3-(2-hydroxy-4-(1-1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol and Parkinsonian-Disorders

The long-term consequences of chronic manganese (Mn) exposure on neurological health is a topic of great concern to occupationally-exposed workers and in populations exposed to moderate levels of Mn. We have performed a comprehensive assessment of Mn effects on dopamine (DA) synapse markers using positron emission tomography (PET) in the non-human primate brain. Young male Cynomolgus macaques were given weekly i.v. injections of 3.3-5.0 mg Mn/kg (n = 4), 5.0-6.7 mg Mn/kg (n = 5), or 8.3-10.0 mg Mn/kg (n = 3) for 7-59 weeks and received PET studies of various DA synapse markers before (baseline) and at one or two time points during the course of Mn exposure. We report that amphetamine-induced DA release measured by PET is markedly impaired in the striatum of Mn-exposed animals. The effect of Mn on DA release was present in the absence of changes in markers of dopamine terminal integrity determined in post-mortem brain tissue from the same animals. These findings provide compelling evidence that the effects of Mn on DA synapses in the striatum are mediated by inhibition of DA neurotransmission and are responsible for the motor deficits documented in these animals.

Topics: Amphetamine; Animals; Cocaine; Corpus Striatum; Cyclohexanols; Disease Models, Animal; Dopamine; Dopamine Agents; Dopamine Plasma Membrane Transport Proteins; Dose-Response Relationship, Drug; Image Processing, Computer-Assisted; Macaca fascicularis; Male; Manganese; Parkinsonian Disorders; Positron-Emission Tomography; Substantia Nigra; Synaptic Transmission; Tetrabenazine; Tyrosine 3-Monooxygenase

Cannabinoid receptors and their endogenous ligands are potent inhibitors of neurotransmitter release in the brain. Here, we show that in a rat model of Parkinson's disease induced by unilateral nigral lesion with 6-hydroxydopamine (6-OHDA), the striatal levels of the endocannabinoid anandamide (AEA) were increased, while the activity of its membrane transporter and hydrolase (fatty-acid amide hydrolase, FAAH) were decreased. These changes were not observed in the cerebellum of the same animals. Moreover, the frequency and amplitude of glutamate-mediated spontaneous excitatory post-synaptic currents were augmented in striatal spiny neurones recorded from parkinsonian rats. Remarkably, the anomalies in the endocannabinoid system, as well as those in glutamatergic activity, were completely reversed by chronic treatment of parkinsonian rats with levodopa, and the pharmacological inhibition of FAAH restored a normal glutamatergic activity in 6-OHDA-lesioned animals. Thus, the increased striatal levels of AEA may reflect a compensatory mechanism trying to counteract the abnormal corticostriatal glutamatergic drive in parkinsonian rats. However, this mechanism seems to be unsuccessful, since spontaneous excitatory activity is still higher in these animals. Taken together, these data show that anomalies in the endocannabinoid system induced by experimental parkinsonism are restricted to the striatum and can be reversed by chronic levodopa treatment, and suggest that inhibition of FAAH might represent a possible target to decrease the abnormal cortical glutamatergic drive in Parkinson's disease.

Topics: Amidohydrolases; Animals; Antiparkinson Agents; Arachidonic Acids; Binding, Competitive; Cannabinoid Receptor Modulators; Cerebellum; Corpus Striatum; Cyclohexanols; Disease Models, Animal; Endocannabinoids; Excitatory Postsynaptic Potentials; Fatty Acids, Unsaturated; Glutamic Acid; Glycerides; In Vitro Techniques; Levodopa; Oxidopamine; Parkinsonian Disorders; Patch-Clamp Techniques; Phospholipase D; Polyunsaturated Alkamides; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Drug