Functional MR imaging can demonstrate the CNS pathway for acupuncture stimulation. Acupuncture at ST.36 and LI.4 activates structures of descending antinociceptive pathway and deactivates multiple limbic areas subserving pain association. These findings may shed light on the CNS mechanism of acupuncture analgesia and form a basis for future investigations of endogenous pain modulation circuits in the human brain.

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.

Receptor supersensitivity is an important concept for understanding neurotransmitter and receptor dynamics. Traditionally, detection of receptor supersensitivity has been performed using autoradiography or positron emission tomography (PET). We show that use of magnetic resonance imaging (MRI) not only enables one to detect dopaminergic supersensitivity, but that the hemodynamic time course reflective of this fact is different in different brain regions. In rats unilaterally lesioned with intranigral 6-hydroxydopamine, apomorphine injections lead to a large increase in hemodynamic response (cerebral blood volume, CBV) in the striato-thalamo-cortico circuit on the lesioned side but had little effect on the intact side. Amphetamine injections lead to increases in hemodynamic responses on the intact side and little on the lesioned side in the same animals. The time course for the increase in CBV after either amphetamine or apomorphine administration was longer in striatum and thalamus than in frontal cortex. (11)C-PET studies of ligands which bind to the dopamine transporter (2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane 1, 5-naphthalnendisulfonate, WIN 35, 428 or CFT) and D2 receptors (raclopride) confirm that there is a loss of presynaptic dopamine terminals as well as upregulation of D2 receptors in striatum in these same animals. Pharmacologic MRI should become a sensitive tool to measure functional supersensitivity in humans, providing a complementary picture to that generated using PET studies of direct receptor binding.

A growing body of evidence indicates a role for D 3 receptors in L-DOPA-induced dyskinesias. This involvement could be amenable to non-invasive in vivo analysis using functional neuroimaging. With this goal, we examined the hemodynamic response to the dopamine D 3 -preferring agonist 7-hydroxy-N,N-di-n-propyl-2 aminotetralin (7-OHDPAT) in naïve, parkinsonian and L-DOPA-treated, dyskinetic rodents and primates using pharmacological MRI (phMRI) and relative cerebral blood volume (rCBV) mapping. Administration of 7-OHDPAT induced minor negative changes of rCBV in the basal ganglia in naïve and parkinsonian animals. Remarkably, the hemodynamic response was reversed (increased rCBV) in the striatum of parkinsonian animals rendered dyskinetic by repeated L-DOPA treatment. Such increase in rCBV is consistent with D 1 receptor-like signaling occurring in response to D 3 stimulation, demonstrates a dysregulation of dopamine receptor function in dyskinesia and provides a potentially novel means for the characterization and treatment of L-DOPAinduced dyskinesia in patients. KeywordsDyskinesia; Parkinson's disease; Dopamine; Dopamine receptor; D 3 ; Striatum; phMRI; Primate Long-term dopamine (DA) replacement therapy in Parkinson's disease (PD) often leads to development of abnormal motor response and dyskinesia (Olanow et al., 2004) through poorly understood mechanisms. DA modulates the basal ganglia output through opposite effects on the postsynaptic DA receptors: D 1 facilitation and D 2 -like (D 2 and D 3 ) inhibition (Beaulieu et al., 2005). Anatomically, D 1 and D 2 -like receptors are partially segre-gated into the striatonigral ("direct") and striatopallidal ("indirect") projections or pathways (Gerfen et al., 1990). However, there is evidence of substantial co-localization of functional D 1 -and D 2 -like receptors on striatal medium spiny projection neurons (Aizman et al., 2000;Pollack, 2004) implying that cross-talk may occur both at circuitry and intracellular levels. DA receptors are 7 transmembrane G-protein-coupled receptors: D 1 receptors are coupled to G αs/olf, increase (Chen et al., 2005;Choi et al., 2006). Pramipexole, a D 3 -preferring agonist, has been shown to reduce cerebral blood flow in cingulate and orbitofrontal areas in monkeys in a PET study (Black et al., 2002). These opposite effects correlate well with the D 1 -mediated facilitation and D 2 gating roles on glutamate transmission in the striatum.While D 3 receptors are not highly expressed in the motor regions of the striatum (Murray et al., 1994;Sokoloff et al., 1990), there is compelling evidence from postmortem studies, of L-DOPA induction of ectopic D 3 receptor expression in D 1 -expressing medium spiny neurons in the striatum of parkinsonian rats (Bordet et al., 1997;Bordet et al., 2000) and macaques Quik et al., 2000). Furthermore, both the presence of L-DOPA-induced dyskinesias in primates and sensitization to L-DOPA in rats (Bordet et al., 1997;Bordet et al., 2000;Guillin et al., 2003) have been correlated with changes in D...