Mapping Dopamine Function in Primates Using Pharmacologic Magnetic Resonance Imaging

Abstract

Dopamine (DA) receptors play a central role in such diverse pathologies as Parkinson's disease, schizophrenia, and drug abuse. We used an amphetamine challenge combined with pharmacologic magnetic resonance imaging (phMRI) to map DA-associated circuitry in nonhuman primates with high sensitivity and spatial resolution. Seven control cynomolgous monkeys and 10 MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated parkinsonian primates were studied longitudinally using both positron emission tomography (PET) and phMRI. Amphetamine challenge (2.5 mg/kg, i.v.) in control monkeys increased relative cerebral blood volume (rCBV) in a number of brain regions not described previously, such as parafascicular thalamus, precentral gyrus, and dentate nucleus of the cerebellum. With the high spatial resolution, we were also able to readily identify changes in rCBV in the anterior cingulate, substantia nigra, ventral tegmental area, caudate (tail and head), putamen, and nucleus accumbens. Amphetamine induced decreases in rCBV in occipital and posterior parietal cortices. Parkinsonian primates had a prominent loss of response to amphetamine, with relative sparing of the nucleus accumbens and parafascicular thalamus. There was a significant correlation between rCBV loss in the substantia nigra and both PET imaging of dopamine transporters and behavioral measures. Monkeys with partial lesions as defined by 2␤-carbomethoxy-3␤-(4-fluorophenyl) tropane binding to dopamine transporters showed recruitment of premotor and motor cortex after amphetamine stimulus similar to what has been noted in Parkinson's patients during motor tasks. These data indicate that phMRI is a powerful tool for assessment of dynamic changes associated with normal and dysfunctional DA brain circuitry in primates.

Enhanced binding of metabotropic glutamate receptor type 5 (mGluR5) PET tracers in the brain of parkinsonian primates

“…These imaging studies confirmed mGluR5 binding to DA target regions (Fig. 1f) matching cortical and subcortical areas with identical distribution to that we described previously using fMRI and amphetamine (Jenkins et al, 2004) (i.e. the areas in which DA release induces an increase in regional cerebral blood volume).…”

“…The loss of [ 11 C]CFT binding was directly correlated with the severity of the parkinsonian signs (p < 0.005) measured by the global motor score in a rating scale based on the motor subscale of the UPDRS (Fig. 1e) as we have previously described in this model (Jenkins et al, 2004). To confirm that the change in [ 11 C]MPEPy binding reflected changes in mGluR5, we examined in 2 other primates, the distribution of the novel compound [ 18 F]FPEB (Hamill et al, 2005;Wang et al, 2007), which has exceptionally high affinity to mGluR5.…”

“…MPTP-lesioned animals had a significant loss of [ 11 C]CFT binding in the putamen (t 1,3 =8.27; p<0.05) with typical preservation of DA innervation of the nucleus accumbens (Fig 1b, (Jenkins et al, 2004)). Regional analysis of [ 11 C]MPEPy was performed in cortical and subcortical areas to examine the motor and limbic DA loops (color coded in Fig.1c, at 3 coronal levels of the macaque brain).…”

“…Systemic administration of MPTP to induce a stable parkinsonism and rating of parkinsonian severity was performed as previously reported by our group in detail (Jenkins et al, 2004). Imaging studies were performed under propofol anesthesia (0.3mg/kg/min iv).…”

“…Regions of interest (ROIs) were delineated based on MRI high resolution anatomical images acquired on a Siemens 3T Trio system, as previously reported by our group (Jenkins et al, 2004;Sanchez-Pernaute et al, 2007) and anatomical atlas (Fig. 1c).…”