neuroactive insecticides: targets, selectivity, resistance

EN58CH06-Casida ARI 5 December 2012 8:11

Neuroactive Insecticides:Targets, Selectivity, Resistance,and Secondary EffectsJohn E. Casida1,∗ and Kathleen A. Durkin2

1Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science,Policy, and Management, 2Molecular Graphics and Computational Facility, College ofChemistry, University of California, Berkeley, California 94720; email: [email protected],[email protected]

Annu. Rev. Entomol. 2013. 58:99–117

The Annual Review of Entomology is online atento.annualreviews.org

This article’s doi:10.1146/annurev-ento-120811-153645

Copyright c© 2013 by Annual Reviews.All rights reserved

∗Corresponding author

Keywords

acetylcholinesterase, calcium channels, GABAA receptor, nicotinicreceptor, secondary targets, sodium channel

Abstract

Neuroactive insecticides are the principal means of protecting crops, people,livestock, and pets from pest insect attack and disease transmission. Cur-rently, the four major nerve targets are acetylcholinesterase for organophos-phates and methylcarbamates, the nicotinic acetylcholine receptor forneonicotinoids, the γ-aminobutyric acid receptor/chloride channel forpolychlorocyclohexanes and fiproles, and the voltage-gated sodium channelfor pyrethroids and dichlorodiphenyltrichloroethane. Species selectivity andacquired resistance are attributable in part to structural differences in bindingsubsites, receptor subunit interfaces, or transmembrane regions. Additionaltargets are sites in the sodium channel (indoxacarb and metaflumizone), theglutamate-gated chloride channel (avermectins), the octopamine receptor(amitraz metabolite), and the calcium-activated calcium channel (diamides).Secondary toxic effects in mammals from off-target serine hydrolase inhibi-tion include organophosphate-induced delayed neuropathy and disruptionof the cannabinoid system. Possible associations between pesticides andParkinson’s and Alzheimer’s diseases are proposed but not established basedon epidemiological observations and mechanistic considerations.

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PCCA:polychlorocycloalkane

Target site: enzyme,receptor, or channelsite at which specificbinding initiates thephysiological change

Cross-resistance:target site (ormetabolic) resistanceconferred by acommon target (ordetoxificationmechanism)

Secondary effect:toxicity from action ata secondary target

Ordeal poison:a poison given to theaccused to determineguilt (dies) orinnocence (lives)

WHY NEUROACTIVE INSECTICIDES?

Insecticides are principal defenses against insect pests of crops, livestock, pets, and people. Mostinsecticides are nerve poisons and have been since dichlorodiphenyltrichloroethane (DDT) andvarious polychlorocycloalkanes (PCCAs) were introduced in the 1940s, followed by organophos-phates (OPs) in the 1950s, methylcarbamates (MCs) in the 1960s, pyrethroids in the 1970s, andneonicotinoids in the 1990s (26, 138). Neurotoxicants are the major synthetic insecticides forseveral reasons (28). They act rapidly to stop crop damage and disease transmission. There aremany sensitive sites at which even a small disruption may ultimately prove to be lethal. A lipoidalsheath protects the insect nerve from ionized toxicants but not from lipophilic insecticides. Poordetoxification mechanisms in nerves provide prolonged toxicant effects.

The nervous system has at least 11 targets or defined modes of action for neuroactive in-secticides (7, 8, 23, 26, 32) (Figure 1, A–K). Primary target site selectivity between insects andpeople plays an important role in insecticide safety, but secondary targets must also be considered.Selection of pest populations for target site resistance and cross-resistance is delayed or circum-vented by shifting modes of action. A diversity of targets is therefore critical for insect and in-secticide management (95). This review considers the targets and species selectivity of neurotoxicinsecticides, the resistance mechanisms in insects, and the secondary effects in mammals, withemphasis on research by the authors. Structures for the insecticides mentioned here are given inrecent manuals or reviews (8, 95, 138).

ACETYLCHOLINESTERASE

Primary Target and Inhibitor Action

The toxicity of OPs and MCs to insects and mammals is attributable to inhibition of acetyl-cholinesterase (AChE), which is responsible for the hydrolysis of acetylcholine (ACh) at synapticregions of cholinergic nerve endings (19, 46, 74) (Figure 1). AChE inhibitors cause ACh to accu-mulate, resulting in excessive stimulation of cholinergic receptors. The MC physostigmine fromcalabar beans (Physostigma venenosum) was used first as an ordeal poison in West Africa and then toestablish the relationships between ACh neurotransmission and AChE activity and its inhibition(20). AChE inhibition by OP and MC insecticides involves phosphorylation and carbamoylation,respectively, of serine in the esteratic site (Figures 1, 2). AChE is inhibited by MCs as the re-versible AChE–MC complex or as the methylcarbamoylated enzyme at serine that reactivatesspontaneously over a short time span (75). The corresponding reaction with OPs yields the phos-phorylated AChE that undergoes aging or reactivates slowly, except with an oxime reactivatorsuch as pralidoxime (19, 46).

