Sites of Action for Neurotoxic Pesticides - American Chemical Society

Chapter 14

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Actions of Drugs and Pesticides on Components of Octopaminergic Neurotransmission J. M. Wierenga and Robert M. Hollingworth Department of Entomology, Purdue University, West Lafayette, IN 47907

The stimulation of the octopaminergic nervous system of invertebrates is a proven strategy for the control of important pest species. This has been achieved in the past by the use of octopamine receptor agonists such as formamidine and imidazoline derivatives. However, other potential strategies to achieve this end include the inhibition of cyclic nucleotide phosphodiesterase, inhibition of the neural reuptake of octopamine, and inhibition of octopamine N-acetyltransferase. Using the American cockroach nervous system, formamidines were found to inhibit both the uptake and acetylation of octopamine, but not with a potency comparable to their effect on octopamine receptors. The tricyclic antidepressant, desipramine, and the benzylamine, xylamine, were the most active inhibitors of these octopamine removal systems. The pharmacological profiles for uptake and N-acetylation appear to be quite similar, but differ from that of the adenylate cyclase-linked octopamine receptor. Over the l a s t decade i t has become increasingly clear that octopamine (OA) plays a number o f discrete and v i t a l roles i n the physiology o f insects through i t s actions as a neuromodulator, neurohormone and neurotransmitter (Ii2,^). Much i s known regarding i t s importance as a peripheral neuroeffector 0 0 , but i t s functions i n setting the degree o f e x c i t a b i l i t y i n parts o f the central nervous system and as a key e l i c i t o r and coordinator o f s p e c i f i c behaviors (5,6,7), though less well understood, may be even more s i g n i f i c a n t for exploitation in insect c o n t r o l . Formamidines (such as chlordimeform (Figure 1) and amitraz) and imidazolines (such as naphazoline and XAMI; Figure 1) cause a series of behavioral and l e t h a l effects i n insects and acarines that may be ascribed e n t i r e l y or i n part to the actions o f these compounds and their common metabolites as powerful agonists at octopamine receptors 0097-6156/87/0356-0191$06.00/0 © 1987 American Chemical Society Hollingworth and Green; Sites of Action for Neurotoxic Pesticides ACS Symposium Series; American Chemical Society: Washington, DC, 1987.


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SITES OF ACTION FOR NEUROTOXIC PESTICIDES

Figure 1. The structures of some compounds which affect octopaminergic systems.

Hollingworth and Green; Sites of Action for Neurotoxic Pesticides ACS Symposium Series; American Chemical Society: Washington, DC, 1987.


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This validates the stimulation o f octopaminergic systems as an e f f e c t i v e strategy for i n s e c t i c i d a l / a c a r i c i d a l action. However, there are several approaches to achieving t h i s end other than by a d i r e c t stimulatory e f f e c t on the octopamine receptor. The action o f octopamine i s probably terminated by carrier-mediated reuptake systems as with other biogenic amines (10). Blocking uptake could r e s u l t i n an increased l e v e l of octopaminergic a c t i v a t i o n . It appears that a major catabolic route for octopamine in insects i s through N-acetylation, a s i t u a t i o n not paralleled i n vertebrates (1*^3). Inhibitors of t h i s N-acetyl transferase a c t i v i t y could also enhance octopaminergic action. In the majority o f cases so far studied, the stimulation of octopamine receptors r e s u l t s i n an enhanced a c t i v i t y o f adenylate cyclase and elevated c y c l i c AMP (cAMP) l e v e l s in the target tissue Π»2>11)· Cyclic nucleotide phosphodiesterase a c t i v i t y i s an important component regulating the i n t r a c e l l u l a r l e v e l of cAMP and i n h i b i t i o n of t h i s enzyme also leads to elevated cAMP l e v e l s . Phosphodiesterase i n h i b i t o r s such as methylxanthines cause behavioral e f f e c t s similar to those induced by octopaminergic agonists and synergize the a c t i v i t y o f these compounds in insects (8,J£). These alternatives to the d i r e c t stimulation o f OA receptors deserve further evaluation as prospects for i n s e c t i c i d a l and i n s e c t i s t a t i c actions. A d d i t i o n a l l y , although i t i s clear that formamidines and imidazolines have potent d i r e c t e f f e c t s on the receptor i t s e l f , i t i s also possible that the octopaminergic stimulation could be augmented by e f f e c t s on other components o f octopamine-activated neurotransmission. E n t i t i e s such as the uptake c a r r i e r and the active s i t e o f octopamine N-acetyltransferase presumably have binding s i t e s for OA and may, l i k e the receptor, be able to bind these synthetic analogs of OA. Using quantum mechanical calculations Tosi et a l . (J_3) have shown that there are strong conformational s i m i l a r i t i e s between formamidine i n s e c t i c i d e s and (R)-octopamine. L i t t l e has been done so far to evaluate the contribution that these alternative actions may make to the o v e r a l l e f f e c t s o f formamidines and imidazolines on invertebrates. Preliminary r e s u l t s from studies i n these areas are described below. Materials and Methods Animals. Adult male cockroaches (Periplaneta americana) were reared at 24 C and fed rat chow and water ad l i b . For 24 hours prior to dissection they were isolated i n i n d i v i d u a l containers. Fireflies (Photinus p y r a l i s ) were caught l o c a l l y and either used immediately, or the whole insects were frozen at -80° C u n t i l use. Tobacco hornworms (Manduca sexta) were reared on an a r t i f i c i a l d i e t and u t i l i z e d in the 3rd or 4th day of the f i n a l l a r v a l i n s t a r . Chemicals. Ring-labelled [ H]-octopamine (44 Ci/mmol) and [2,8- H]adenosine S ^ ' - c y c l i c phosphate (41 Ci/mmol) were purchased from Amersham Corp., Arlington Hts., IL. Xylamine was synthesized by the method of Ransom et a l . (14). Chlordimeform (CDM), N-demethylchlordimeform (DCDM), and N,N-bisdemethylchlordimeform (DDCDM) were synthesized as described by Hollingworth (15). 2-(2,3-xylylaminomethyl)-2-imidazoline (XAMI) was synthesized from 2-chloromethyl-2-imidazoline (16). N-Acetyloctopamine was


