Longitudinal magnetic resonance imaging reveals striatal hypertrophy in a rat model of long-term stimulant treatment.
Stimulant treatment is highly effective in mitigating symptoms associated with attention-deficit/hyperactivity disorder (ADHD), though the neurobiological underpinnings of this effect have not been established. Studies using anatomical magnetic resonance imaging (MRI) in children with ADHD have suggested that long-term stimulant treatment may improve symptoms of ADHD in part by stimulating striatal hypertrophy. This conclusion is limited, however, as these studies have either used cross-sectional sampling or did not assess the impact of treatment length on their dependent measures. We therefore used longitudinal anatomical MRI in a vehicle-controlled study design to confirm causality regarding stimulant effects on striatal morphology in a rodent model of clinically relevant long-term stimulant treatment. Sprague Dawley rats were orally administered either lisdexamfetamine (LDX, 'Vyvanse') or vehicle (N=12 per group) from postnatal day 25 (PD25, young juvenile) until PD95 (young adult), and imaged one day before and one day after the 70-day course of treatment. Our LDX dosing regimen yielded blood levels of dextroamphetamine comparable to those documented in patients. Longitudinal analysis of striatal volume revealed significant hypertrophy in LDX-treated animals when compared to vehicle-treated controls, with a significant treatment by time point interaction. These findings confirm a causal link between long-term stimulant treatment and striatal hypertrophy, and support utility of longitudinal MRI in rodents as a translational approach for bridging preclinical and clinical research. Having demonstrated comparable morphological effects in both humans and rodents using the same imaging technology, future studies may now use this rodent model to identify the underlying cellular mechanisms and behavioral consequences of stimulant-induced striatal hypertrophy.
Department of Psychiatry, New York State Psychiatric Institute, Columbia University College of Physicians and Surgeons, New York, NY, USA.
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D
Biezonski
Center for Biomedical Imaging and Neuromodulation, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
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R
Shah
Department of Psychiatry, New York State Psychiatric Institute, Columbia University College of Physicians and Surgeons, New York, NY, USA.
A
A
Krivko
Department of Psychiatry, New York State Psychiatric Institute, Columbia University College of Physicians and Surgeons, New York, NY, USA.
J
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Cha
Center for Biomedical Imaging and Neuromodulation, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
D N
DN
Guilfoyle
Center for Biomedical Imaging and Neuromodulation, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
J
J
Hrabe
Center for Biomedical Imaging and Neuromodulation, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
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S
Gerum
Center for Biomedical Imaging and Neuromodulation, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
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S
Xie
Department of Psychiatry, New York State Psychiatric Institute, Columbia University College of Physicians and Surgeons, New York, NY, USA.
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Y
Duan
Institute for the Developing Mind, Children's Hospital Los Angeles and the Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
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R
Bansal
Langley Porter Psychiatric Institute, University of California, San Francisco, San Francisco, CA, USA.
B L
BL
Leventhal
Institute for the Developing Mind, Children's Hospital Los Angeles and the Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
B S
BS
Peterson
Department of Psychiatry, New York State Psychiatric Institute, Columbia University College of Physicians and Surgeons, New York, NY, USA.
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C
Kellendonk
Department of Psychiatry, New York State Psychiatric Institute, Columbia University College of Physicians and Surgeons, New York, NY, USA.
J
J
Posner
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003913:Dextroamphetamine / Q000097:blood; D006984:Hypertrophy; D000069478:Lisdexamfetamine Dimesylate / Q000494:pharmacology*; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D017072:Neostriatum / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000473:pathology; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley
D000697:Central Nervous System Stimulants; D000069478:Lisdexamfetamine Dimesylate; D003913:Dextroamphetamine