−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→Figure 1Proposed sites of neuroactive insecticide action on nerve impulses, neuromuscular transmission, and synaptic receptors adapted fromBloomquist (8), Casida & Quistad (28), and many other sources. The presynaptic nerve terminals (�–�, �) and the postsynaptic cell(�–�, �) or muscle cell (�) are shown. In the nicotinic and γ-aminobutyric acid (GABA) receptor/channel cross-sections (�, �),four of the five subunits and one binding site are arbitrarily shown per channel. The number of commercial insecticides or prototypenatural products (number of compounds) (95) that act at each site (A–K) are given in parentheses. Abbreviations: ACh, acetylcholine;DDT, dichlorodiphenyltrichloroethane; MC, methylcarbamate; nAChR, nicotinic acetylcholine receptor; OP, organophosphate;PCCA, polychlorocycloalkane.

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1. AChE and nicotinic receptor/cation channel excitatory synapse

A

B

B D

AChACh

ACh

Na+

Na+

Cl –

K+

ACh ACh

ACh

ACh

ACh

AChEACh choline + acetate

Excitatorypostsynapticpotential

Extracellular

Intracellular

Actionpotential

ACh

Vesicles

–

Neurotransmitters

Insecticides (number of compounds)

ACh CH3C(O)OCH2CH2N+(CH3)3

GABA NH2CH2CH2CH2C(O)OH

AOP (65), MC (26), physotigmine:AChE inhibitors

BNicotine, neonicotinoids (7):nAChR agonists

CNereistoxin analogs (4):nAChR blocker

DSpinosyns (2): nAChR allostericactivators

FAvermectins (4): activators,modulators

GDDT, pyrethroids, pyrethrins,veratridine (44): modulators

H Indoxacarb (1): blocker

I Metaflumizone (1): blocker

Ryanodine, diamides (2): activators

K

J

Amitraz (1): mimics

EFiproles (2), PCCAs (2), picrotoxin:noncompetitive antagonists,blockers and convulsants

Octopamine HO CHOHCH2NH2

Glutamate

O O

HO OH

NH2

2. GABA receptor/CI– channel inhibitory synapse

F

E F

G

G Cl–

G GABA

Extracellular

GABAopens

Intracellular

G

Vesicles

G = GABA

–

E

Inhibitorypostsynaptic

potential

Block of action potential

3. Glutamate receptor excitatory synapse3

Glu

Cl –

Glu

Na+

Ca++Excitatory postsynapticpotential

F

4. Voltage-dependent Na+ channel

Na+

Action

potentialControlactionpotential

Glu = glutamate

Vesicles

Type 1 pyrethroidsrepetitive firing

Type 2 pyrethroidssuppression ofaction potential

Ca++

G I–

Glu

Glu

Glu

Glu

5. Ca2+– activated Ca2+ channel

ATP Mg2+ Ca2+

Ca2+ Musclecontraction

Ca2+

channelVoltagesensor

Ryanodinereceptor

Sarcoplasmicreticulum

TransversetubuleC

ell

me

mb

ran

e

J

6. Octopamine receptor coupled to second messengers

K

OA

OA

OA Elevation ofcyclic AMP

Neuroexcitation

OA

OA

OA = octopamine

2

4

5 6

1

www.annualreviews.org • Neuroactive Insecticides 101

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AChE – chlorpyrifos oxon nAChR – imidacloprid

AA A A2'

6'

9'

L

L

L

L

T T

T

T

Extracellular

binding

domain

Trans-

membrane

domain

Intracellular

nAChR-heteropentamer AChBP-homopentamer

Side view

Top view

L

BP

BP

BP

BP

BP

O

O

O

Br

Br

N

NN

Cl Cl

CF3

NH2

SN O

CF3

N

N

NH

N

N+

Cl

OO–

Heteropentamer Homopentamer

β3β3

α1

α1γ2

NCA

AT

L

L

TA

LT

SL

T V

V T L

β3

β3β3

β3β3

NCA

A

TL

L

TA

LT

AL

T A

A T L

a

GABAAR – fipronilc Na+ channel - deltamethrind

b

H447*S203*

G120

Y337

F295

Y119

E334*

G121

F338

N

Cl

Cl

Cl

P

O

O O

O

L141

N131

L143

W174

W79

Y118

Y224

C226

C227

Y231

F1530

F1534

F1538

F1537

M918*

C933L932*

T929*

L925*


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Agonist: substancethat combines with areceptor to initiate aresponse

