tetrodotoxin and Parkinson-Disease--Secondary

Alterations of striatal synaptic transmission have been associated with several motor disorders involving the basal ganglia, such as Parkinson's disease. For this reason, we investigated the role of group-III metabotropic glutamate (mGlu) receptors in regulating synaptic transmission in the striatum by electrophysiological recordings and by using our novel orthosteric agonist (3S)-3-[(3-amino-3-carboxypropyl(hydroxy)phosphinyl)-hydroxymethyl]-5-nitrothiophene (LSP1-3081) and l-2-amino-4-phosphonobutanoate (L-AP4). Here, we show that both drugs dose-dependently reduced glutamate- and GABA-mediated post-synaptic potentials, and increased the paired-pulse ratio. Moreover, they decreased the frequency, but not the amplitude, of glutamate and GABA spontaneous and miniature post-synaptic currents. Their inhibitory effect was abolished by (RS)-alpha-cyclopropyl-4-phosphonophenylglycine and was lost in slices from mGlu4 knock-out mice. Furthermore, (S)-3,4-dicarboxyphenylglycine did not affect glutamate and GABA transmission. Finally, intrastriatal LSP1-3081 or L-AP4 injection improved akinesia measured by the cylinder test. These results demonstrate that mGlu4 receptor selectively modulates striatal glutamate and GABA synaptic transmission, suggesting that it could represent an interesting target for selective pharmacological intervention in movement disorders involving basal ganglia circuitry.

Topics: Aminobutyrates; Animals; Antiparkinson Agents; Dose-Response Relationship, Drug; Electrophysiology; Excitatory Amino Acid Agonists; Excitatory Postsynaptic Potentials; GABA Agonists; gamma-Aminobutyric Acid; Glutamic Acid; Male; Movement; Neostriatum; Oxidopamine; Parkinson Disease, Secondary; Patch-Clamp Techniques; Rats; Rats, Wistar; Receptors, Metabotropic Glutamate; Sympatholytics; Synaptic Transmission; Tetrodotoxin

Microdialysis was used to study the biotransformation of L-dopa in intact and denervated striata of rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the substantia nigra. Microdialysis probes were placed in the intact and in the denervated striatum. Observations were then made on freely moving rats. Extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxyphenylacetic acid (homovanillic acid; HVA) were monitored before, during and after the local administration of L-dopa via the microdialysis probe for 20 min. A dose-dependent increase in extracellular dopamine levels was seen in intact striatum after application of L-dopa in concentrations ranging between 100 nmol/l and 10 mumol/l. In the denervated striatum, the severity of the lesion influenced dopamine formation, so that no dose-effect relation could be established. The effects of the continuous intra striatal infusion of nomifensine, tetrodotoxin or benserazide on the L-dopa-induced dopamine outflow revealed that in the intact striatum this dopamine release is mainly voltage dependent. It was concluded that in the denervated striatum other cells of non-neuronal origin and containing aromatic L-amino acid decarboxylase make a major contribution to the increase in extracellular dopamine levels. Furthermore, L-dopa itself shows no dopamine-releasing properties, at least under the present experimental conditions.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Benserazide; Biotransformation; Corpus Striatum; Denervation; Dopamine; Dose-Response Relationship, Drug; Drug Interactions; Homovanillic Acid; Levodopa; Male; Microdialysis; Nomifensine; Oxidopamine; Parkinson Disease, Secondary; Rats; Rats, Wistar; Tetrodotoxin

Unilateral 6-hydroxydopamine-induced lesions of the substantia nigra have been used as an experimental model for Parkinson's disease. Although the biochemical and the behavioural effects of striatal denervation have been widely characterized, the physiological and pharmacological changes caused by dopamine depletion at the cellular level are still unknown. We studied the electrical activity of single rat striatal neurons recorded intracellularly in vitro from a brain slice preparation. Recordings were obtained at different periods after the denervation (4, 6, 8 months). In dopamine-denervated slices, unlike naive slices, most of the neurons showed spontaneous depolarizing postsynaptic potentials. The percentage of cells showing spontaneous depolarizing postsynaptic potentials was maximal 4 months after the denervation. In most of the dopamine-denervated neurons (60%) spontaneous depolarizing postsynaptic potentials were reversibly blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM), an antagonist of non-N-methyl-D-aspartate glutamate receptors. In some neurons, however, the amplitude of spontaneous depolarizing postsynaptic potentials was reduced by bicuculline (30 microM) suggesting that they were mediated by the release of endogenous gamma-aminobutyric acid (GABA). Intrinsic membrane properties (membrane potential, input resistance and firing pattern) and postsynaptic responses to different agonists of excitatory amino acid receptors were not altered in neurons recorded from dopamine-depleted slices. In dopamine-depleted slices, unlike in naive slices, LY 171555 (0.1-10 microM), a D2 dopamine receptor agonist, reduced the frequency and the amplitude of CNQX-sensitive spontaneous depolarizing postsynaptic potentials and reduced the amplitude of glutamate-mediated synaptic potentials evoked by cortical stimulation. LY 171555 did not affect the membrane responses to exogenous glutamate. SKF 38393 (3 microM), a D1 dopamine receptor agonist, decreased postsynaptic excitability of striatal neurons recorded from naive animals. On the contrary, this agonist was ineffective in most of the cells obtained from dopamine-depleted slices. These results suggest that dopamine-denervation augments neuronal excitability in the striatum. Abnormal excitability of striatal neurons is not caused by changes of the intrinsic membrane properties of these cells, but is the result of increased glutamatergic cortical inputs to the striatum. Dopamine-denervation also

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Animals; Corpus Striatum; Denervation; Dopamine; Dopamine Agents; Ergolines; Male; Oxidopamine; Parkinson Disease, Secondary; Quinoxalines; Quinpirole; Rats; Rats, Wistar; Substantia Nigra; Synaptic Membranes; Tetrodotoxin