Robert B. Innis, MD, PhD, Branch and Section Chief
My laboratory develops and uses positron emission tomographic (PET) radioligands to study pathophysiology in several neuropsychiatric disorders. Working in close collaboration with the radiochemistry laboratory of Dr. Victor Pike, we use in vivo imaging to evaluate novel PET radioligands, first in animals, then in healthy human subjects, and finally in patients. My laboratory has multidisciplinary expertise in pharmacology, animal experimentation, clinical neuroscience, digital image analysis, and human evaluation of investigational radiopharmaceuticals. In addition to traditional receptor targets, we use radiolabeled probes for in vivo imaging of intracellular signal transduction (e.g., cAMP phosphodiesterase), gene expression (e.g., dopamine transporters expressed on transplanted embryonic stem cells), and a mitochondrial protein that is a marker for inflammatory cells (activated microglia and macrophages).
I strongly emphasize training and career development for everyone in my laboratory, whether the person is here for a time-limited period (e.g., graduate student or postdoctoral fellow) or a permanent staff position (e.g., Staff Scientist). I frequently give lectures to the group on ad hoc topics and also teach two courses: writing a scientific paper and pharmacokinetic modeling. In addition, the laboratory has a journal club, project meetings, and thumbnail presentations. Trainees improve their skills at verbal presentation at these laboratory meetings as well as at formal NIH-wide venues and international meetings.
I am fortunate to have outstanding people in my laboratory at different levels of career development, from graduate students to senior investigators (see People, below). For example, as of July 2012, my laboratory has a graduate student in the joint PhD program in neuroscience between NIH and the Karolinska Institutet (Stockholm, Sweden). This jointly mentored PhD program offers outstanding opportunities for training and research for a select group of accomplished and goal-directed students who are expected to emerge as future leaders. In addition, my laboratory has attracted several MD/PhD investigators because of its translational work and has physicians from three medical specialties: psychiatry, neurology, and nuclear medicine.
Imaging is performed in primates and rodents to assess the utility of new probes and to explore models of human pathophysiology. For example, we imaged the serotonin transporter in adult monkeys with a history of maternal deprivation to explore the role of serotonin in the abnormal behaviors of these animals as adults (Ichise et al., 2006; PDF ). We have also imaged transgenic mice to demonstrate, for example, the role of arrestin3 in the internalization of D2 dopamine receptors (Skinbjerg et al. 2009; PDF).
About one-third of our PET scans are performed in animals, and two-thirds in humans. Our research includes "first-in-human" use of novel PET radioligands - e.g., a new probe for the metabotropic glutamate subtype 5 (mGluR5) receptor, the cannabinoid CB1 receptor, a probe for cellular inflammation, and a substrate for P-glycoprotein transporter at the blood-brain barrier. We are now using these radioligands to study the pathophysiology of several neuropsychiatric disorders, including major depressive disorder, autism, HIV infection of the brain, schizophrenia, Alzheimer's disease, drug and alcohol abuse, and epilepsy.
Robert B. Innis, MD, PhD
Chief, Molecular Imaging Branch, NIMH
Bldg. 10, Rm. B1D43
10 Center Drive MSC 1026
Bethesda, MD 20892-1026
Office Tel: 301-594-1368
E-mail Dr. Innis
Branch Administrative Manager:
Email Ms. Alzona
1) PET imaging of translocator protein as a biomarker for neuroinflammation
Translocator protein 18 kDa (TSPO) is a mitochondrial protein that is overexpressed in neuroinflammatory cells (activated microglia and reactive astrocytes), thus acting as a biomarker for inflammation in brain. We developed two promising radioligands— [11C]PBR28 and [18F]PBR06—that are specific for TSPO and that have a much greater specific signal than the prototypical agent, [11C]PK 11195 (Kreisl et al., 2010a; PDF). We found that our radioligands could image inflammation surrounding stroke in rats (Imaizumi et al., 2007; PDF) and provided positive preliminary results in human disorders with localized areas of neuroinflammation, including stroke (Kreisl et al., 2009; PDF) and epilepsy (Hirvonen et al., 2012a; PDF). William Kreisl MD (neurologist and Assistant Clinical Investigator) has recently reported that patients with Alzheimer’s disease have increased TSPO binding that correlates with disease severity (Kreisl et al., 2013. PDF). Interestingly, patients with mild cognitive impairment (MCI) did not have elevated TSPO binding, suggesting that neuroinflammation may mark the transition from MCI to Alzheimer’s disease.
