Sustained unilateral blockade of rat striatal M(1) muscarinic receptors with m1-toxin1 in vivo.
m1-Toxin1 is a trace component of the venom of the green mamba that antagonizes M(1) muscarinic receptors specifically and irreversibly in vitro. It was injected into the right caudatoputamen of Wistar rats to occlude M(1) receptors specifically for several days ("M(1) knockdown"), and to begin to establish the unknown effects of striatal M(1)-neurotransmission on movement. The extent and duration of M(1)-blockade were evaluated with receptor binding assays and light microscopic autoradiography, using 1-2 nM [3H]pirenzepine to assess unoccupied M(1) receptors. An injection of 27 pmol m1-toxin1 blocked almost all of the M(1) receptors in one caudatoputamen (4 pmol), followed by their slow recovery to supranormal levels (115%) during a week. During maximum M(1)-blockade, the binding of 1 nM [3H]N-methylscopolamine to striatal membranes was reduced by only half, indicating no blockade of M(4) receptors, which comprise 51% of striatal muscarinic receptors. It is concluded that m1-toxin1 can produce acute, focal, selective, unilateral and long-lasting M(1)-blockade for investigations of the effects of M(1)-neurotransmission in vivo. Rats with extensive unilateral striatal M(1)-blockade appeared normal, and did not show unilateral deficits in spontaneous forearm use, in contrast to rats with unilateral 6-hydroxydopamine lesions of the substantia nigra. Since M(1)-blockade should decrease the activity of both striatonigral and striatopallidal projection neurons, and the relative activity of these neurons is believed to control movement, the results suggest that a balanced decrease in the activity of these neurons on one side of the brain does not produce a right/left imbalance in spontaneous movement.
Liang
J
J
Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, P.O. Box 016189, Miami, FL 33101, USA.
Gutierrez-Ford
C
C
Potter
L T
LT
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D004546:Elapid Venoms / Q000494:pharmacology*; D007839:Functional Laterality / Q000187:drug effects / Q000502:physiology; D008297:Male; D009068:Movement / Q000187:drug effects / Q000502:physiology*; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000503:physiopathology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D004546:Elapid Venoms; D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; C083667:m1-toxin; D000109:Acetylcholine; D004298:Dopamine