Electrophysiology of dopamine-denervated striatal neurons. Implications for Parkinson's disease.
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 alters the physiological responses to dopamine receptor stimulation. Nigral lesions induce supersensitivity of D2 dopamine receptors controlling the release of glutamate and reduce the inhibitory influence of D1 receptors at postsynaptic level. These functional changes of the striatal neurons may alter the output signals from the striatum to the other structures of the basal ganglia and then produce most of the physiopathological changes observed in Parkinson's disease.
Calabresi
P
P
Dipartimento Sanità, Università di Roma Tor Vergata, Italy.
Mercuri
N B
NB
Sancesario
G
G
Bernardi
G
G
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism / Q000503:physiopathology*; D003714:Denervation; D004298:Dopamine / Q000172:deficiency*; D015259:Dopamine Agents / Q000494:pharmacology; D004873:Ergolines / Q000494:pharmacology; D008297:Male; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000503:physiopathology*; D011810:Quinoxalines / Q000494:pharmacology; D019257:Quinpirole; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000378:metabolism / Q000503:physiopathology*; D013570:Synaptic Membranes / Q000187:drug effects / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology
D015259:Dopamine Agents; D004873:Ergolines; D011810:Quinoxalines; D019257:Quinpirole; D013779:Tetrodotoxin; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D016627:Oxidopamine; D004298:Dopamine