Sites of Action for Neurotoxic Pesticides - ACS Publications - American

Chapter 8

Interactions of Insecticides with GABA-Operated and Voltage-Dependent Chloride Channels

Downloaded by CORNELL UNIV on August 29, 2016 | http://pubs.acs.org Publication Date: November 9, 1987 | doi: 10.1021/bk-1987-0356.ch008

M. E. Eldefrawi, D. B. Gant, I. M. Abalis, and A. T. Eldefrawi Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201

receptors of mammalian and insect brains are identified by binding of radioactive ligands and GABAinduced C1 fluxes. Cyclodienes and lindane inhibit stereospecifically and competitively the binding of [ S] t-butylbicyclophosphorothionate ([ S]TBPS) to the Cl channel component of the GABAA receptor in rat brain. Endrin and endosulfan I are the most potent inhibitors at nM concentrations, followed by endosulfan II and heptachlor epoxide, then dieldrin, lindane, heptachlor and aldrin. There is good correlation between their potencies as inhibitors of [ S]TBPS binding and the GABAstimulated, bicuculline-inhibited C1 influx into rat brain microsacs. This suggests that they act as noncompetitive blockers of the GABAA receptor. They also inhibit with a different order of potency [ S]TBPS binding to the voltage-dependent chloride channel in Torpedo electric organ, which has no GABA or glycine receptors, with lindane being much more potent than endrin.α-Cyanophenoxybenzyl(type II) pyrethroids are generally more potent than type I pyrethroids in inhibiting the GABA-induced C1 flux. Avermectin Bia (AVM) potentiates binding of [ H]flunitrazepam, inhibits binding of [H]muscimol and [ S]TBPS to rat brain membranes, and induces bicuculline-inhibited C1 influx into brain microsacs. AVM also induces another C1 flux that is not affected by GABAergic drugs. It is suggested that both the GABAA receptor and voltage-dependent chloride channel bind TBPS, cyclodienes, lindane and AVM with different affinities. Insect GABAA receptors differ from those of mammalian brain in having a lower affinity for bicucul line and a higher affinity for AVM as shown by [H]muscimol binding to honey bee brain. The house fly muscle receptor also has a lower affinity for clonazepam and a higher one for Ro5-4864 than the rat brain receptor. Such differences can be utilized to develop selective insecticides. GABAA

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0097-6156/87/0356-0107$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

x-Aminobutyric a c i d (GABA) i s the major i n h i b i t o r y neurotransmitter in vertebrate and invertebrate brains as well as crustacean and insect s k e l e t a l muscles. GABA i s synthesized i n GABAergic neurons by enzymatic decarboxylation o f glutamic acid, i s stored within v e s i c l e s in GABAergic nerve terminals, i s released by a Ca -dependent process, i n t e r a c t s with GABA receptors, and i s reaccumulated i n the nerve terminal by an active transport process (see Enna (1)). GABA synapses, which are abundant i n mammalian brains, are divided into two types based on the pharmacology o f t h e i r receptors. GABAA receptors are prédominently postsynaptic, are activated by muscimol but not baclofen, and are s e n s i t i v e to p i c r o t o x i n and b i c u c u l l i n e . GABAB receptors are l o c a l i z e d presynaptically, are activated by baclofen but not muscimol, and are i n s e n s i t i v e to p i c r o t o x i n and bicuculline. The a c t i v a t i o n of GABA receptors r e s u l t s i n sedation and a decrease i n muscle tone and motor a c t i v i t y , while their i n h i b i t i o n leads to e x c i t a t i o n and generalized seizures. It i s generally held that the G A B A A receptor (designated GABA receptor from here on) i s a glycoprotein which traverses postsynaptic membranes and functions as a chemically gated chloride channel (2,3). GABA receptors of the mammalian brain carry several binding s i t e s : the recognition s i t e f o r GABA and the competitive inhibitor b i c u c u l l i n e , the s i t e that binds the t r a n q u i l i z i n g benzodiazepines (e.g., valium), and s i t e s that are more c l o s e l y associated with the chloride channel moiety o f the receptor, which bind the depressant barbiturates and convulsants (e.g., picrotoxin and tbutylbicyclophosphorothionate (TBPS) (4,5) (see Figure 1)). It i s important to know that a l l these s i t e s are a l i o s t e r i c a l l y coupled so that binding o f one drug a f f e c t s binding o f another and that binding to any o f the s i t e s may i n h i b i t the receptor's function. We are using [ H]-muscimol, [ H]flunitrazepam and [ S]TBPS to l a b e l the GABA recognition s i t e , the benzodiazepine-tranquilizer s i t e and the picrotoxin-convulsant s i t e , respectively, u t i l i z i n g binding assays that are measured by f i l t r a t i o n on Whatman GF/B f i l t e r s (6-8). As shown i n Table I, GABA a f f e c t s the binding o f a l l three ligands d i f f e r e n t l y . We are also studying GABA receptor function by means o f i t s GABA-induced, b i c u c u l l i n e - s e n s i t i v e C l " i n f l u x into membrane microsacs (9).


