Differential modulation of muscarinic receptors in the rat brain by repeated exposure to methyl parathion.
The neurochemical and behavioral effects of repeated subdermal administration of methyl parathion (MP) at low doses were investigated. Adult male rats were treated repeatedly with either vehicle or MP subcutaneously (3 mg/kg/day) and observed for the signs of toxicity during the treatment period. The toxic sign, tremor, reached maximum right after 9th injection in MP-treated rats, and declined thereafter. Animals were sacrificed and brains were taken 1 week or 3 weeks after the daily treatment for measurement of acetylcholinesterase (AChE) activity and binding of radioligands, [3H]QNB (nonselective), [3H]pirenzepine (M1-selective), and [3H]AF-DX384 (M2-selective) to muscarinic receptors. With this treatment regimen, the AChE activity in the blood dropped quickly and maintained at 30% of the control level after 6 injections. After 3 weeks of treatment, MP caused 80-90% AChE inhibition and substantial reductions in [3H]QNB binding (9-33%), [3H]pirenzepine binding (9-22%) and [3H]AF-DX384 binding (6-38%) in different brain regions, including striatum, hippocampus, frontal cortex, thalamus and midbrain. After 1 week of treatment, the inhibition of AChE in brain regions was from 54 to 74%, whereas receptor densities were only marginally affected in a few regions. The timing of the changes in receptor population correlates well with the changes in behaviors during the repeated MP exposure. Our findings suggest that down-regulation of muscarinic receptors plays a role in the development of tolerance to MP. And, the regulations of muscarinic receptors were different among receptor subtypes and brain regions.
Sun
Tingting
T
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
Ma
Tangeng
T
Ho
Ing K
IK
D000110:Acetylcholinesterase / Q000032:analysis / Q000097:blood; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D015536:Down-Regulation; D006651:Histocytochemistry; D007279:Injections, Subcutaneous; D008297:Male; D008743:Methyl Parathion / Q000633:toxicity*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011813:Quinuclidinyl Benzilate / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors / Q000187:drug effects*; D043585:Receptor, Muscarinic M2 / Q000037:antagonists & inhibitors / Q000187:drug effects*; D014202:Tremor / Q000139:chemically induced; D014316:Tritium
D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D014316:Tritium; C065959:AFDX 384; D010890:Pirenzepine; D008743:Methyl Parathion; D011813:Quinuclidinyl Benzilate; D000110:Acetylcholinesterase