Selective D1 and D2 dopamine agonists differentially alter basal ganglia glucose utilization in rats with unilateral 6-hydroxydopamine substantia nigra lesions

Abstract

he relative roles of D1 and D2 dopamine receptor stimulation in mediating the antiparkinsonian effects of dopaminergic drugs remain unclear. To determine the functional metabolic consequences of selective dopamine receptor stimulation, we used 2-deoxyglucose (2-DG) autoradiography to examine the effects of the D1 agonist SKF-38393 and the D2 agonist LY-171555 on regional cerebral glucose utilization (RCGU) in rats with unilateral 6-hydroxydopamine (6-OHDA) substantia nigra lesions. SKF-38393 (0.5-25.0 mg/kg) and LY-171555 (0.01-5.0 mg/kg) produced indistinguishable behavioral responses, including vigorous contralateral rotation. Treatment with each drug similarly increased glucose utilization, dose-dependently, in the parafascicular thalamus, subthalamic nucleus, deep layers of the superior colliculus, and lateral midbrain reticular formation ipsilateral to the nigral lesion; glucose utilization was decreased in the ipsilateral lateral habenula. By contrast, the D1 and D2 agonists differentially altered glucose utilization in the entopeduncular nucleus (EP) and the substantia nigra pars reticulata (SNr). SKF-38393, 5.0 and 25.0 mg/kg, increased glucose utilization 127 and 275%, respectively, in the pars reticulata ipsilateral to the lesion. LY-171555, 1.0 and 5.0 mg/kg, caused maximal contralateral turning, yet did not alter glucose utilization in the ipsilateral SNr. The glucose utilization response of the ipsilateral EP paralleled that of the SNr demonstrating large increases following administration of SKF-38393 and minimal change following the use of LY-171555. The results demonstrate that the selective D1 agonist reproduces the marked glucose utilization increases (2-3-fold above control values) in the EP and SNr that were previously observed using L-DOPA and apomorphine in this model, whereas the selective D2 agonist does not.(ABSTRACT TRUNCATED AT 250 WORDS)

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

“…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).…”

The Response of Subthalamic Nucleus Neurons to Dopamine Receptor Stimulation in a Rodent Model of Parkinson’s Disease

“…Moreover, the excitatory effects of the D1 receptor agonist seemed to be enhanced in the lesioned rat because a dose of SK F 38393 that did not significantly alter the firing of STN neurons in the intact rat significantly increased the firing in the lesioned rat. Augmentation of responses to D1 receptor agonists in the STN of the lesioned rat have been reported previously in studies measuring biochemical indexes of neuronal activation such as c-fos expression (Ruskin and Marshall, 1995) and glucose metabolism (Trugman and Wooten, 1987). One aspect of the D1 receptor-mediated effect in the STN that was altered by lesion was the role of the dopamine D2 receptor.…”

“…Dopamine D1 receptor stimulation was found to enhance the expression of c-fos in the STN of 6-hydroxydopamine-lesioned rats (Ruskin and Marshall, 1995), suggesting that the activity of STN neurons was increased. 2-Deoxyglucose uptake in the subthala-mus of dopamine-depleted monkeys (Mitchell et al, 1992) and rats (Trugman and Wooten, 1987;Engber et al, 1990) was also found to be increased after administration of dopamine receptor agonists; however, the interpretation of this result is unclear because it could reflect increased metabolism in inhibitory and/or excitatory afferents. Another study reported that the variability in response among STN neurons to the dopamine receptor antagonist haloperidol was increased in lesioned rats (Hollerman and Grace, 1992).…”

In vivo imaging of disturbed pre- and post-synaptic dopaminergic signaling via arachidonic acid in a rat model of Parkinson's disease

“…The regional cerebral metabolic rate for glucose, rCMR glc , thought to represent energy consumed following depolarization of fine pre-synaptic axonal terminals (Sokoloff, 1999), is elevated in ipsilateral more than contralateral globus pallidus, lateral habenula, parafascicular and subthalamic nuclei and superior colliculus in 6-OHDA lesioned rats administered quinpirole (Morelli et al, 1993;Trugman & Wooten, 1987), as were our k* responses (Table 2). D-amphetamine increased rCMR glc less on the lesioned than intact side in one study (Wooten & Collins, 1983), as we found with our k* responses, but results in other studies involving rCMR glc are inconsistent (Palacios & Wiederhold, 1985;Trugman & Wooten, 1987).…”