2+

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Table I. Binding of [ H]Flunitrazepam, [ H]Muscimol and [ S]TBPS to Rat Brain Membranes i n the Presence and Absence of Specific Drugs

Radioactive ligand + drug

3

[ H]Flunitrazepam (1 nM) [ H]Flunitrazepam (1 nM) + 10 juM GABA [ H]Muscimol (4 nM) [ H] Muscimol (4 nM) + 20 AJM GABA* [ S]TBPS (2 nM) [ S]TBPS (2 nM) + 10 >uM GABA 3

3

3

3S

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a

Specific binding (pmol/g tissue) 6.3 + 12.3 + 6.7 + 1.1 ± 1.6 + 0.1 +

F i n a l solution contained IX ethanoïT SOURCE: Data are from ref. 6.

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

0.2 0.3 0.3 0.06 0.14 0.08

8. ELDEFRAWI ET AL.

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Interactions of Insecticides

NEUROTR ANSMITTER

AGON 1ST

COMPETITIVE ANTAGONIST ,N-CH


3

Η Ν 2

Χ

CH

2

GABA

Muscimol

ALLOSTERIC POTENTIATORS

Diazepam

Figure 1. receptor.

Pentobarbital

(+) Bicuculline

ALLOSTERIC INHIBITORS

Picrotoxinin

TBPS

Chemical structures o f drugs that interact with the


GABAA

110


A c t i o n o f Cyclodienes and Lindane on GABA Receptor 3

Cyclodienes and lindane have no e f f e c t on the binding of [ H]muscimol or [ H ] f l u n i t razepam t o r a t brain membranes, but are potent i n h i b i t o r s o f [ S]TBPS binding (6) and the GABA-induced C 1 ~ i n f l u x into brain microsacs (10). Similar actions have been reported on both [ *S]TBPS binding (Il» 12) and the GABA-induced flux (13). The action i s s t e r e o s p e c i f i c and correlates f o r the most part with t h e i r mammalian t o x i c i t i e s (Table I I ) . 3

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Table I I . E f f e c t o f Insecticides on [ S]TBPS Binding to, and GABA-induced C 1 " Influx into, Rat Brain Microsacs


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Insecticide (IAIM)

3 6

X o f control Cl-influx*

3 6

Control, 100 >uM GABA and no i n s e c t i c i d e Cyclodienes Endrin Dieldrin Endosulfan I Endosulfan II Heptachlor Heptachlor epoxide Hexachlorocyclohexanes (BHC) χ,-BHC (lindane)

s-mc Pyrethroids Allethrin Fluvalinate 1R, cis,oCSKJypermethrin 1R, trans, ci^^Cypermethrin

3S

[ S]TBPS binding ICso (nM)