Antagonist: substancethat combines with areceptor to oppose aresponse

Selectivity and Resistance

Inhibitor specificity between the AChE of insects and mammals and between susceptible and tol-erant strains of insects contributes to selective toxicity and resistance (19, 46). For example, theselectivity of methyl paraoxon for inhibiting house fly (Musca domestica) versus bovine erythrocyteAChE is greatly increased on introducing a 3-methyl substituent to yield the oxon of the fenitroth-ion insecticide (58). Further, diisopropyl paraoxon is a relatively poor inhibitor for honey bee (Apismellifera) compared to house fly AChE (18). Mutations in some resistant strains confer low OPand MC inhibitor sensitivity (101, 142) and potentially altered inhibitor specificity. As yet anotherexample, (+/−)-profenofos is effective on some insects resistant to other OPs, possibly because(+)-profenofos acts directly and (−)-profenofos after biosulfoxidation (53, 146), resulting in twotoxicants with different leaving groups on AChE phosphorylation. Unlike humans, some insects(e.g., aphids and mosquitoes) have a sensitive cysteine in the acyl pocket of AChE, providing anopportunity, not yet fully realized, for target site selective sulfhydryl reagent inhibitors (108, 117).

NICOTINIC RECEPTOR

Primary Target and Agonist Action

ACh is the endogenous agonist and principal excitatory transmitter for rapid neurotransmission inthe insect central nervous system and the mammalian central and peripheral nervous systems (90,130, 131, 133). ACh released from the presynaptic membrane interacts with the agonist bindingsite at the extracellular domain of the ACh receptor (AChR) ion channel complex (92, 131, 151)(Figure 1). The receptor then undergoes a conformational change leading to channel opening,influx of extracellular Na+, and efflux of intracellular K+. Actions resembling those of nicotine areassociated with the nicotinic receptor (nAChR) and those similar to muscarine are attributed tothe muscarinic receptor (mAChR), i.e., ACh has both nicotinic and muscarinic actions. The searchfor muscarinic antagonists and agonists selective on insects relative to mammals has thus far beenunsuccessful (61). Nicotine is more toxic to mammals than to most insects, and systematic structuralchanges have not greatly improved its potency or safety (150). The breakthrough discovery ofthe highly insecticidal but photolabile nithiazine with a nitromethylene moiety and no cationicsubstituent (126) acting as an nAChR agonist (119) led ultimately to photostabilized compoundsselective for insects relative to mammals, commercialized as imidacloprid (IMI) (70, 71) and sixanalogs designated neonicotinoids (67, 68, 133, 151). The guanidine or amidine unit is coplanar

←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−Figure 2Structural models of four primary targets of major neuroactive insecticides showing the proposed docking positions and some bindingsite residues designated as in the cited literature. (a) Chlorpyrifos oxon and AChE (mouse) showing the catalytic charge relay complex(∗) of S203, E334, and H447, with specificity conferred by interactions with additional sites and pockets (not shown) (98).(b) Imidacloprid and nAChR showing structural comparison of Torpedo nAChR and Aplysia AChBP (which has no transmembranedomain or cytoplasmic end) (135) and homology model of Myzus α2β1 nAChR based on AChBP, with proposed docking position ofIMI and some binding site residues (137). The binding region includes 118, 174, 224, 226, 227, and 231 of the α subunit and 79, 131,141, and 143 of the β subunit. (c) Fipronil and GABAAR (human) chloride ionophore shown as a native (α1)2(β3)2γ2 heteropentamerand a recombinant β3 homopentamer of enhanced insecticide or noncompetitive antagonist (NCA) sensitivity. The proposed β3homopentamer channel gating amino acids are A2′, T6′, and L9′ (31), with the 6′T facing into the channel as shown in the uppercross-sections. (d ) Deltamethrin and voltage-gated Na+ channel of house fly (Musca domestica) in an open conformation with residues(∗) implicated in binding of M918, L925, T929, and L932 in the S4-S5 linkers, S5 helices, pore helices, and S6 helices (38, 39, 140).Abbreviations: AChBP, acetylcholine binding protein; AChE, acetylcholinesterase; BP, binding pocket; GABA, γ-aminobutyric acid;GABAAR, GABA type A receptor; nAChR, nicotinic acetylcholine receptor.


