Effects of acute chlorpyrifos exposure on in vivo acetylcholine accumulation in rat striatum.
This study examined the acute effects of chlorpyrifos (CPF) on cholinesterase inhibition and acetylcholine levels in the striatum of freely moving rats using in vivo microdialysis. Adult, male Sprague-Dawley rats were treated with vehicle (peanut oil, 2 ml/kg) or CPF (84, 156 or 279 mg/kg, sc) and functional signs of toxicity, body weight and motor activity recorded. Microdialysis was conducted at 1, 4 and 7 days after CPF exposure for measurement of acetylcholine levels in striatum. Rats were then sacrificed and the contralateral striatum and diaphragm were collected for biochemical measurements. Few overt signs of cholinergic toxicity were noted in any rats. Body weight gain was significantly affected in the high-dose (279 mg/kg) group only, while motor activity (nocturnal rearing) was significantly reduced in all CPF-treated groups at one day (84 mg/kg) or from 1-4 days (156 and 279 mg/kg) after dosing. Cholinesterase activities in both diaphragm and striatum were markedly inhibited (50-92%) in a time-dependent manner, but there were relatively minimal dose-related changes. In contrast, time- and dose-dependent changes in striatal acetylcholine levels were noted, with significantly higher levels noted in the high-dose group compared to other groups. Maximal increases in striatal acetylcholine levels were observed at 4-7 days after dosing (84 mg/kg, 7-9-fold; 156 mg/kg, 10-13-fold; 279 mg/kg, 35-57-fold). Substantially higher acetylcholine levels were noted when an exogenous cholinesterase inhibitor was included in the perfusion buffer, but CPF treatment-related differences were substantially lower in magnitude under those conditions. The results suggest that marked differences in acetylcholine accumulation can occur with dosages of CPF eliciting relatively similar degrees of cholinesterase inhibition. Furthermore, the minimal expression of classic signs of cholinergic toxicity in the presence of extensive brain acetylcholine accumulation suggests that some compensatory process(es) downstream from synaptic neurotransmitter accumulation limits the expression of toxicity following acute CPF exposure.
Karanth
Subramanya
S
Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, 264 McElroy Hall, Stillwater, OK 74078, USA.
Liu
Jing
J
Mirajkar
Nikita
N
Pope
Carey
C
D000109:Acetylcholine / Q000378:metabolism*; D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D002555:Cerebrospinal Fluid / Q000737:chemistry / Q000378:metabolism; D004390:Chlorpyrifos / Q000008:administration & dosage / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000633:toxicity; D002940:Circadian Rhythm / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D003964:Diaphragm / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015312:Hemodialysis Solutions / Q000737:chemistry / Q000378:metabolism; D007279:Injections, Subcutaneous; D007306:Insecticides / Q000008:administration & dosage / Q000633:toxicity; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D015430:Weight Gain / Q000187:drug effects
D002800:Cholinesterase Inhibitors; D015312:Hemodialysis Solutions; D007306:Insecticides; D004390:Chlorpyrifos; D000109:Acetylcholine