Aged rats are more sensitive to the acute toxicity of the prototype
organophosphate insecticide,
parathion. We compared the acute effects of
parathion on diaphragm and brain regional
cholinesterase activity,
muscarinic receptor binding and striatal
acetylcholine levels in 3- and 18-month-old male Sprague-Dawley rats. Adult and aged rats were surgically implanted with a microdialysis
cannula into the right striatum 5-7 days prior to
parathion treatment. Rats were given either vehicle (
peanut oil, 2 ml/kg) or one of a range of dosages of
parathion (adult: 1.8, 3.4, 6.0, 9.0, 18 and 27 mg/kg, s.c.; aged: 1.8, 3.4, 6 and 9 mg/kg, s.c.) and
body weight, functional signs of toxicity, and nocturnal motor activity were recorded for seven days. Three and seven days after
parathion treatment, microdialysis samples were collected and rats were subsequently sacrificed for biochemical measurements. Higher dosages of
parathion led to significant time-dependent reductions in
body weight in both age groups. Rats in both age groups treated with lower dosages showed few overt signs of
cholinergic toxicity while equitoxic high dosages (adult, 27 mg/kg; aged, 9 mg/kg) elicited marked signs of
cholinergic toxicity (
involuntary movements and SLUD [i.e., acronym for Salivation, Lacrimation, Urination and Defecation] signs) with peak effects being noted 3-4 days
after treatment. Nocturnal activity (ambulation and rearing) was reduced in both age groups following
parathion dosing, with more prominent effects in adults and rearing being more consistently affected. Dose- and time-dependent inhibition of
cholinesterase activity was noted in both diaphragm and striatum. Total
muscarinic receptor ([(3)H]
quinuclidinyl benzilate, QNB) binding was significantly lower in aged rats, and both total binding and
muscarinic agonist ([(3)H]
oxotremorine methiodide] binding was significantly reduced in both age-groups treated with the highest dosages of
parathion (adult, 27 mg/kg; aged, 9 mg/kg). In contrast to relatively similar levels of
cholinesterase inhibition, striatal extracellular
acetylcholine levels were significantly lower (2.2- to 2.9-fold) in aged rats at both 3 and 7 day time-points compared to adult rats treated with equitoxic dosages (i.e., 9 and 27 mg/kg, respectively). No age-related differences in in vitro striatal
acetylcholine synthesis or in vivo
acetylcholine accumulation following direct infusion of the
cholinesterase inhibitor neostigmine (1 microM) were noted. While aged rats are more sensitive than adults to the acute toxicity of
parathion, lesser
acetylcholine accumulation was noted in the striatum of aged rats exhibiting similar levels of
cholinesterase inhibition. These findings suggest that lesser
acetylcholine accumulation may be required to elicit
cholinergic signs in the aged rat, possibly based on aging-associated changes in
muscarinic receptor density.