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nAChR: nicotinicacetylcholine receptor

AChBP: acetylcholinebinding protein

GABAAR: GABAreceptor type A

and electronically conjugated with the nitro or cyano substituent, which facilitates partial negative(δ−) charge flow toward the tip (135, 136). They act as agonists at multiple nAChR subtypes, withdifferential selectivity between insects and mammals conferred by only minor structural changes(132, 134).


Electrophysiological experiments and radioligand binding studies with [3H]nicotine,[3H]epibatidine, and [3H]IMI (83, 84) establish remarkable similarities within insect nAChRsand selectivity between insect and mammalian receptors (133, 134, 135). Nicotine, epibati-dine, and desnitro-IMI (referred to collectively as nicotinoids) are protonated at physiologicalpH and undergo cation-π interaction with tryptophan at an nAChR subsite of the α4/β2 interfacein mammals (135, 136). Precise binding site interactions were established by crystallographyand photoaffinity labeling studies, with ACh binding protein (AChBP) from hemolymph ofthe mollusk Aplysia californica and the snail Lymnaea stagnalis as models for the insect andmammalian nAChR, respectively, followed by homology modeling (90, 128, 135, 137), illustratedfor Myzus in Figure 2. Binding subsite specificity plays a major role in selective toxicity forprotonated nicotinoids in mammals and electronegative tip neonicotinoids in insects. Thesulfoximine insecticides (i.e., sulfoxaflor) have both structural similarities to and differences fromneonicotinoids consistent with their unique behavior as nicotinic agonists (145). Neonicotinoidresistance associated with a modified nAChR binding site has been observed in planthoppers,aphids, and a few other species (3, 85, 86, 90, 92).

Channel Blockers and Allosteric Activators

Cartap is a noncompetitive blocker of the nAChR (81) and spinosyns act at yet another uniquesite in the nAChR (73), and as such there is no cross-resistance between neonicotinoids, cartap,and spinosyns (95).

CHLORIDE CHANNEL

Primary GABA Receptor Target and Antagonist Action

γ-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter of insects and mammalsand serves as the agonist for opening the pentameric transmembrane Cl− channel (6, 14, 22, 102,105) (Figure 1). The human brain GABA type A receptor (GABAAR) consists of various combi-nations of sixteen α subunits, seven β subunits, and four γ subunits, typically two α, two β, andone γ subunit. Insect GABARs exist as several different subtypes and form a class distinct fromany vertebrate GABAARs (14). The resistance-to-dieldrin (RDL) GABAR subtype is expressedin many insects, and RDL homomers closely mimic the pharmacology of in situ insect GABARs(47, 48). Picrotoxinin (PTX), the insecticide and fish poison of the fishberry plant (Anamirtacocculus), was used to probe Cl− channel functions, showing that GABA opens the channel andPTX blocks Cl− flux (102). Several billion pounds of PCCAs, including lindane, toxaphene, andthe cyclodienes such as α-endosulfan, were used in crop protection before their mode of actionwas established (11, 22). They were joined in 1993 by the 1-phenylpyrazole fipronil, which is oflower acute toxicity to mammals. Radioligand binding and electrophysiological studies led to therecognition that the action of PCCAs and fipronil was similar to or the same as that of PTX anda series of insecticidal trioxabicyclooctanes (22, 34, 41). [3H]dihydroPTX was developed first as a


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EBOB: ethynylbicy-cloorthobenzoate

Common target:compounds acting atthe same binding site,leading to similarphenotype andcross-resistance

Defined mode ofaction: target site andbiochemical andelectrophysical effectsconsistent withorganismal response

radioligand for the PTX site (91), followed by the improved bicyclophosphorothionate [35S]TBPSand two bicycloorthobenzoates, [3H]TBOB for studies with mammals and particularly [3H]EBOBfor investigations with insects and mammals (33, 42, 79, 80, 107, 127). They all block GABA-induced signals and Cl− flux (62) on binding to a noncompetitive antagonist (NCA) or insecticidebinding site at the receptor subunit interface (Figures 1, 2). Importantly, the human GABAARrecombinant β3-homopentamer resembles the insect receptor in sensitivity and specificity forNCAs (114, 115), prompting exhaustive site-directed mutagenesis (cysteine scanning), which pin-pointed the critical active site as pore-facing residues A2′, T6′, and L9′ and led to a binding sitemodel that fits several widely diverse classes of insecticidal NCAs (30, 31).