b

Rat t o x i c i t y (oral IDs ο, mg/kg)*

100 18 32 0 30 55 36

3 100 3 60 400 70

10 46 18 240 90 40

54 93

150 >10,000

125 6,000 680

83 56 28 64

*Each i n s e c t i c i d e was added i n 2Ô-*iï aqueous aïiquots to 180 jul of rat brain membrane f o r 10 min at 37°C before addition of the buffer containing 100 JUM GABA and 0.2 juCi of C 1 ~ then f i l t r a t i o n . Each value i s the mean o f three experiments. *The concentration of i n s e c t i c i d e that i n h i b i t s 50* o f the binding of 2 nM [ S]TBPS to r a t brain membranes. *Rat t o x i c i t y values were obtained from EPA publication-600/2-81-011, "Analytic Reference Standards and Supplemental Data f o r Pesticides and Other Organic Compounds". The r a t o r a l LDso f o r the racemic mixture of cypermethrin i s 251 mg/kg. The mouse intracerebral LDso values are 0.6 jug/g brain weight f o r the \R,cis heptachlor epoxide > d i e l d r i n > endosulfan I I > lindane = heptachlor (10). I t i s c l e a r that heptachlor epoxide, which i s more t o x i c than the parent compound heptachlor, i s also a more potent i n h i b i t o r o f the GABA-induced C l " i n f l u x and binding o f [ S]TBPS to r a t brain (Figure 3). I t should be pointed out that the higher concentrations o f these i n s e c t i c i d e s that are needed to i n h i b i t C 1 ~ flux than [ S]TBPS binding r e s u l t from the need t o maximize C 1 " flux i n the assay by using 100 >uM GABA. This requires much higher concentrations o f i n s e c t i c i d e t o i n h i b i t C 1 ~ f l u x than i f lower GABA concentrations are used. Cyclodienes apparently bind to the convulsant s i t e o f the GABA receptor that binds picrotoxinin, as suggested by the competitive displacement o f [ S]TBPS binding by endrin (Figure 5). The high a f f i n i t y that GABA receptors have f o r cyclodienes and t h e i r s t e r e o s p e c i f i c i t y suggest that these receptors are l i k e l y to be primary targets f o r the t o x i c action o f cyclodienes. 35

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Action o f Cyclodienes Ctennel

and Lindane on a Voltage-dependent

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Chloride

[ S]TBPS also binds t o a voltage-dependent chloride channel found i n abundance i n the e l e c t r i c organ o f the e l e c t r i c ray (Torpedo sp.) (Figure 6). This tissue contains only acetylcholine receptors but no GABA or glycine receptors. Cyclodiene i n s e c t i c i d e s and lindane also i n h i b i t t h i s binding, but lindane i s much more potent than the cyclodienes (Table III) (16). I t i s i n t e r e s t i n g t o note that the GABAergic drugs that bind t o the GABA or the benzodiazepine sites have no e f f e c t on [ S]TBPS binding to the voltage-dependent c h l o r i d e channel, while drugs that bind to, or are near, the i o n i c channel moiety o f the receptor (e.g., p i c r o t o x i n i n and pentobarbital) are active, though less so than the i n s e c t i c i d e s (16). It i s reasonable t o assume that binding o f [ S]TBPS to b r a i n membranes encompasses binding to both the GABA-operated and the voltage-dependent chloride channels. The more t o x i c stereoisomers o f several cyclodiene p a i r s are more potent i n d i s p l a c i n g [ S]TBPS from the voltage-dependent C l " channel o f Torpedo. For example, at 1 juM, d i e l d r i n and endrin i n h i b i t 40 and 100%, respectively, and endosulfan I and II i n h i b i t 42 and 72%, respectively. In addition, the more t o x i c heptachlor epoxide i s more potent than heptachlor. These r e s u l t s suggest that i f present i n higher concentrations, cyclodienes w i l l a f f e c t voltage-dependent chloride channels as well, but at lower concentrations t h e i r e f f e c t may be r e s t r i c t e d to the GABA-operated chloride channels. The s i t u a t i o n i s reversed f o r lindane, which has 35

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- L o g insecticide conc.(M)

- L o g insecticide cone.(M) Figure 2. Inhibition by endrin, d i e l d r i n , endosulfan I and I I of s p e c i f i c 2 nM (Reproduced with permission from r e f . 6. Copyright 1985 Academic.)


Hollingworth and Green; Sites of Action for Neurotoxic Pesticides ACS Symposium Series; American Chemical Society: Washington, DC, 1987. 36

Figure 3. I n h i b i t i o n o f 100 juM GABA-induced C 1 " i n f l u x into r a t brain microsacs by cyclodiene i n s e c t i c i d e s . (Reproduced with permission from r e f . 10. In press, Academic.)


00



114

-Log

insecticide cone.(M)

Figure 4. Inhibition by hexachlorocyclohexane isomers of s p e c i f i c 2 nM [ S]TBPS binding to rat brain membranes. (Reproduced with permission from r e f . 6. Copyright 1985 Academic.) 35

0.4 ·

5

10

15

20

pmolet bound /g tissue 35

Figure 5. Scatchard p l o t of the binding of [ S]TBPS to the GABA receptor of rat brain i n the absence (o) and presence of 1 nM (·), 3 nM (x), and 10 nM (Δ) endrin. B, amount bound i n pmol/g tissue; F, free [ S]TBPS concentration. (Reproduced with permission from r e f . 6. Copyright 1985 Academic.) 35


8.