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synthesized using the method of Anderson (17_). A l l other compounds were obtained from Sigma Chemical Co., St. Louis, MO. Biochemical Assays. Phosphodiesterase a c t i v i t y was assayed i n homogenates of the cockroach central nervous system using a modification of the anion exchange column method described by Thompson et a l . (1_8) with [3H]-cAMP as the substrate. Cockroach nerve cords (10-20 mg tissue/ml) were homogenized i n ice-cold T r i s buffer (62.5 mM, pH 7.7 (25°C) containing 6.3 mM MgS04 and 2.5 mM mercaptoethanol). The incubation mixture consisted of 140 u l buffer, 20 u l tissue homogenate, 20 u l of i n h i b i t o r or buffer, and 20 u l o f cAMP solution (1 mM, 2.4 uCi/ml). This mixture was incubated at 30°C for 20 min, the reaction was stopped by b o i l i n g , and after cooling, 100 u l cobra venom solution (1 mg/ml) was added. This was incubated at 30°C f o r 30 min, then 1 ml methanol was added. The mixture was loaded onto an anion exchange column (5.0 χ 0.5 cm, Dowex-1, 200-400 mesh, pH 5.0 i n methanol) and eluted with 1 ml methanol. The column was drained and the eluent was counted i n a l i q u i d s c i n t i l l a t i o n counter (LSC). Adenylate cyclase a c t i v i t y was measured e s s e n t i a l l y as described by Nathanson and Greengard (1j>) except that a mixture o f ATP (0.75 mM) and GTP (0.15 mM) was used to i n i t i a t e the reaction. The amount of cAMP i n the reaction mixture was determined with an assay k i t from Amersham Corp. based on the method of Tovey et a l . (20). Tissue homogenates were made from f i r e f l y l i g h t organs, and the ventral nerve cords o f adult Periplaneta and l a r v a l Manduca. The uptake o f octopamine into the ventral nerve cord of P. americana (21) and octopamine N-acetyltransferase a c t i v i t y (22) were also assayed on the abdominal portion o f the ventral nerve cord from cold-anesthetized cockroaches. For the uptake experiments, the nerve cord was blotted, weighed, then pre-incubated i n normal or Na-free saline (augmented with Tris) for 10 min. The nerve cord was then incubated i n OA-containing saline (2 uM, 4 uCi/ml) plus compound (100 uM) for 10 min at 28°C. The nerve cords were rinsed b r i e f l y i n i c e cold s a l i n e , digested, then counted by LSC. Na-dependent uptake was calculated as: t o t a l uptake ( i n the presence o f Na) minus Na-independent uptake ( i n the absence of Na). For the NAT assays, the nerve cords were homogenzied (5 cords/ml) i n ice-cold phosphate buffer (50 mM, pH 7.0, containing 0.65 mM d i t h i o t h r e i t o l ) . The homogenate was centrifuged at 17 000xg for 5 min and the supernatant was stored at -80°C f o r up to two weeks. The nerve cord homogenates were assayed for NAT a c t i v i t y by incubating with equal amounts (25 ul) of 1mM acetyl CoA, ["^HJ-octopamine (40 uM, 16 uCi/ml) and phosphate buffer (pH 7.0) or compound (1 mM). After incubation at 30°C f o r 30 min, a 10 u l sample was spotted on a methanol-prewashed s i l i c a gel TLC plate together with OA and NAOA standards. The plate was developed in n-butanol:acetic acidrwater (4:1:5), then dried thoroughly. The resulting separation was visualized with iodine, the spots were scraped, the compounds eluted with water, and the amounts of OA and NAOA were determined by LSC. The percent OA converted to NAOA was calculated as: 100 χ (cpm NAOA)/ (cpm NAOA plus cpm OA). f


