreversible methamphetamine-induced neuronal loss. As shown previously, both administration protocols also caused significant loss of striatal dopaminergic fibers. Multiple low doses of methamphetamine induced more fiber loss than a single high dose, with the greatest loss occurring 1 day postreatment, followed by a progressive recovery. Despite partial recovery, some deficits in dopamine fibers persisted 30 days after treatment. This neuronal damage had functional consequences: mice exhibited a drastic decrease in movement and motor coordination 1 to 3 days after drug delivery, coincident with the peak nerve fiber loss. Motor activity and motor coordination recovered 7 days after methamphetamine, in parallel with the partial recovery of dopamine nerve fibers.
    The next step would be to confirm these observations in human methamphetamine abusers and to study the molecular mechanisms involved in this degeneration as well as to explore possible neuroprotection strategies.
    The extent of neuron loss we observed is not sufficient to induce parkinsonism on its own, since the clinical symptoms of Parkinson’s Disease appear when there is greater than 60% loss of dopamine cells in the substantia nigra and over 80% loss of striatal dopamine fibers. However, the neuronal loss and fiber damage caused by methamphetamine use likely confers a persistent vulnerability to subsequent insults, increasing the risk of developing Parkinson’s Disease.