Elsevier

Neurobiology of Disease

Volume 27, Issue 2, August 2007, Pages 220-227
Neurobiology of Disease

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

https://doi.org/10.1016/j.nbd.2007.04.016Get rights and content

Abstract

A growing body of evidence indicates a role for D3 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 D3-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 D1 receptor-like signaling occurring in response to D3 stimulation, demonstrates a dysregulation of dopamine receptor function in dyskinesia and provides a potentially novel means for the characterization and treatment of l-DOPA-induced dyskinesia in patients.

Section snippets

Rodent studies

All animal studies were performed following NIH guidelines and were approved by the IACUC at McLean Hospital and Harvard Medical Area. Naïve and 6-OHDA-lesioned adult female Sprague-Dawley rats (200–250 g) were purchased from Charles River Laboratories and Taconic. The animals were unilaterally lesioned by 6-OHDA injection (4 μl; 2 μg/μl) into the medial forebrain bundle. An appropriate level of denervation was evaluated by the rotational response to apomorphine (0.05 mg/kg) and amphetamine

Effects of DA denervation and chronic l-DOPA administration on the rCBV response to 7-OHDPAT in 6-OHDA-lesioned hemiparkinsonian rats

In naïve anesthetized rats 7-OHDPAT administration induced a negative change in rCBV in the nucleus accumbens (Figs. 1a–b) (Choi et al., 2006) corresponding to the anatomical distribution of the D3 receptor (Murray et al., 1994), which is highly expressed in the ventromedial shell of the nucleus accumbens, olfactory tubercle and islands of Calleja and low in the motor striatum (Sokoloff et al., 1990). The hemodynamic changes induced by 7-OHDPAT in the nucleus accumbens were larger than the

Discussion

In this study we examined in vivo dynamic changes in response to 7-OHDPAT using phMRI in naïve, parkinsonian and l-DOPA-treated, dyskinetic animals. We used 2 complementary models: the unilateral acute 6-OHDA rodent model that, although not without limitations as a model for dyskinesia, is quite informative and allow us to compare this study with our previous studies mapping normal distribution of DA receptors in the rodent brain, and a bilateral primate model that closely resembles PD and the l

Acknowledgments

We are grateful to Jack McDowell and Jennifer Pagel for excellent technical help and to Dr Anna Liisa Brownell and staff in her lab for the PET studies. This work was supported by the NINDS P50 NS-39793 and N.E.R.P.R.C. Center Grant P51RR00168.

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