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115


ELDEFRAWI E T AL.

150

ο»

ε ν» Ο

100


ο. ω 50

100 2 0 0 500 KBr concentration ( m M )

10 C S 3 TBPS M

20

1000

30

bound ( pmol/mg protein)

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Figure 6. Binding o f [ S]TBPS t o Torpedo e l e c t r i c organ membranes. A. E f f e c t of KBr concentration on 3 nM [ S]TBPS binding. Symbols and bars represent means + S.D. of t r i p l i c a t e experiments. B. Scatchard plot o f [ S]TBPS binding i n presence o f 200 mM KBr at 21°C. Nonspecific binding was that observed i n the presence o f 4.5 JUM unlabeled TBPS. The points are the means of three experiments. (Reproduced with permission from r e f . 16. Copyright 1985 Pergamon Press.) 35

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a 10-fold lower a f f i n i t y f o r the GABA receptor's chloride channel, and thus would p r e f e r e n t i a l l y i n h i b i t the voltage-dependent chloride transport at lower concentration, and also would i n h i b i t the GABAoperated chloride channel at higher concentrations. Table III. Inhibition of pss]TBPS Binding to the Putative VoltageDependent* Chloride Channel in Torpedo Electric Organ and the GABA Receptor Chloride Channel in Rat Brain Ki QuM)

Drug


Torpedo

TBPS Picrotoxinin Pentobarbital Endrin Lindane

electroplax

Rat brain

1.37 100.00 110.00 0.75 0.04

0.05 0.20 58.00 0.03 0.15

SOURCE: Reproduced with permission from ref. 16. Copyright 1985 Pergamon Press. Action of Pyrethroids on GABA Receptors Since diazepam delayed the onset o f t o x i c i t y symptoms produced by type II pyrethroids, i t was suggested that they i n h i b i t e d GABA receptors (17). Later, i t was found that type II pyrethroids were more potent than type I i n i n h i b i t i n g [ S]TBPS binding to r a t brain GABA receptors (18). We also f i n d that pyrethroids i n h i b i t GABAinduced C 1 " f l u x with the cfc-cyano-containing type I I f l u v a l i n a t e being more potent than the type I a l l e t h r i n (Table I I ) . The higher potency of the lRjCiSjOff isomer than the 1R, trans, qS isomer o f cypermethrin i n i n h i b i t i n g the GABA-induced C 1 ~ influx suggests that t h e i r e f f e c t s are s t e r e o s p e c i f i c and related t o t h e i r mammalian toxcities. Based on the c h a r a c t e r i s t i c s o f i n h i b i t i o n o f [ S]TBPS binding to the GABA receptor, the action o f pyrethroids i s suggested to be a l l o s t e r i c at a s i t e d i f f e r e n t from the cyclodiene binding site. The data suggest that though the voltage-dependent sodium channel may be the primary target f o r pyrethroid action, the GABA receptors may be a secondary target. The high a f f i n i t y that the GABA receptor has f o r type II pyrethroids and the close r e l a t i o n s h i p o f t h e i r e f f e c t s to t h e i r mammalian t o x i c i t i e s , suggests that t h i s s i t e may i n fact be an important s i t e o f action f o r the type II pyrethroids, although not the type I pyrethroids. However, the higher potency o f type II pyrethroids on the voltage-dependent sodium channel, and the disruption o f conduction that r e s u l t s from i n h i b i t i o n o f i n a c t i v a t i o n o f less than 0.1* o f sodium channels i n an axon (19), suggests that the sodium channel may be the primary target f o r type I and type I I pyrethroids. 3S

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Action o f Avermectin on GABA Receptor and Chloride Channel Avermectin Bia (AVM) acts on both GABA-operated and voltage-dependent chloride channels, but i t s action on both i s quite d i f f e r e n t from those o f cyclodienes, lindane or pyrethroids. In r a t brain preparations, AVM induces C I " i n f l u x which i s i n h i b i t e d by the 3 6