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Results and Discussion Phosphodiesterase I n h i b i t i o n . The formamidine, chlordimeform (CEM), i t s two active N-demethylated metabolites (DCDM and DDCDM), and a representative imidazoline, XAMI, were studied as i n h i b i t o r s o f the cAMP phosphodiesterase of the cockroach CNS (Table I ) .


TABLE I. Inhibition of cAMP Phosphodiesterase from Cockroach CNS 3

% Inhibition (mean + S.D.)

Inhibitor Theophylline Papaverine IBMX Chlordimeform DC DM DDCDM ΧΑΜ I

(CDM)

IC50 (mM)

4 57 66 + 7 2 89 (+) 7 5 (+) 3 + 6

14

4

(+) 6 _+ 26

0.56 0.51 0.11 — — — —

(+) indicates stimulation rather than i n h i b i t i o n Final concentration, 1 mM At a screening concentration of 1.0 mM, none of these compounds gave noteworthy i n h i b i t i o n . The known phosphodiesterase i n h i b i t o r s theophylline, isobutyl-3-methylxanthine (IBMX), and papaverine caused considerable i n h i b i t i o n at 1 mM and had IC50 values between 0.1 and 1.0 mM. It therefore seems u n l i k e l y that the excitatory e f f e c t s caused by these octopaminergic agonists i n invertebrates can be related to i n h i b i t i o n of cAMP phosphodiesterase a c t i v i t y . C y c l i c AMP Synthesis. The a c t i v i t y of adenylate cyclase from several insect sources was measured i n the presence of OA and other octopaminergic agonists (Table I I ) . The results are corrected for basal (unstimulated) adenylate cyclase a c t i v i t y and expressed as the Ka (concentration to cause a half-maximal stimulation of cAMP synthe s i s ) and Vmax (maximum stimulation observed, related to the maximum stimulation observed with octopamine). The c h a r a c t e r i s t i c s o f the three preparations were similar i n regard to t h e i r Ka values for octopamine but d i f f e r e d widely with the synthetic agonists, DCDM and ΧΑΜ I. In each case the Ka values for these compounds were lower than those for OA, sometimes by a considerable margin (e.g. DCDM with Manduca and XAMI with Periplaneta). On the other hand these synthetic agents were only p a r t i a l agonists except i n the case o f DCDM with Manduca where the maximum l e v e l o f stimulation was indistinguishable from that seen with OA. Somewhat similar r e s u l t s showing enhanced but varying potencies o f synthetic agonists for octopamine receptors i n insects have been reported previously ( 9 t 2 3 ) · Since a f u l l physiological response may be achieved i n vivo with only p a r t i a l (10-20% o f maximum) stimulation o f tissue cAMP l e v e l s , the potential a c t i v i t y o f such synthetic agonists i n stimulating some insect octopaminergic systems may approach the low nanomolar range, but t h i s w i l l vary considerably between species.


