Vanderbilt University Medical Center researchers, working with colleagues in Texas, have found that insulin levels affect the brain’s dopamine systems, which are involved in drug addiction and many neuropsychiatric conditions.
In addition to suggesting potential new targets for treating drug abuse, the findings raise questions as to whether improper control of insulin levels – as in diabetes – may impact risk for attention deficit hyperactivity disorder (ADHD) or influence the effectiveness of current ADHD medications.
The study, led by Aurelio Galli, Ph.D., in the Center for Molecular Neuroscience and Calum Avison, Ph.D., in the Institute of Imaging Science (VUIIS), appears online this week in the Public Library of Science Biology (PLoS Biology).
The psychostimulant drugs amphetamine and cocaine, as well as related medications for ADHD, block the reuptake of the neurotransmitter dopamine by dopamine transporters (DATs) and increase the level of dopamine signaling. Some of these compounds, including amphetamine, also cause a massive outpouring of dopamine through DATs.
The resulting surge of synaptic dopamine alters attention, increases motor activity and plays an important role in the addictive properties of psychostimulants.
But the link between insulin status and dopaminergic function is not readily apparent.
“In the 1970s, there were articles showing that, in animals with type 1 diabetes, psychostimulants like amphetamine would not increase locomotor behavior,” said Galli, associate professor of Molecular Physiology and Biophysics. “We didn’t have a clear understanding of why that was happening.”
This sparked Galli and colleagues to investigate the link between insulin signaling and amphetamine action.
Using a rat model of type 1 – or juvenile – diabetes in which insulin levels are depleted, Galli’s group assessed the function of the dopaminergic pathway in the striatum, an area of the brain rich in dopamine.
In the absence of insulin, amphetamine-induced dopamine signaling was disrupted, they found. Dopamine release in the striatum was severely impaired and expression of DAT on the surface of the nerve terminal – where it normally acts to inactivate dopamine – was significantly reduced.
The lack of the protein on the plasma membrane prevents the amphetamine-induced increase in extracellular dopamine, and in turn, amphetamine fails to activate the dopamine pathways that stimulate reward, attention and movement, Galli noted.
The researchers then restored insulin by pulsing the hormone back into the brain of the diabetic animals and found that the system returns to normal, indicating that the lack of insulin in the striatum directly affected amphetamine action.
To connect the physiological findings to activity in the intact brain, collaborators in the VUIIS, led by Avison, developed a probe for brain DAT activity using functional magnetic resonance imaging (fMRI).
“You can do molecular dissection in very well defined model systems and break the system down into its constituents,” said Avison, professor of Radiology and Radiological Sciences, and professor of Pharmacology. “But the question is: how does that relate to the intact brain? What’s the relevance to overall functioning in the intact system?”
Working with Galli and Avison, Jason Williams, Ph.D., used fMRI to demonstrate that in normal, healthy rats with plenty of insulin, amphetamine increased neural activity in the striatum. But in diabetic animals, activity in the striatum was suppressed.
“This finding is in vivo evidence that, in the intact diabetic rat, loss of insulin has compromised DAT trafficking to the plasma membrane,” Avison said. “These experiments show that there is likely a strong interplay between these important dopamine neurotransmitter systems and insulin signaling mechanisms, which we know are altered in diabetes”
The results are some of the first to link insulin status and dopaminergic brain function and hold several implications for human health and disease.
“This is really the first mechanistic connection in vivo between diabetes and amphetamine action,” Galli said. “This offers a completely new perspective on the influence of this disease (diabetes) on brain function, as well as diseases with altered dopamine signaling, such as schizophrenia and ADHD.”
The findings suggest that ADHD risk may have an insulin-dependent component and that control of insulin levels and response to the hormone may be an important determinant of amphetamine efficacy in patients with ADHD, Galli noted.
“We have described a novel mechanism by which diabetes may affect brain function.”
Melissa Marino | EurekAlert!
Finnish research group discovers a new immune system regulator
23.02.2018 | University of Turku
Minimising risks of transplants
22.02.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg
A newly developed laser technology has enabled physicists in the Laboratory for Attosecond Physics (jointly run by LMU Munich and the Max Planck Institute of Quantum Optics) to generate attosecond bursts of high-energy photons of unprecedented intensity. This has made it possible to observe the interaction of multiple photons in a single such pulse with electrons in the inner orbital shell of an atom.
In order to observe the ultrafast electron motion in the inner shells of atoms with short light pulses, the pulses must not only be ultrashort, but very...
A group of researchers led by Andrea Cavalleri at the Max Planck Institute for Structure and Dynamics of Matter (MPSD) in Hamburg has demonstrated a new method enabling precise measurements of the interatomic forces that hold crystalline solids together. The paper Probing the Interatomic Potential of Solids by Strong-Field Nonlinear Phononics, published online in Nature, explains how a terahertz-frequency laser pulse can drive very large deformations of the crystal.
By measuring the highly unusual atomic trajectories under extreme electromagnetic transients, the MPSD group could reconstruct how rigid the atomic bonds are...
Quantum computers may one day solve algorithmic problems which even the biggest supercomputers today can’t manage. But how do you test a quantum computer to...
For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.
In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...
Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale
Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...
15.02.2018 | Event News
13.02.2018 | Event News
12.02.2018 | Event News
23.02.2018 | Physics and Astronomy
23.02.2018 | Health and Medicine
23.02.2018 | Physics and Astronomy