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

    213—Amphetamine and Related Drugs: Neural Mechanisms of Addiction

    Sunday, November 10, 2013, 1:00 pm - 4:00 pm

    213.12: Methamphetamine neurotoxicity-induced attenuation of resting state functional connectivity between the dorsolateral caudate putamen and cortical regions

    Location: 23A

    *J. A. STARK, J. K. BRYNILDSEN, H. LU, B. LADENHEIM, J. L. CADET, T. J. ROSS, Y. YANG, E. A. STEIN;
    NIH NIDA, Baltimore, MD

    Abstract Body: Methamphetamine (METH) abuse leads to neuronal toxicity and cognitive and motor deficits that continue into abstinence. However, toxicity-induced alterations in neurocircuitry remain to be understood. In this rodent magnetic resonance imaging (MRI) study, we applied resting-state functional connectivity analysis (RSFC) to determine acute and longitudinal effects of METH-induced neurotoxicity on neurocircuitry. It was hypothesized that RSFC of the caudate putamen (CPu) with cortical areas would be impaired while other brain circuits may compensate for this dysfunction.
    Male Sprague-Dawley rats received neurotoxic doses of METH (n=50) or saline (n=25) in a single day. Core temperature was recorded at regular intervals. Rats were imaged -2 days (scan 1, pretreatment), 14 days (scan 2), and 3 months (scan 3) after METH under 0.5% isoflurane anesthesia + dexdomitor® infused s.c. at 0.025 mg/kg/hr. Each scan session included two T2* gradient-EPI resting state datasets: TR=1 s, matrix = 64x64, FOV=32 mm, slice number =13, 520 volumes. Brains were harvested for analysis of neurotransmitters and metabolites (n=8/group after scan 2; n=17/group after scan 3).
    METH-induced striatal dopamine depletion in animals sacrificed after scan 2 negatively correlated with METH-induced hyperthermia. Therefore, temperature was used as a surrogate for toxicity in imaging regression analysis. Regression analysis of the difference score between scan 2 and 1 with average temperature during injections revealed a negative correlation between degree of toxicity and circuit strength between the dorsolateral CPu (dlCPu) and the retrosplenial cortex (RSCx), and between the dlCPu and the posterior parietal cortex (PPC). The difference score between scan 3 and scan 2 for the dlCPu seed revealed no significant correlation, suggesting there was no recovery of this circuit alteration.
    These data are the first demonstration of METH-induced alterations in neurocircuitry at rest in any species and are consistent with established METH toxicity-induced neurochemical changes. This circuit is thought to be involved in higher order sensory processing and integration of sensorimotor information for navigation control of habitual actions. Therefore, reduced circuit strength between the dlCPu and the RSCx and PPC may be related to known deficits in goal-directed behavior and memory. Further, dopamine receptor density is correlated with information transfer between the prefrontal and PPC. These brain regions may provide a circuit based target for research and treatment interventions. This work was funded by the Intramural Research Program of NIDA/NIH.

    Lay Language Summary: Our research shows that methamphetamine disrupts communication within brain circuits involved in memory, motivation, sensory processing and the integration of sensory information. We also show that the degree of disruption is dependent upon the amount of methamphetamine consumed, and on the individual themselves. Communication between some brain regions remain disrupted over a long period of time after drug administration, while communication between other regions, including those involved in automatic or habitual responses, seemed to recover or strengthen, perhaps to compensate for disruption elsewhere.
    Scientists have previously demonstrated that methamphetamine taken in large amounts can cause neuronal cell death in both human users and animals. Of all abused drugs, neuronal toxicity is unique to methamphetamine abuse. The impact of methamphetamine toxicity on brain function, such as emotional control, memory, and planning ability, are poorly understood at the present time. However, acquiring this knowledge is critical for understanding addiction and relapse, and developing treatment programs to support long term abstinence. These questions motivated our research.
    Our findings are particularly important for several reasons. Much of the human methamphetamine research has been somewhat inconsistent, likely due to enormous individual differences in methamphetamine use along with differential use of other abused drugs. For example, some, but not all, previous studies have shown that methamphetamine users struggle with daily tasks, such as navigation, that require planning and decision making. Researchers have also seen varied results when comparing problem solving and planning ability in methamphetamine users before and after they became abstinent from drug taking. Our data suggests that these varied results may, in fact, be due to differences in how individuals respond to the drug combined with the amount and types of drugs consumed. Our study also provides insight as to whether these difficulties in planning and decision making - among others - may be due to methamphetamine use, or reflect pre-existing characteristics of the individual. Using animal models for research offers the advantage of being able to control when and how much exposure to drugs occurs, restrict exposure to other compounds, and the ability to assess behavior or brain activity before and after exposure to drugs in the same individual, which is not possible for human studies. Our data using an animal model of methamphetamine use supports the idea that communication in brain circuits that support decision making and planning is altered by the methamphetamine treatment itself.
    To test our hypothesis, rats underwent resting-state functional magnetic resonance imaging, followed by a day of treatments with different doses of methamphetamine, or placebo. Rats were imaged again two weeks and 3 months after treatment to assess both the initial impact of methamphetamine on brain function, and whether or not the initial damage lessened over time. Resting-state MRI is used to map brain areas that share a similar “brain wave” or activity pattern. Brain areas that share the same pattern are thought to be functionally connected.
    Follow-up research will focus on studying how the structure of the brain is affected by methamphetamine use, and then to understand the relationship between these changes in brain structure and the changes in brain communication - or function - described above. Our research will help us to more fully understand the relationship between methamphetamine use and the problems experienced by abstinent, former methamphetamine users, and may help target key brain areas for new treatment strategies to improve brain function and facilitate methamphetamine abstinence.