8. ELDEFRAWI ET AL.

117


competitive antagonist b i c u c u l l i n e . The AVM-induced i n f l u x i s much less than that induced by GABA (Figure 7). AVM acts l i k e GABA i n potentiating binding o f [ H]flunitrazepam and i n h i b i t i n g binding o f [ H]muscimol (Figure 8) and [ S]TBPS to rat brain membranes, and induces b i c u c u l l i n e - s e n s i t i v e C 1 ~ i n f l u x , though to a lower degree than does GABA. This suggests that AVM binds t o the GABA recognition s i t e and acts as a p a r t i a l agonist (8). AVM also binds to the GABA recognition s i t e o f insect GABA receptors (Table IV). Because o f the complexity o f the chemical structure o f AVM (a macrocyclic lactone), i t i s l i k e l y that only a very small part of the molecule binds to the GABA receptor. I n h i b i t i o n o f [ S]TBPS binding by AVM could r e s u l t from the a l i o s t e r i c e f f e c t o f occupation of the GABA s i t e , or from d i r e c t occupation o f the TBPS s i t e , thus acting as a hyperpolarizing blocker. 3

3

3S

36


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Table IV. The E f f e c t s o f GABAergic Drugs on the High A f f i n i t y Binding o f [ H]Muscimol to Honey Bee Brain Membranes i n Comparison with Their Reported E f f e c t s on [ H]Muscimol Binding to Rat Brain' Membranes 3

3

Apparent ICso (juM) Drugs

Honey bee b r a i n *

Muscimol AVM GABA (+)Bicuculline

0.006 0.003 0.042 >1000

Rat b r a i n *

0.01 0.038 6.2

a

Data presently obta nM~ (^H1»ISC£MT. Thus, apparent ICso values, calculated from l o g dose-response curves, are based on i n h i b i t i o n of binding that represented ~75% high a f f i n i t y and 25* low a f f i n i t y binding. The actual IC50 values are s i g n i f i c a n t l y lower. fusing 8.4 nM [ H]muscimol (20). 3

SOURCE: Data are from r e f . 7. 3 6

AVM also induces another C 1 " transport i n r a t brain neurosynaptosomes that i s i n s e n s i t i v e to b i c u c u l l i n e but i s i n h i b i t e d by the s p e c i f i c chloride channel i n h i b i t o r 4,4-dithiocyano-2,2 s t i l b e n e d i s u l f o n i c acid (DIDS) (Figure 9). This C 1 " flux i s s e n s i t i v e t o GABAergic drugs that a f f e c t the channel function (e.g., picrotoxinin, TBPS and pentobarbital). I t suggests that AVM also activates chloride channels and agrees with the a c t i v a t i o n by AVM o f the GABA-operated and voltage-dependent chloride channels i n locust muscle (21). ,

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Comparison o f Insect and Vertebrate GABA Receptors It i s important to note that there are differences i n drug s p e c i f i c i t i e s o f GABA receptors o f insects and mammals. Examples are the i n s e n s i t i v i t y to b i c u c u l l i n e o f [ H]muscimol binding to honey bee brain, and the very high potency o f AVM (7) (Table IV), compared t o rat brain binding. B i c u c u l l i n e i s also i n e f f e c t i v e i n i n h i b i t i n g GABA-induced C l ~ i n f l u x into membranes from cockroach nerve cord 3

3 e


118


ε

i

•

AVM

•

AVM + bicuculline 100 μΜ


o

ΙΟ"

GABA cone.

I0*

7

6

4xl0"

6

CAVM1 (M)

3 e

Figure 7. Influx of C l ~ into rat brain microsacs, which i s activated by GABA ( l e f t panel) or AVM (right panel), and i s inhibited by bicuculline. Maximum C l ~ influx i s that obtained with 100 jM GABA. Each bar represents the S.D. of three experiments. CI* influx into microsacs i n absence of drugs was 808 dpm, i n presence of 100 juM GABA, 1795 dpm, and i n presence of 1 juM AVM,. 1104 dpm. Thus, GABA- and AVM- induced C l ~ influxes were 987 dpm and 296 dpm, respectively. (Reproduced with permission from ref. 8. Copyright 1986 VCH Publishers.) ^ 3 e

3 6

3 e

200

2 c ο ο β> > ο σ

- 100

η

100

ο υ ο

ο Ε

-

8

7

6

5

50 .=

4

-log AVM Cone. (M) Figure 8. The dose-dependent effect of AVM on the binding of 4 nM [ H]muscimol (·) and 2 nM [ H]flunitrazepam (pHjFlu) (o) to rat brain membranes. Control binding of [ H]muscimol and [ S]TBPS i n the absence of AVM was 5.6 pmol/g tissue and 1.3 pmol/g tissue, respectively, while i n [ H]flimitrazepam binding, the control was 5.8 pmol/g tissue. (Reproduced with permission from ref. 8. Copyright 1986 VCH Publishers.) 3

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8. ELDEFRAWI ET AL.

