Sensitization of Dopamine‐Stimulated Adenylyl Cyclase in the Striatum of 1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine‐Treated Rhesus Monkeys and Patients with Idiopathic Parkinson's Disease

Abstract

Dopamine-stimulated adenylyl cyclase activity was measured in striatal homogenates of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rhesus monkeys and humans with idiopathic Parkinson's disease and compared with the activity in control tissue. No differences between parkinsonian and control tissue were found in the presence of 20 mM NaCl. However, when 120 mM NaCl was included in the assay medium, a significantly higher increase in the Vmax of dopamine-stimulated adenylyl cyclase activity was observed in the caudate of MPTP-parkinsonian rhesus monkeys and the putamen of patients with idiopathic Parkinson's disease. No such sensitization was seen in the MPTP-treated rhesus putamen or human Parkinson's disease caudate tissue. A role of D2 receptors in this sensitization could be ruled out by the concomitant use of the D2 antagonist l-sulpiride and by [3H]spiperone saturation analysis of the D2 receptor density, which was found at control level in the caudate tissue of MPTP-treated rhesus monkeys. Similarly, on the basis of saturation binding with the D1 selective ligand 125I-SCH 23982, there was no difference in caudate nucleus D1 receptor densities between control and MPTP-treated monkeys. Our results point to a region-specific functional sensitization of D1 receptors as a consequence of severe dopaminergic denervation of the striatum and suggest the possibility of a therapeutic potential of a D1 agonist with full intrinsic activity in Parkinson's disease.

Persistent Increase in Olfactory Type G-Protein α Subunit Levels May Underlie D1Receptor Functional Hypersensitivity in Parkinson Disease

“…As in the 6-OHDA lesioned rat model (Herve et al, 1993), dopaminestimulated adenylyl cyclase activity is increased in the putamen of parkinsonian patients (Pifl et al, 1992;Tong et al, 2004). In both lesioned rats and parkinsonian patients, the increased D 1 -stimulated cAMP production occurs in the absence of significant increase in the D 1 R levels (Shinotoh et al, 1993;Turjanski et al, 1997;Hurley et al, 2001;Cai et al, 2002).…”

“…Hypersensitivity of dopamine receptors after dopamine denervation may play a crucial role in the genesis of long-term L-dopa adverse effects (Bezard et al, 2001). Activation of dopamine receptors has important consequences on neuronal plasticity (Greengard et al, 1999;Berke and Hyman, 2000;Gerfen, 2000a), and modifications of dopamine receptor signaling in PD may lead to the development of abnormal responses to L-dopa. In support of this hypothesis, D 1 receptor (D 1 R) hypersensitivity is associated with alterations of synaptic plasticity in a rat model of L-dopa-induced dyskinesia (Picconi et al, 2003), and dopamine-stimulated adenylyl cyclase is increased in PD (Pifl et al, 1992;Tong et al, 2004). The mechanisms of D 1 R hypersensitivity are unclear, because in contrast to D 2 receptor (D 2 R) (Creese et al, 1977;Lee et al, 1978), D 1 R number appears unchanged (Shinotoh et al, 1993;Turjanski et al, 1997;Hurley et al, 2001).…”

Maladaptive striatal plasticity in l-DOPA-induced dyskinesia

“…Bezard et al, 2003, Hurley et al, 1996, Mela et al, 2010 and Quik et al, 2000). Although increased receptor expression at the plasma membrane may contribute to D 1 supersensitivity (Guigoni et al, 2007), denervation-induced supersensitivity of DA receptors is generally attributed to altered signal transduction mechanisms in the dopaminoceptive neuron (Gerfen, 2003, Pifl et al, 1992, Prieto et al, 2009 and Zhen et al, 2002). The following alterations have been documented to occur in the DA-denervated striatum: (1) aberrant activation of non-canonical signaling cascades downstream of D 1 receptors; (2) exuberant activation of canonical signaling pathways following D 1 and D 2 receptor stimulation and (3) reduced expression of negative signaling modulators.…”

Pimavanserin, a 5-HT2A inverse agonist, reverses psychosis-like behaviors in a rodent model of Parkinson's disease

“…However, destruction of dopamine neurons has been shown to result in a number of adaptations in dopamine signaling that might underlie such a paradoxical increase in amphetamine-induced activity. For example, lesions of the nigrostriatal dopamine system result in a supersensitivity of striatal D 1 and D 2 dopamine receptors (Hu et al, 1990;Pifl et al, 1992;Calabresi et al, 1993;Gerfen, 2003). Furthermore, intrastriatal infusions of D 1 receptor agonists induce hyperlocomotion in dopamine depleted rats compared with sham controls that is reversed by 5-HT 2A receptor antagonism (Bishop et al, 2003(Bishop et al, , 2005.…”