Effect of Single Nucleotide Polymorphism. We discovered that about 10% of the population has low affinity to the TSPO radioligand [11C]PBR28 (Kreisl et al., 2010b; PDF), which was later shown to be caused by a common single nucleotide polymorphism in exon 3 of the TSPO gene. The resulting three groups are homozygous for high affinity state (HH), homozygous for low affinity state (LL), or heterozygous (HL). In a recent study, we sought to assess the utility of in vitro receptor binding to distinguish these three groups (HH, LL, and HL) and to extrapolate its impact on the sensitivity of future clinical PET studies (Kreisl et al., 2012; PDF). More specifically, we sought to determine: 1) if TSPO genotype correlates with in vitro PBR28 binding using peripheral leukocytes and in vivo using brain PET imaging; 2) if differential affinity exists for PBR28 in both controls and in disease states (in this case, schizophrenia); and 3) if correcting for genotype improves the sensitivity of PBR28 to detect group differences in TSPO density measured in postmortem brain from schizophrenia subjects and healthy controls. We found that in vitro displacement assays with peripheral leukocytes accurately predicted TSPO genotype in all subjects. Thus, it appears that either leukocyte binding or genotyping can be used to accurately separate TSPO genotypes. In vivo, brain uptake of [11C]PBR28 was on average 40% higher in HH than in HL subjects, but with significant overlap. In addition, TSPO binding in postmortem brain from individuals with schizophrenia was 16% higher than in control brain, an effect that was statistically significant only after correcting for TSPO genotype. Our results strongly suggest that clinical studies with [11C]PBR28 will have increased statistical power and require smaller sample sizes if they incorporate the genotype of the subjects. Thus, we recommend measuring the Ala147Thr polymorphism in all future studies using [11C]PBR28, as well as in other second-generation TSPO radioligands.
2) cAMP Phosphodiesterase4 (PDE4) in depression
The proposed mechanism of action of antidepressant medications is to upregulate the cyclic adenosine monophosphate (cAMP) signaling cascade. Phosphodiesterase4 (PDE4) is an enzyme that metabolizes cAMP and may play a mechanistic role in antidepressant efficacy. For example, chronic antidepressant treatment of animals increases PDE4, and a PDE4 inhibitor (rolipram) was found to have antidepressant effects in both animals and humans. We evaluated the PET radioligand [11C](R)-rolipram in rodents and found that in vivo radioligand binding can monitor the phosphorylation (activation) status of PDE4 (Itoh et al., 2010; PDF). Masahiro Fujita, MD, PhD (nuclear medicine physician and Staff Scientist) recently studied the safety, kinetics, and test/retest reproducibility of [11C](R)-rolipram in healthy subjects (Zanotti Fregonara et al., 2011; PDF). Dr. Fujita is imaging patients with major depressive disorder before and after antidepressant treatment;. Our PET results confirm for the first time the "cAMP theory of depression," which posits that low cAMP signaling predisposes to depression and that antidepressants of various types increase cAMP signaling. That is, [11C](R)-rolipram binding in brain of patients with major depressive disorder at baseline (i.e., taking no medications) was decreased 18% compared to controls (P = 0.002) (Fujita et al., 2012. PDF). Preliminary analysis of the repeat PET after about two months treatment with SSRI show a comparable upregulation (i.e., normalization) of [11C](R)-rolipram binding (in progress).
3) Imaging the cannabinoid CB1 receptor
The cannabinoid CB1 receptor mediates the effects of marijuana. CB1 receptors are found in nearly every organ in the body, and may be involved in several neuropsychiatric and metabolic disorders. We developed two radioligands for the CB1 receptor for which more than 80% of the brain uptake in monkey brain is specifically bound to receptor. We extended the evaluation of both radioligands to healthy human subjects and found that the longer-lived agent—[18F]FMPEP-d2—provided a more precise measure of receptor density than the shorter-lived 11C-labeled analog (Terry et al., 2010; PDF). These initial studies conducted in healthy subjects, as well as prior rodent studies (Terry et al., 2008; PDF), were performed by Garth Terry, who at the time was a student in the joint PhD program in neuroscience between the NIH and the Karolinska Institutet (Stockholm, Sweden).