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Figure 9. The e f f e c t o f AVM and GABAergic drugs on C 1 ~ e f f l u x from r a t brain microsacs. Each bar represents the S.D. o f three experiments. The membranes were incubated with 10 juCi C 1 " i n 3 ml f o r 60 min at 4°C, then 100 n l aliquots were incubated f o r 2 min at 21°C i n 5 ml o f buffer containing AVM, DIDS or both simultaneously. The ordinate i s the difference i n C 1 ~ count inside the microsacs between 2 min and 0 time i n the presence o f drug divided by the values i n the absence o f any drug ( i . e . , basal C 1 " e f f l u x ) and calculated as a %. A negative value i s obtained when the count at 2 min (e.g., 8171 + 421) i n presence o f 0.2 mM DIDS i s above that i n absence o f drugs at 0 time. 3 6

3 6

3 6

(Reproduced with permission from r e f . 8. Copyright 1986 VCH Publishers.)


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NEUROTOXIC PESTICIDES

consistent with i t s ineffectiveness on i d e n t i f i e d neurons i n the same cord measured e l e c t r o p h y s i o l o g i c a l l y (Wafford et a l . (22))· GABA receptors identified i n house f l y thoracic muscle membranes by [ H]flunitrazepam binding also show differences from rat brain GABA receptors (23). The insect muscle receptors have higher affinity than the rat brain receptor for the convulsant benzodiazepine Ro5-4864 and lower a f f i n i t y f o r clonazepam i n i n h i b i t i n g [ H]flunitrazepam binding (Table V). This makes them more like the peripheral-type benzodiazepine receptors i n mammalian tissues, which are not linked to GABA-regulated anion channels and are suggested to be calcium channels (24). Such differences i n drug s p e c i f i c i t i e s might be exploited to develop i n s e c t - s p e c i f i c and environmentally safer i n s e c t i c i d e s . 3


3

Table V. Comparison of Benzodiazepine Binding Sites in Different Species and Tissues

Ki Compound

House f l y thorax

F limit razepam Diazepam Clonazepam Ro5-4864

290 488 146,000 680

a

(nM) Mammalian brain

2.72» 27.4» 1.13» 100,000*

+ 35 + 60 + 3,522 + 75

a

Each value i s the mean of three separate experiments, performed in t r i p l i c a t e , + standard deviation. »Data on [ H]f lunitrazepam binding to human cerebral cortex membranes from Speth et a l . (25). °Data calculated from ICso values of [ H]diazepam binding to rat tissues from Braestrup and Squires (26). SOURCE: Data are from ref. 23. 3

3

The data presented above show c l e a r l y that GABA receptors of mammalian brain are targets f o r the t o x i c action of cyclodiene, xBHC and pyrethroids. Although, the binding and flux assays, used so s u c e s s f u l l y to study interactions of these i n s e c t i c i d e s with mammalian brain, have had l i m i t e d success when applied to insect tissues, there i s ample evidence to suggest that GABA receptors of insects are targets f o r AVM (7, 21) cyclodienes and pyrethroids (17, 22). Conclusions In summary, our data suggest that GABA receptors i n mammalian and insect brains are targets f o r i n s e c t i c i d e s , which are e i t h e r i n h i b i t o r s or a c t i v a t o r s of receptor function. The GABA receptor may be a primary target f o r cyclodienes and possibly AVM, but a secondary target f o r lindane and pyrethroids. On the other hand, the voltagedependent chloride channel may be a primary target f o r lindane and possibly AVM. There are differences i n the drug s p e c i f i c i t i e s of the GABA receptors of insects and vertebrates, which can be a basis f o r development of s e l e c t i v e i n s e c t i c i d e s . Both the GABA-operated and the voltage-dependent chloride channels are molecular targets f o r the


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action and neurotoxicity o f i n s e c t i c i d e s with d i f f e r e n t chemical structures, and p o t e n t i a l targets f o r many more to be developed. Acknowledgments The research reported herein was financed i n part by NIH grant ES 02594. We thank Sharon Boardley f o r excellent word processing.


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Sites of Action for Neurotoxic Pesticides - ACS Publications - American

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