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SITES OF ACTION FOR NEUROTOXIC PESTICIDES TABLE I I . Effects of Drugs on cAMP Synthesis i n Several Insect Tissues


F i r e f l y Lantern Cockroach nerve cord Hornworm nerve cord

XAMI

DC DM

Octopamine Ka (nM)

Vmax (MA)

Ka (nM)

Vmax (MA)

Ka (nM)

2500 2000 3000

100 100 100

470 600 33

85 57 100

280 7 150

Vmax (MA) 85 76 74

Effects of Drugs on the Uptake of Octopamine. Several drugs were tested for their effects on both components (Na-dependent and Na-independent) of uptake. The f i n a l concentration o f C H]-octopamine (2 uM) was chosen so that about 50% of the uptake was Na-dependent and 50% was Na-independent. Based on the study of Evans (21), the former f r a c t i o n , which i s r e a d i l y saturable and shows a high a f f i n i t y for OA, probably relates to one or more s p e c i f i c uptake systems, while the Na-independent fraction i s not r e a d i l y saturable, shows a low a f f i n i t y for OA and may relate to i t s absorption onto the perineurium. Drugs were assayed on both fractions at 0.1 mM. No s i g n i f i c a n t 020%) i n h i b i t i o n o f the Na-independent fraction was seen with any compound. However, several of these agents proved to be e f f e c t i v e i n h i b i t o r s of Na-dependent uptake (Table I I I ) .

TABLE I I I . Inhibition o f Na-Dependent Octopamine Uptake and Ν-Acetyltransferase i n the Cockroach CNS

Inhibitor Xylamine Desipramine Chlordimeform DC DM DDCDM Synephrine NAOA Naphazoline XAMI

% Uptake Inhibition (mean + S.D.) 61 86 (+)3 17 33 100 18 28 20

+ 6 + 11 + 7 + 9 + 9

8

+ 9 + 7 + 11

% NAT Inhibition (mean + S.D.) 93 65 16 28 52 88 1 (+)2 (+)7

+ + + + + + + + +

2 3 5 4 6 2 6 5 5

F i n a l concentration, 0.1 mM F i n a l concentration, 0.25 mM

While chlordimeform i t s e l f did not block uptake at t h i s concentration, DCDM and, p a r t i c u l a r l y , DDCDM did cause i n h i b i t i o n . It i s worth noting that the unmethylated formamidine, DDCDM, most c l o s e l y approximates the structure of OA i n t h i s s e r i e s . These





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r e s u l t s can be compared to those reported recently by Scott and Knowles (24) who concluded that CDM and DCDM did not i n h i b i t the uptake o f labelled OA into the cockroach nerve cord. However, i t should be noted that these workers did not demonstrate any Na-dependent uptake in their preparation. Synephrine, the N-methylated analog of OA, completely blocked uptake at t h i s concentration. The two imidazolines, naphazoline and XAMI, were somewhat e f f e c t i v e as uptake blockers (20-30% i n h i b i t i o n ) , comparable to DCDM and DDCDM. The t r i c y c l i c antidepressant desipramine, a known amine uptake blocker in vertebrates, showed good potency in the cockroach system, as o r i g i n a l l y described by Evans (21). F i n a l l y , the N-chloroethyl benzylamine d e r i v a t i v e , xylamine, has been described as a potent, s p e c i f i c and i r r e v e r s i b l e i n h i b i t o r of norepinephrine uptake in mammals (25). It was an active i n h i b i t o r of uptake in the cockroach preparation. E f f e c t o f Drugs on the N-Acetyltransferase A c t i v i t y o f the Cockroach Ventral Nerve Cord. In order to determine the metabolic fate o f octopamine taken into the cockroach nerve cord, nerve cords were incubated with high s p e c i f i c a c t i v i t y C3H3-octopamine according to the methods used to determine uptake, homogenized and the supernatant spotted on a TLC p l a t e . After development in butanol:acetic acidrwater (4:1:5), the plates were subjected to electrophoresis at pH 2.05 (formic acid, 0.47 M; acetic a c i d , 1.40 M) i n the second dimension. A t y p i c a l autoradiograph i s shown i n Figure 2. V i r t u a l l y a l l of the r a d i o a c t i v i t y was located in the peaks that cochromatographed with octopamine (47.5%) and N-acetyloctopamine (50.8%). Two other minor unknown metabolites (1 and 2) were also detected. I t i s noteworthy that p-hydroxymandelic acid (p-OHMA), the potential product o f monoamine oxidase (MAO) a c t i v i t y , was not detected. This agrees with the now generally accepted idea that MAO i s not an important means o f octopamine metabolism in those insects so far studied and that N-acetylation i s the major metabolic fate for biogenic amines in the insects CNS Π,22,26-28). The r a p i d i t y o f t h i s reaction i n the nerve cord i s clear from the observation that even after a b r i e f exposure to labelled OA, greater than 50% was converted to the N-acetyl analog. As i n h i b i t o r s o f N-acetyltransferase a c t i v i t y , the formamidines showed a pattern similar to their e f f e c t on OA uptake i . e . CDM was the least active member o f the series with DCDM and DDCDM increasingly more active. At 0.25 mM, DDCDM caused about 50% i n h i b i t i o n of NAT a c t i v i t y . L i t t l e previous work has been published on N-acetyl transferase i n h i b i t o r s i n insects. However, the i n h i b i t i o n by CDM o f NAT acting on tryptamine was reported by A l l a i s et a l . (29). They showed that 1.2 mg o f CDM applied t o p i c a l l y to locusts reduced subsequent NAT a c t i v i t y in the brain in v i t r o by approximately 35%. Synephrine, as a potential substrate for NAT, showed considerable i n h i b i t i o n , but naphazoline and XAMI were i n a c t i v e . Desipramine proved to be quite e f f e c t i v e as an i n h i b i t o r o f NAT, but the most active compound in t h i s group was xylamine. More detailed study o f the i n h i b i t i o n by t h i s compound gave an IC50 of less than 1 uM (without preincubation with the enzyme before addition o f the substrate) and showed that the i n h i b i t i o n was progressive and