In collaboration with the National Institute of Drug Abuse (NIDA), we then investigated whether heavy cannabis (marijuana, hashish) smoking downregulated cannabinoid CB1 receptors in human brain. Chronic cannabis smoking can result in dependence, and rodent studies show reversible downregulation of brain cannabinoid CB1 receptors after chronic exposure to cannabis. Using PET imaging, we found reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in human subjects who chronically smoke cannabis (Hirvonen et al, 2012b; PDF). Downregulation correlated with years of cannabis smoking and was selective to cortical brain regions. After about four weeks of abstinence from cannabis, CB1 receptor density returned to normal levels. This work was the first direct demonstration of cortical cannabinoid CB1 receptor downregulation as a neuroadaptation in human brain that may promote cannabis dependence.
In collaboration with the National Institute of Alcohol Abuse and Alcoholism (NIAAA), we scanned patients with alcoholism using a similar experimental design. : at baseline and after one month abstinence. In contrast to cannabis abusers who had regionally selective and reversible down regulation of CB1 receptor, patients with alcoholism had a global reduction of CB1 receptors that did not reverse after one month of abstinence (Hirvonen et al., 2012c; PDF).
4) Measuring Permeability-glycoprotein (P-gp) dysfunction in brain using [11C]dLop.
Permeability-glycoprotein (P-gp) is an efflux transporter that is widely distributed in the body and affects the distribution and excretion of many toxins and drugs. For example, P-gp at the blood-brain barrier is thought to protect the brain from toxins but can also block the entry of therapeutic drugs (Kannan et al., 2009; PDF). P-gp overexpression is one mechanism whereby cancers become resistant to therapeutic drugs; indeed, P-gp was discovered as an efflux transporter on tumor cells that had become resistant to cancer drugs. Its gene is called MDR (multi-drug resistance).
Our laboratory developed an 11C-labeled analog of loperamide—[11C]dLop—to measure P-gp function at the blood-brain barrier. Although a potent opiate agonist, loperamide (Imodium®) lacks central effects because P-gp avidly blocks its entry into the brain. Using a P-gp inhibitor (tariquidar), we found that brain uptake of [11C]dLop is inversely proportional to P-gp function in monkeys (Liow et al., 2009; PDF) and in humans (Kreisl et al., 2010b; PDF).
Pavitra Kannan, a graduate student in the joint PhD program in neuroscience between the NIH and the Karolinska Institutet (Stockholm, Sweden), studied dLop both in vitro and in vivo in animals. She demonstrated that dLop is selective for P-gp among the three most prevalent efflux transporters at the blood-brain barrier (Kannan et al. 2010; PDF). Extending this work, she recently found that [11C]dLop (a weak base) becomes ionically trapped in acidic vesicles in the brain, thereby providing a mechanism for PET signal amplification (Kannan et al, 2011, PDF).
We are extending this work to see whether [11C]dLop is clinically useful for measuring the P-gp dysfunction hypothesized to occur in two brain disorders. Specifically, increased P-gp function at the blood-brain barrier is believed to cause drug resistance in epilepsy and in HIV infection of the brain. To determine whether P-gp function is increased in these two disorders, we are administering tariquidar, a P-gp inhibitor, and then performing PET scans with [11C]dLop. Paolo Zanotti Fregonara, MD, PhD (nuclear medicine physician and Visiting Fellow) is directing the epilepsy study. William Kreisl, MD (neurologist and Assistant Clinical Investigator) is leading the HIV study.
5) Development of novel radioligands
In close collaboration with the laboratory of Victor Pike, we are developing many new PET radioligands for protein targets in the brain. Our ongoing projects include probes for several receptors in the brain, including metabotropic glutamate receptor 1 (mGluR1), metabotropic glutamate subtype 5 (mGluR5), N-methyl-D-aspartate (NMDA), oxytocin, nociceptin orphanin peptide (NOP), and histamine H1. Some of these projects are being conducted in collaboration with pharmaceutical companies, which provide significant expertise in the pharmacology of the target as well as extensive capacity for in vitro screening and medicinal chemistry. Newly developed radioligands whose use has been extended to humans include radioligands for mGluR5 (Simeon et al., 2007, PDF and Brown et al., 2008, PDF)
and NOP receptors (Pike et al., 2011, PDF
and Kimura et al., 2011, PDF).
