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The substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) are the two major mesencephalic dopaminergic systems. Mesencephalic dopamine denervation is followed by long-term modifications in striatum and cortex that preserve dopamine functions. Here, we have studied the impact of isolated bilateral 6-hydroxydopamine lesioning of the SNc or the VTA on D1 and D2 dopamine receptor binding in striatal and cortical areas of rat. Neither SNc nor VTA bilateral partial lesioning changed D2 binding at the striatal or cortical level. Intriguingly, only VTA lesioning increased D1 binding in the cortex, whereas both bilateral partial lesioning of the SNc or the VTA increased striatal D1 binding. This suggests that increased cortical D1 binding could be an indicator of VTA lesioning. Further behavioural experiments may explain the pathophysiological meaning of increased cortical D1 binding, and determine whether this observation is involved in compensatory mechanisms. [Copyright &y& Elsevier]

Adenosine A 1 /A 2A receptors (A 1 R/A 2A R) represent targets in nondopaminergic treatment of motor disorders such as Parkinson's disease (PD). As an innovative strategy, multitargeting ligands (MTLs) were developed to achieve comprehensive PD therapies simultaneously addressing comorbid symptoms such as sleep disruption. Recognizing the wake-promoting capacity of histamine H 3 receptor (H 3 R) antagonists in combination with the "caffeine-like effects" of A 1 R/A 2A R antagonists, we designed A 1 R/A 2A R/H 3 R MTLs, where a piperidino-/pyrrolidino(propyloxy)phenyl H 3 R pharmacophore was introduced with overlap into an adenosine antagonist arylindenopyrimidine core. These MTLs showed distinct receptor binding profiles with overall nanomolar H 3 R affinities ( K i < 55 nM). Compound 4 ( ST-2001 , K i (A 1 R) = 11.5 nM, K i (A 2A R) = 7.25 nM) and 12 ( ST-1992 , K i (A 1 R) = 11.2 nM, K i (A 2A R) = 4.01 nM) were evaluated in vivo . l-DOPA-induced dyskinesia was improved after administration of compound 4 (1 mg kg -1 , i.p. rats). Compound 12 (2 mg kg -1 , p.o. mice) increased wakefulness representing novel pharmacological tools for PD therapy.

Parkinson's disease motor symptoms are treated with levodopa, but long-term treatment leads to disabling dyskinesia. Altered synaptic transmission and maladaptive plasticity of corticostriatal glutamatergic projections play a critical role in the pathophysiology of dyskinesia. Because the noble gas xenon inhibits excitatory glutamatergic signaling, primarily through allosteric antagonism of the N-methyl-d-aspartate receptors, we aimed to test its putative antidyskinetic capabilities. We first studied the direct effect of xenon gas exposure on corticostriatal plasticity in a murine model of levodopa-induced dyskinesia We then studied the impact of xenon inhalation on behavioral dyskinetic manifestations in the gold-standard rat and primate models of PD and levodopa-induced dyskinesia. Last, we studied the effect of xenon inhalation on axial gait and posture deficits in a primate model of PD with levodopa-induced dyskinesia. This study shows that xenon gas exposure (1) normalized synaptic transmission and reversed maladaptive plasticity of corticostriatal glutamatergic projections associated with levodopa-induced dyskinesia, (2) ameliorated dyskinesia in rat and nonhuman primate models of PD and dyskinesia, and (3) improved gait performance in a nonhuman primate model of PD. These results pave the way for clinical testing of this unconventional but safe approach. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)