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i r r e v e r s i b l e . Probably the mechanism o f i n h i b i t i o n involves alkylation through a reactive aziridinium product (14). Significance of Ν-Acetyloctopamine as a Metabolite of Octopamine. Since N-acetyloctopamine (NAOA) i s the major product o f OA metabolism and i s rapidly produced after uptake of OA, we thought that N-acetylation might represent an i n a c t i v a t i o n process. N-Acetyloctopamine was already found to be inactive compared to OA on c r a y f i s h heart and s k e l e t a l muscle (30). To shed further l i g h t on t h i s question we examined the a b i l i t y o f NAOA to stimulate adenylate cyclase a c t i v i t y i n homogenates from the isolated adult f i r e f l y l i g h t organ. As shown i n Figure 3 OA stimulated t h i s preparation with a concentration for h a l f maximal stimulation o f about 2 uM. N-Acetyloctopamine on the other hand caused v i r t u a l l y no increase i n cAMP synthesis over the very low basal l e v e l . A s l i g h t but reproducible stimulation was observed at about 1 mM, but t h i s could have been due to small amounts o f the precursor OA being present as an impurity. In any case, i n t h i s well-studied octopaminergic system, NAOA i s at best a very weak agonist. Further study showed that i t did not act as an antagonist of octopamine-stimulated adenylate cyclase either. The data presented in Table I I I indicate that NAOA has l i t t l e or no effect on either Na-dependent OA uptake or on NAT. Thus i t appears to have no s i g n i f i c a n t interaction with octopaminergic systems. Tentatively then, one can conclude that N-acetylation represents a mechanism o f inactivation for OA. f

Relationship of Uptake, Ν-Acetyltransferase and the OA Receptor. As pointed out i n i t i a l l y , a l l three of these biochemical e n t i t i e s have recognition s i t e s for octopamine. I t i s interesting therefore to compare their responses to the same series o f drugs. There are d i s t i n c t differences i n the properties o f the octopamine-sensitive adenylate cyclase compared to the other two a c t i v i t i e s e.g. naphazoline and XAMI (Table II) are very active i n stimulating cAMP synthesis, but do not interact strongly with the uptake system or NAT. Also the e f f e c t o f the formamidines, DC DM and DDCDM, which stimulate adenylate cyclase at micromolar concentrations, i s much more potent i n the case o f the adenylate cyclase than with uptake or NAT. On the other hand, xylamine i s active against both uptake and NAT, but does not interact with comparable potency with the adenylate cyclase system of the f i r e f l y l i g h t organ (Hollingworth, unpublished). There i s an intriguing degree o f c o r r e l a t i o n between the responses of uptake and NAT to the limited series o f drugs studied, as shown i n Table III (r = 0.81, ρ < 0.01). Although there i s no reason a p r i o r i why these two systems should have similar pharmacology, i t may be that N-acetylation i n some way l i m i t s or i s involved i n the uptake process into the nerve cord, p a r t i c u l a r l y i n view o f the e f f i c i e n c y with which N-acetylation occurs. This p o s s i b i l i t y i s being studied further. These results indicate that the N-demethylation products of chlordimeform have i n h i b i t o r y e f f e c t s on both the reuptake of OA into the cockroach nerve cord and on i t s subsequent N-acetylation to the putatively inactive NAOA. In both cases the tendency o f these r e s u l t s would be to increase the a c t i v i t y o f endogenous octopamine. Whether these e f f e c t s occur with a potency that would make them