||Administrative Branch Manager, (301) 594-1089, firstname.lastname@example.org|
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|Maria D. Ferraris Araneta, CRNP
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|Masahiro Fujita, MD, PhD.
||Staff Scientist, (301) 451-8898, email@example.com|
||Psychologist, (301) 435-8982, firstname.lastname@example.org|
|Robert Gladding, CNMT
||Research PET Technologist, (301) 594-1432, email@example.com|
|Ioline Henter, MA
||Nurse Specialist, (301) 496-1342, firstname.lastname@example.org |
|Robert Innis, MD, PhD
||Branch and Section Chief, Senior Investigator, (301) 594-1368, Robert.Innis@nih.gov|
||Contractor, (301) 443-3007, email@example.com|
|William C. Kreisl, MD
||Assistant Clinical Investigator, (301) 451-8894, firstname.lastname@example.org|
|Jeih-San Liow, PhD
||Staff Scientist (301) 451-8862, Liowj@intra.nimh.nih.gov|
|Talakad Lohith, MD, PhD
||Visiting Fellow, (301) 594-6759,|
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|Tetsuya Tsujikawa, MD, PhD
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|Alicia E. Woock, BS
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|Paolo Zanotti Fregonara, MD, PhD
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|Sami Zoghbi, PhD
||Staff Scientist, (301) 435-7911, email@example.com|
P-gp: an efflux transporter that protects the brain but also causes drug resistance in brain and in peripheral tumors:
1) P. Kannan, K.R. Brimacombe, J.S. Liow, S.S. Zoghbi, C. Morse, A. Taku, V.W. Pike, C. Halldin, R.B. Innis, M.M. Gottesman, and M.D. Hall.
N-Desmethyl-Loperamide is selective for P-Glycoprotein among three ATP-binding cassette transporters at the blood-brain barrier. Drug Metab. Disposition, 38: 917-922, 2010. (PDF File)
2) P. Kannan, C. John, S.S. Zoghbi, C. Halldin, M.M. Gottesman, R.B. Innis, and M.D. Hall.
Imaging the function of P-glycoprotein with radiolabeled substrates: pharmacokinetics and in vivo applications. Clin. Pharmacol. Ther.,
86: 368-376, 2009. (PDF File)
3) J.-S. Liow, W. Kreisl, S.S. Zoghbi, N. Lazarova, N. Seneca, R.L. Gladding, A. Taku, P. Herscovitch, V.W. Pike, and R.B. Innis
P-glycoprotein function at the blood-brain barrier imaged using 11C-N-desmethyl-loperamide in monkeys. J. Nucl. Med.,
50: 108-115, 2009. (PDF File)
4) W.C. Kreisl, J.-S. Liow, N. Kimura, N. Seneca, S.S. Zoghbi, P. Herscovitch, V.W. Pike, and R.B. Innis.
P-glycoprotein function at the blood-brain barrier in humans can be quantified with the substrate radiotracer 11C-N-desmethyl-loperamide. J. Nucl. Med., 51: 559-566, 2010.
5) P. Kannan, K.R. Brimacombe, W.C. Kreisl, J.-S. Liow, S.S. Zoghbi, S. Telu, Y. Zhang, V.W. Pike, C. Halldin, M.M. Gottesman, and R.B. Innis, and M.D. Hall.
Lysosomal trapping of a radiolabeled substrate of P-glycoprotein as a mechanism for signal amplification in PET. Proc. Natl. Acad. Sci. USA. 108: 2593–2598, 2011. (PDF File)
Translocator Protein (TSPO): a biomarker for inflammation
1) M. Imaizumi, H.-J. Kim, S.S. Zoghbi, E. Briard, J. Hong, J.L. Musachio, J.M. Hallenbeck, C. Ruetzler, D-M. Chuang, V.W. Pike, R.B. Innis, and M. Fujita.
PET imaging with [11C]PBR28 can localize and quantify upregulated peripheral benzodiazepine receptors associated with cerebral ischemia in rat. Neurosci. Lett., 411: 200-205, 2007. (PDF File)
2) W.C. Kreisl, M. Fujita, Y. Fujimura, N. Kimura, K.J. Jenko, P. Kannan, J. Hong, C.L. Morse, S.S. Zoghbi, R.L. Gladding, S. Jacobson, U. Oh, V.W. Pike, and R.B. Innis.
