Mapping the Effects of Three Dopamine Agonists with Different Dyskinetogenic Potential and Receptor Selectivity Using Pharmacological Functional Magnetic Resonance Imaging

Abstract

The mechanisms underlying dopamine agonist-induced dyskinesia in Parkinson's disease remain poorly understood. Similar to patients, rats with severe nigrostriatal degeneration induced by 6-hydroxydopamine are more likely to show dyskinesia during chronic treatment with unselective dopamine receptor agonists than with D2 agonists, suggesting that D1 receptor stimulation alone or in conjunction with D2 receptor stimulation increases the chances of experiencing dyskinesia. As a first step towards disclosing drug-induced brain activation in dyskinesia, we examined the effects of dopamine agonists on behavior and blood oxygenation level-dependent (BOLD) signal in the striatum and motor cortex of rats with unilateral nigrostriatal lesions. Rats were rendered dyskinetic before pharmacologic functional magnetic resonance imaging by means of a repeated treatment regime with dopamine agonists. The unselective agonist apomorphine and the selective D1/D5 agonist SKF-81297 induced strong forelimb dyskinesia (FD) and axial dystonia and increased BOLD signal in the denervated striatum. Besides, SKF-81297 produced a significant but smaller BOLD increase in the intact striatum and a symmetric bilateral increase in the motor cortex. The D2 family agonist quinpirole, which induced mild dyskinesia on chronic treatment, did not produce BOLD changes in the striatum or motor cortex. Further evidence to support an association between BOLD changes and dyskinesia comes from a direct correlation between scores of FD and magnitude of drug-induced BOLD increases in the denervated striatum and motor cortex. Our results suggest that striatal and cortical activation induced by stimulation of D1/D5 receptors has a primary role in the induction of peak dose dyskinesia in parkinsonism.

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

“…We previously showed that D 1 agonists produce large positive CBV changes in the striatum, while D 2 /D 3 agonists (norpropylapomorphine, quinpirole and 7-OHDPAT) produce negative CBV changes in rats (Chen et al, 2005;Choi et al, 2006). Using BOLD a recent study in dyskinetic rodents has reported similar positive changes with D 1 (or non-selective) agonists (Delfino et al, 2007) while D 2 did not produce positive BOLD changes. Thus, since the CBV change observed in the dyskinetic animals is positive it is unlikely due to lack of specificity of the 7-OHDPAT for D 3 over D 2 receptors as the D 2 receptor activation should produce a negative CBV change.…”

“…These data clearly indicate a D 3 preference of 7-OHDPAT in vivo. Moreover, in another recent study (Delfino et al, 2007), quinpirole (a D 2 preferring agonist) did not increase BOLD signal, or induce sensitization -strongly arguing against a sensitization of D 2 receptors in dyskinetic rats. Lastly, we have some preliminary evidence using the selective D 3 antagonist SB277011 supporting D 3 involvement in the rCBV change observed in the striatum of dyskinetic animals (Sanchez-Pernaute and Jenkins, unpublished observation) as the aberrant activation reported here was suppressed on the ipsilateral side by the D 3 antagonist, while 6-OHDA-lesioned rats showed bilateral medial activation similar to what we have shown previously with eticlopride, a D 3 /D 2 antagonist (Chen et al, 2005).…”

Dopamine-Induced Dissociation of BOLD and Neural Activity in Macaque Visual Cortex

“…However, amphetamines are known to increase DA levels as well as alter the kinetics of other neurochemicals that affect the regional CBV [34], whereas CBV responses may differ from BOLD responses [35]. Different DARs exert different effects on the hemodynamic signals [30]; stimulation of D1 receptors (D1Rs) increases CBV and BOLD responses [30,32], whereas blocking these receptors decreases them [30,36]. The activation and deactivation of D2 receptors (D2Rs) produce opposite effects [37].…”

“…The effects of DA on the hemodynamic signals have been extensively addressed using different pharmacological agents in rats and monkeys [29][30][31][32][33]. For instance, amphetamines decreased CBV responses in occipital regions [33].…”

Activation of DREAM (Downstream Regulatory Element Antagonistic Modulator), a Calcium-Binding Protein, Reduces L-DOPA-Induced Dyskinesias in Mice

“…L-DOPA-induced dyskinesia (LID) is causally linked with hyperstimulation of dopamine D1 receptors (D1R) located on direct pathway medium spiny neurons (MSNs) of the severely denervated striatum (1)(2)(3). In the dopamine-depleted striatum, L-DOPA activates a cAMP-dependent signalling cascade via PKA activation (4,5), resulting in abnormally increased phosphorylation of DARPP-32 and activation of the Ras/ERK signalling pathway in the same neurons (1,(6)(7)(8)(9).…”