Pyrethroid insecticides and the gamma-aminobutyric acidA receptor complex: motor activity and the acoustic startle response in the rat.
Two behavioral tests, motor activity and the acoustic startle response (ASR), were used to test for dose-addition of cismethrin, a Type I, or deltamethrin, a Type II pyrethroid, with compounds active at the gamma-aminobutyric acid (GABAA) receptor complex (picrotoxin, muscimol and chlordiazepoxide). Additivity was assessed using a simplified version of isobolographic analysis using chlorpromazine and haloperidol as positive controls for dose-additivity. Dosage-effect functions for all compounds were determined for both motor activity and the ASR. The effects of various combinations of chlorpromazine (0.5-4.0 mg/kg) and haloperidol (0.05-0.2 mg/kg) on motor activity indicate dose-addition. To test for dose-addition of pyrethroids and GABAergic compounds, cismethrin (3-18 mg/kg) or deltamethrin (2-6 mg/kg) were administered 90 min before testing, either alone, or before treatment with picrotoxin (0.25-2.0 mg/kg), muscimol (0.6-2.5 mg/kg) or chlordiazepoxide (2.5-10 mg/kg) administered 20 to 30 min before testing. All compounds produced dosage-dependent decreases in motor activity. Muscimol and picrotoxin decreased ASR amplitude, increased ASR latency and reduced ASR sensitization to increasing background noise levels. Chlordiazepoxide had no effect on any measure of the ASR. Results from the interaction studies indicate dose-addition of the effects of picrotoxin and deltamethrin on motor activity and the ASR. Additivity of dose was not seen with any other combination. These data suggest that the in vivo effects of the Type II pyrethroid deltamethrin may be due in part to interaction with the picrotoxinin binding site of the GABAA receptor-ionophore complex. In addition, these results are consistent with reported differential effects of the two classes of pyrethroids on the GABAA receptor complex.
Crofton
K M
KM
Neurotoxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina.
Reiter
L W
LW
D000818:Animals; D002707:Chlordiazepoxide / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009118:Muscimol / Q000494:pharmacology; D009570:Nitriles; D010852:Picrotoxin / Q000494:pharmacology; D011722:Pyrethrins / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects*; D013216:Reflex, Startle / Q000187:drug effects*
D002707:Chlordiazepoxide; D002712:Chlorides; D006220:Haloperidol; D009118:Muscimol; D009570:Nitriles; D010852:Picrotoxin; D011722:Pyrethrins; D011963:Receptors, GABA-A; C017180:decamethrin; C017498:cismethrin