Comparison of [11C]-(R)-PK 11195 and [11C]PBR28, two radioligands for translocator protein (18 kDa) in human and monkey: implications for positron emission tomographic imaging of this inflammation biomarker. NeuroImage, 649: 2924-2932, 2010. (PDF File)
3) W.C. Kreisl, G. Mbeo, M. Fujita, S.S. Zoghbi, V.W. Pike, R.B. Innis, and J.C. McArthur.
Stroke incidentally identified with improved positron emission tomography for microglia activation. Arch. Neurol., 66: 1288-1289, 2009. (PDF File)
4) J. Hirvonen, W.C. Kreisl, M. Fujita, I. Dustin, S. Miranda, Y. Zhang, C. Morse, V.W. Pike, R.B. Innis, and W.H. Theodore. Increased in vivo expression of an inflammatory marker in temporal lobe epilepsy. J. Nucl. Med. 53: 234-240, 2012a.. (PDF File)
5) W.C. Kreisl, K.J. Jenko, C.S. Hines, C.H. Lyoo, W. Corona, C.L. Morse, S.S. Zoghbi, T. Hyde, J.E. Kleinman, V.W. Pike, F.F. McMahon, and R.B. Innis. A genetic polymorphism for translocator protein 18 kDa affects both in vitro and in vivo radioligand binding in human brain to this putative biomarker of neuroinflammation. J. Cereb. Blood Flow Metab. In press. 2012 (PDF File)
Metabotropic Glutamate Subtype 5 (mGluR5) Receptors that may have pathophysiological or treatment roles in Fragile-X syndrome and in schizophrenia:
1) F.G. Siméon, A.K. Brown, S.S. Zoghbi, V.M. Patterson, R.B. Innis, and V.W. Pike.
Synthesis and simple 18F-labeling of a high affinity 2 (fluoromethyl)thiazole derivative ([18F]SP203) as a radioligand for imaging monkey brain metabotropic glutamate subtype-5 receptors with PET. J. Med. Chem., 50: 3256-3266, 2007. (PDF File)
2) A.K. Brown, Y. Kimura, S.S. Zoghbi, F.G. Siméon, J-S. Liow, W.C. Kreisl, A. Taku, M. Fujita, V.W. Pike, and R.B. Innis.
Metabotropic glutamate subtype 5 receptors are quantified in the human brain with a novel radioligand for PET. J. Nucl. Med., 49: 2042-2048, 2008. (PDF File)
cAMP-dependent phosphodiesterase that may play a pathophysiological and treatment roles in major depressive disorder:
1) T. Itoh, K. Abe, J. Hong, O. Inoue, V.W. Pike, R.B. Innis, and M. Fujita. .
Effects of cAMP dependent protein kinase activator and inhibitor on in vivo PET rolipram binding to phosphodiesterase 4 in conscious rats. Synapse, 64: 172-176, 2010. (PDF File)
2) P. Zanotti Fregonara, S.S. Zoghbi, J.-S. Liow, E. Luong, R. Boellaard, R.L. Gladding, V.W. Pike, R.B. Innis, and M. Fujita.
Kinetic analysis in human brain of [11C](R)-rolipram, a positron emission tomographic radioligand to image phosphodiesterase 4: a retest study and use of an image-derived input function. NeuroImage, 283: 1903-1909, 2011. (PDF File)
3) F. Fujita, C.S. Hines, S.S. Zoghbi, A.G. Mallinger, L.P. Dickstein, J.-S. Liow, Y. Zhang, V.W. Pike, W.C. Drevets, R.B. Innis, and C.A. Zarate. Downregulation of brain phosphodiesterase type IV measured with 11C-(R)-rolipram PET in major depressive disorder. Biol. Psych. In press. 2012. (PDF File)
Cannabinoid CB1 receptors that may play pathophysiological role in alcoholism and schizophrenia:
1) G. Terry, J.-S. Liow, E. Chernet, S.S. Zoghbi, L. Phebus, C.C. Felder, J. Tauscher, J.M. Schaus, V.W. Pike, C. Halldin, and R.B. Innis.
