Objectives-Functional MRI (fMRI) holds the promise of non-invasive mapping of human brain function in both health and disease. Yet its sensitivity and reliability for mapping higher cognitive function are still being determined. Using verbal fluency as a task, the objective was to ascertain the consistency of fMRI on a conventional scanner for determining the anatomic substrate of language between subjects and between sexes. Comparison was made with previous PET studies. Methods-Using a 1.5 Tesla magnet and an echoplanar pulse sequence, whole brain fMRI was obtained from 12 normal right handed subjects (6 males and 6 females) as they performed a verbal fluency task. However, decremental responses were seen over a much larger area of the posterior cortex than had been anticipated by prior studies. The ability to see a response in each subject individually suggests that fMRI may be useful in the preinterventional mapping of pathological states, and oVers a non-invasive alternative to the Wada test for assessment of hemispheric dominance. There were no gross diVerences in the pattern of activation between male and female subjects. (J Neurol Neurosurg Psychiatry 1998;64:492-498)

Extensive neuroanatomical, neurophysiological, and behavioral evidence demonstrates that GABAergic neurons inhibit endogenous dopamine release in the mammalian corpus striatum. Positron emission tomography (PET) studies in adult female baboons, using the dopamine D2-specific radiotracer 11C-raclopride, were undertaken to assess the utility of this imaging technique for measuring these dynamic interactions in vivo. 11C-raclopride binding was imaged prior to and following the administration of either gamma-vinyl-GABA (GVG), a specific suicide inhibitor of the GABA-catabolizing enzyme GABA transaminase, or lorazepam, a clinically prescribed benzodiazepine agonist. Striatal 11C-raclopride binding increased following both GVG and lorazepam administration. This increase exceeded the test/retest variability of 11C-raclopride binding observed in the same animals. These findings confirm that changes in endogenous dopamine concentrations resulting from drug-induced potentiation of GABAergic transmission can be measured with PET and 11C-raclopride. Finally, this new strategy for noninvasively evaluating the functional integrity of neurophysiologically linked transmitter systems with PET supports its use as an approach for assessing the multiple mechanisms of drug action and their consequences in the human brain.

Though the blockade of dopamine transporters (DAT) is associated with cocaine's and methylphenidate's reinforcing effects, it is the stimulation of dopamine (DA) receptors, achieved by increases in synaptic DA, that enables these effects to occur. Positron emission tomography (PET) and [11C]raclopride were used to assess the levels of occupancy of DA D2 receptors by dopamine achieved by doses of cocaine or methylphenidate previously documented to block over 70% of DAT. Studies were performed in five baboons using a paired scan protocol designed to measure DA D2 receptor availability (Bmax/Kd) at baseline conditions and after intravenous administration of either cocaine or methylphenidate. Cocaine (1-2 mg/kg) or methylphenidate (0.5 mg/kg) administered 5 min prior to [11C]raclopride decreased Bmax/Kd by 29+/-3% and 32 + 4%, respectively. Smaller reductions in Bmax/Kd (13% for cocaine given 30 min before [11C]raclopride and 25+/-10% for methylphenidate given 40 min before [11C]raclopride) were seen with longer periods between drug and radioligand. These observations are consistent with the slower striatal clearance kinetics of [11C]methylphenidate than [1C]cocaine observed in previous PET experiments and with the approximately twofold higher potency of methylphenidate than cocaine in in vitro experiments. Though the elevation of synaptic DA induced by >70% occupancy of DAT by these drugs lead to a modest increase in occupancy of D2 receptors (25-30%), further studies are required to assess if this is an underestimation because of differences in D2 receptor binding kinetics between raclopride and DA.

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