In vivo evidence of D3 dopamine receptor sensitization in parkinsonian primates and rodents with l-DOPA-induced dyskinesias

Abstract

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...

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

“…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).…”

Nociceptin/orphanin FQ receptor blockade attenuates MPTP-induced parkinsonism

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