Positron emission tomography imaging using an inverse agonist radioligand to assess cannabinoid CB1 receptors in rodents. NeuroImage, 41: 690-698, 2008. (PDF File)
2) G.E. Terry, J. Hirvonen, J-S. Liow, S.S. Zoghbi, R. Gladding, J.T. Tauscher, J.M. Schaus, L. Phebus, C.C. Felder, C.L. Morse, S.R. Donohue, V.W. Pike, C. Halldin, and R.B. Innis.
Imaging and quantitation of cannabinoid CB1 receptors in human and monkey brain using 18F-labeled inverse agonist radioligands. J. Nucl. Med., 51: 112-120, 2010. (PDF File)
3) J. Hirvonen, R.S. Goodwin, C.-T. Li, G.E. Terry, S.S. Zoghbi, C. Morse, V.W. Pike, N.D. Volkow, M.A. Huestis, and R.B. Innis. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in heavy cannabis users. Mol. Psychiatry. 17: 642-649, 2012b.
. (PDF File)
4) J. Hirvonen, P. Zanotti Fregonara, J.C. Umhau, D.T. George, D. Rallis-Frutos, C.H. Lyoo, C.-T. Li, C.S. Hines, H. Sun, G. Terry, S.S. Zoghbi, C. Morse, V.W. Pike, R.B. Innis, and M. Heilig. Reduced cannabinoid CB1 receptor binding in alcohol dependence measured with positron emission tomography. Mol. Psychiatry. In press. 2012c.
Nociceptin Orphanin Peptide Receptor (NOP) that may play roles in alcoholism, drug addiction, and anxiety:
1) V. W. Pike, K.S. Rash, Z. Chen, C. Pedregal, M.A. Statnick, Y. Kimura, J. Hong, S.S. Zoghbi, M. Fujita, S.L. Gackenheimer, J.A. Tauscher, V.N. Barth, and R.B. Innis.
Synthesis and evaluation of radioligands for imaging brain NOP receptors with positron emission tomography. J. Med. Chem., 54: 2687-2700, 2011. (PDF File)
2) T.G. Lohith, S.S. Zoghbi, C.L. Morse, M.F. Araneta, V.N. Barth, N.A. Goebl, J.A. Tauscher, V.W. Pike, R.B. Innis and M. Fujita.
Brain and whole-body imaging of nociceptin/orphanin FQ peptide (NOP) receptors in humans using a novel PET ligand 11C-NOP-1A. J. Nucl. Med., 53: 385-392, 2012. (PDF File)
Imaging dopaminergic neurotransmission:
1) A. Rodriguez-Gomez, J.-Q. Lu, I. Velasco, S. Rivera, S.S. Zoghbi, J-S. Liow, J.L. Musachio, F.T. Chin, H. Toyama, J. Seidel, M.V. Green, P.K. Thanos, M. Ichise, V.W. Pike, R.B. Innis, and R.D.G. McKay.
Persistent dopamine functions of neurons derived from embryonic stem cells in a rodent model of Parkinson disease. Stem Cells, 25: 918-928, 2007. (PDF File)
2) N. Seneca, S.S. Zoghbi, M. Skinbjerg, J.-S. Liow. J. Hong, D.R. Sibley, V.W. Pike, C. Halldin, and R.B. Innis.
Occupancy of dopamine D2/3 receptors in rat brain by endogenous dopamine measured with the agonist positron emission tomography radioligand [11C]MNPA. Synapse, 62: 756-763, 2008. (PDF File)
3) M. Skinbjerg, J.-S. Liow, N. Seneca, J. Hong, S. Lu, A. Thorsell, M. Heilig, V.W. Pike, C. Halldin, D.R. Sibley, and R.B. Innis.
D2 dopamine receptor internalization prolongs the decrease of radioligand binding after amphetamine: a PET study in a receptor internalization-deficient mouse model. NeuroImage, 50: 1402-1407, 2010. (PDF File)
M. Ichise, D.C. Vines, T. Gura, G.M. Anderson, S.J. Suomi, J.D. Higley, R.B. Innis.
Effects of early life stress on [11C]DASB PET imaging of serotonin transporters in adolescent peer- and mother-reared rhesus monkeys. J. Neurosci., 26: 4638-4643, 2006. (PDF File)