199

ELECTROPHORESIS (pH» 2.0) TLC À

NAOA ^ f c (50.8%)

Ο


W

OA M (47.5%) B:A:W (4:1:5)

«4—1 (0.4«>/) o

W

JS)

( 1

2 . o 3

/ o )

p-OHMA

ORIGIN

Figure 2. I l l u s t r a t i o n of the metabolism of OA by isolated cockroach nerve cords. Nerve cords were incubated according to the methods for measuring OA uptake, then homogenized (3 nerve cords/300 u l ) , and 30 u l of the homogenate was spotted on the TLC plate for two dimensional analysis. Autoradiographs were made and the spots were then scraped and counted. Values shown are the mean of two determinations. The i d e n t i t i e s of compounds 1 and 2 were not determined.

Log. Concentration (M) Figure 3. Stimulation of adenylate cyclase from the f i r e f l y lantern by either octopamine or N-acetyl octopamine.



200


s i g n i f i c a n t contributors to the o v e r a l l octopaminergic action o f the formamidines i s not clear. However, since DC DM and DDCDM stimulate adenylate cyclase a c t i v i t y i n cockroach nerve cord homogenates at concentrations well below 1 uM i n v i t r o (Table II, 3p while the e f f e c t s on uptake and NAT are most evident at millimolar concentrations, i t i s l i k e l y that these other actions are not the major cause o f octopaminergic stimulation i n vivo. The same arguments hold with the imidazoline, XAMI. The observation that both xylamine and desipramine are potent i n h i b i t o r s o f octopamine uptake and acetylation suggests that they, and t h e i r r e l a t i v e s , represent potential tools for the assessment of the s u i t a b i l i t y o f these systems as a target for the development o f novel insect control agents. Preliminary studies with xylamine injected into adult American cockroaches and adult tobacco budworms suggests that the a c t i v i t y i s depressive rather than stimulatory. However, more detailed studies o f the physiological and behavioral actions o f these compounds are warranted. Acknowledgments We thank Dr. H. Hashemzadeh for his assistance i n performing some o f the cAMP assays, and Mrs. L. Caesar for her technical assistance. Supported in part by NIH t r a i n i n g grant T32 ES07039.

References Cited 1. Evans, P. D. In "Comprehensive Insect Physiology Biochemistry and Pharmacology"; Kerkut, G. Α.; Gilbert, L. I., Eds.; Pergamon: Oxford, 1985; Vol. 11, pp. 499-530. 2. Orchard, I.; Can. J. Zool. 1982, 60, 659-9. 3. David, J.-C.; Coulon, J.-F. Prog. Neurobiol. 1985, 24, 141-85. 4. Orchard, I.; Lange, A. B. This volume. 5. Sombati, S.; Hoyle, G. J. Neurobiol. 1984, 15, 481-506. 6. Kinnamon, S. C.; Klaassen, L. W.; Kammer, A. E.; Claassen, D. J. Neurobiol. 15, 283-93. 7. Linn, C. E.; Roelofs, W. L. This Volume. 8. Hollingworth, R. M.; Lund, A. E. In "Pesticide Chemistry: Human Welfare and the Environment"; Miyamoto, J . ; Kearney, P. C., Eds.; Pergamon: Oxford, 1983; Vol. 3, pp. 15-24. 9. Nathanson, J. A. Mol. Pharmacol. 1985, 28, 254-268. 10. Iverson, L. L. Br. J. Pharmacol. 1971, 571-91. 11. Bodnaryk, R. P. Insect Biochem. 1982, 12, 1-6. 12. Nathanson, J. A. Science 1984, 226, 184-187. 13. Tosi, C.; Barino, L.; Scrodamaglia, R. Theochem 1984, 15, 241-250. 14. Ransom, R. W.; Kammerer, R. C.; Cho, A. K. Molec. Pharmacol. 1982, 21, 380-6. 15. Hollingworth, R. M. Environ. Health Perspect. 1976, 14, 57-69. 16. Kristinsson, H.; Traber, W. U.S. Patent 4 254 133, 1981. 17. Anderson, S. O. Insect Biochem. 1971, 1, 157-70.



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Sites of Action for Neurotoxic Pesticides - American Chemical Society

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