D1-like and D2-like dopamine receptors synergistically activate rotation and c-fos expression in the dopamine-depleted striatum in a rat model of Parkinson's disease

Abstract

Selective agonists for D1-like and D2-like dopamine receptors can interact synergistically to enhance each other's actions on locomotion and behavior in experimental animals. Clinically, the combination of the D2 agonist bromocriptine with L-dopa (which has pronounced D1 effects) is a highly effective treatment for Parkinson's disease. The mechanisms underlying this important receptor interaction are poorly understood and are the subject of intense study in vitro. In rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway, D1-selective (but not D2-selective) dopamine agonists produce a marked increase in expression of the immediate-early gene c-fos in the striatum ipsilateral to the 6-OHDA lesion. In the experiments reported here, we have used this in vivo model to explore the possibility that combinations of D1-selective and D2-selective agonists might have effects on c-fos transcription that are different from those exhibited by D1 or D2 agonists administered alone. We examined the effects of the D1-selective agonist SKF-38393 and the D2-selective agonist quinpirole (LY 171555) on the expression of Fos-like protein and c-fos mRNA in the caudoputamen and made parallel behavioral observations in the same animals. A low dose of SKF-38393 produced little contraversive rotation and little induction of Fos-like immunoreactivity in the striatum. A low dose of quinpirole elicited contralateral rotation but little or no induction of Fos-like immunoreactivity in the caudoputamen; there was, however, induction of Fos in the globus pallidus ipsilateral to the 6-OHDA lesion. Combination of the low dose of SKF-38393 and quinpirole produced a synergistic effect on rotation and elicited, in the dopamine-depleted caudoputamen, a striking pattern of Fos-like protein expression in which Fos-positive neurons were concentrated in striosomes and in the dorsolateral caudoputamen. Northern blot analysis showed that c-fos mRNA was expressed following combined agonist treatment but was not detectable after the single-agonist treatments. Both the contraversive rotation and the induction of Fos-like immunoreactivity were blocked by the preadministration of the D1-preferring antagonist SCH-23390 and the D2-selective antagonist raclopride in combination. Pretreatment with the glutamate NMDA receptor antagonist MK-801 also blocked the induction of Fos-like immunoreactivity, and it reversed the rotation. These findings suggest a D1/D2 synergistic mechanism that involves the participation of D1-responsive striatonigral and D2-responsive striatopallidal output pathways, and that is sensitive to glutamatergic modulation.

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

“…Our present findings showing that quinpirole does not induce BOLD changes in 6-OHDA-lesioned rats are consistent with previous studies establishing that D2 family agonists do not increase 2-deoxyglucose uptake and immediate early gene expression in the striatum of parkinsonian rats (Trugman and Wooten, 1987;Robertson et al, 1989;Paul et al, 1992;LaHoste et al, 1993). Contrasting with this lack of neuronal activation in the striatum, quinpirole induces mild AIMs and strong turning behavior in 6-OHDA-lesioned rats, which were sensitized to dopamine agonists (present findings and Delfino et al, 2004; see also Robertson et al, 1989;Paul et al, 1992). On the other hand, the D1/D5 agonist SKF-81297 induced a strong striatal and cortical bilateral activation, which was higher in rats repeatedly exposed to the same agonist before MRI examination, and which was significantly higher than that induced by apomorphine.…”

“…In normal rats, D2 family agonists increase BOLD in brain regions enriched in D3 receptors, like the nucleus accumbens, but have little if any effect in dorsal striatum and motor cortex (Ireland et al, 2005). Our present findings showing that quinpirole does not induce BOLD changes in 6-OHDA-lesioned rats are consistent with previous studies establishing that D2 family agonists do not increase 2-deoxyglucose uptake and immediate early gene expression in the striatum of parkinsonian rats (Trugman and Wooten, 1987;Robertson et al, 1989;Paul et al, 1992;LaHoste et al, 1993). Contrasting with this lack of neuronal activation in the striatum, quinpirole induces mild AIMs and strong turning behavior in 6-OHDA-lesioned rats, which were sensitized to dopamine agonists (present findings and Delfino et al, 2004; see also Robertson et al, 1989;Paul et al, 1992).…”

“…On the other hand, the D1/D5 agonist SKF-81297 induced a strong striatal and cortical bilateral activation, which was higher in rats repeatedly exposed to the same agonist before MRI examination, and which was significantly higher than that induced by apomorphine. Early studies of 2-deoxyglucose uptake and immediate early gene expression recognized a powerful stimulatory effect of D1/D5 agonists in parkinsonian rats (Trugman and Wooten, 1987;Robertson et al, 1989;Paul et al, 1992;LaHoste et al, 1993). More recent work emphasized the bilateral effects of D1/D5 agonists on gene expression in the parkinsonian rat brain (Keefe and Gerfen, 1995;Blandini et al, 2003;Taymans et al, 2005) and demonstrated that direct stimulation of D1/D5 receptors in the denervated striatum can activate the motor cortex bilaterally (Keefe and Gerfen, 1995;Blandini et al, 2003).…”

Biphasic changes in locomotor behavior and in expression of mRNA for NGFI-A and NGFI-B in rat striatum following acute caffeine administration

“…In agreement with this basic hypothesis, the D, receptor agonist quinpirole was found to induce a marked reduction of the expression of mRNA for NGFI-A and NGFI-B. Quinpirole does not alter the expression of c-&s (Paul et al, 1992) unless c-fos expression is enhanced, for example, by reserpine treatment (Cole and Di Figlia, 1994). Interestingly, caffeine (25 mg/kg) had an effect of equal magnitude, and its effect was not clearly additive to that of quinpirole.…”

Augmented D1 Dopamine Receptor Signaling and Immediate-Early Gene Induction in Adult Striatum After Prenatal Cocaine

“…Genes induced in striatal neurons by systemic psychostimulant administration include c-fos (42,43), zif 268 (44) and homer 1a (45,46). Such gene induction is principally mediated by D 1 -like receptors; however, D 2 -like receptors additionally modulate such effects (47,48). Notably, psychostimulantinduced gene regulation is abolished by D 1 receptor blockade (42,44,49,50), or by targeted deletion of D 1 receptors (51-54).…”