The major GABAergic insecticides have higher potency on the native house fly or Drosophila recep-tor and the human β3-homopentamer than on the less sensitive mammalian native (α1)2(β3)2γ2

heteropentamer brain receptor. In house fly brain, lindane, α-endosulfan, and fipronil block thechannel by binding to the critical pore residues with IC50 values of 0.5–3 nM (115). The insectversus mammalian target site specificity (105) is much greater for lindane and fipronil than forα-endosulfan (115) and is uniquely large for a highly selective isoxazoline (104).

Cross-resistance between some of the PCCAs was the first indication of a common targetand defined mode of action (22). Almost all major insect pests have been selected for resistanceto insecticides acting at the GABA-gated Cl− channel. In most cases, the resistance is due to asingle point mutation; e.g., in cyclodiene-resistant RDL Drosophila, alanine is replaced by serine inthe ion channel lining of the transmembrane 2 region, which confers insensitivity and establishesthe binding site as being in the channel pore (35, 47, 48). Cross-resistance usually extends fromthe PCCAs to fipronil, which acts at the same or closely related sites.

Glutamate and GABA Receptor Activators

Avermectin and analogs open the Cl− channel on binding to the GABAAR at a site coupled tobut distinct from the antagonist site (40, 63). However, the nematicidal and insecticidal activity ofavermectin analogs is most likely due to binding to glutamate-gated Cl− channels (37, 149), andthe normally low toxicity to mammals is due to the P glycoprotein drug pump acting as a part ofthe blood-brain barrier that restricts avermectin entry into the mammalian brain (76).

SODIUM CHANNEL

Primary Voltage-Dependent Target and Modulator Action

Voltage-gated Na+ channels open and close in response to changes in membrane potential (5).In the mammalian brain there are one alpha and two β subunits. The pore-forming α subunitconsists of a single polypeptide chain with four internally homologous domains (I–IV), each havingsix transmembrane helices (S1–S6). The domain II S4-S5 linker, S5 and S6 helices, and domainIII S6 helix interface the lipid bilayer and are therefore accessible to lipid-soluble ligands (38, 39,123) The insect Na+ channel proteins also consist of four homologous domains, each with sixtransmembrane segments (122).

The pyrethrins (from pyrethrum flowers), synthetic pyrethroids, and DDT, despite differentorigins or structures, are considered together because of similar insecticidal mechanisms. They acton axonal neurotransmission at insect voltage-gated Na+ channel recognition sites to block Na+


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transport, enhance channel inactivation, prolong the course of the Na+ current during depolar-ization, and induce a residual slow-acting current (“tail current”) (6, 94, 122). Pyrethroid action isconsidered to be of two types (2, 24, 50). Pyrethrins and synthetic pyrethroids lacking an α-cyanogroup, e.g., allethrin and permethrin, and the α-cyano compound fenpropathrin induce excitation(Type I action) on binding to resting or inactivated channels, shifting the voltage dependence ofactivation to more negative potentials and causing a slowly activating Na+ current responsible forrepetitive activity. Deltamethrin and related α-cyano pyrethroids that exhibit writhing and con-vulsive signs in mammals (Type II action) induce profound use-dependent modification of Na+

currents, implying preferential binding to activated Na+ channel states, and recruit increasingnumbers of Na+ channels into permanent open states, which results in use-dependent depolariza-tion, inactivation of unmodified channels, and blockage of conduction. Based on these differences,consideration has been given to whether Types I and II pyrethroids should fall into the samecategory or be considered separately in risk analyses and residue tolerances (125).


The higher potency of DDT and pyrethroids on insects than on mammals is proposed to be dueto several features. First, the insect target is intrinsically more sensitive than that of mammals.Second, the target has a negative temperature coefficient; i.e., the insecticides are more effective atthe ambient temperature of insects (e.g., 15◦C–20◦C) than that of people (37.5◦C). Other selectivityfactors are lipophilicity for selective pickup by the insect epicutide and enzymatic detoxification.The 1R-resmethrin cis and trans isomers are almost equal in insecticidal activity but greatly differentin mammalian toxicity, which may be due to both target site specificity and relative detoxificationrates (24, 78, 124). Fish are extremely sensitive to most pyrethroid esters but apparently less soto the pyrethroid ethers etofenprox and silafluofen, possibly due to their low aqueous solubility(138).

When DDT first lost its effectiveness for controlling house flies, it was surprising to observecross-resistance to the pyrethrins (16) and all synthetic pyrethroids, which was confirmed byelectrophysiological studies on nerve sensitivity, suggesting a common mode of action (5, 122).Resistance to pyrethroids and DDT in Musca is conferred by the L1014F (kdr) mutant alone orwith M918T (superkdr) in domain II of the α subunit (15, 38, 140). The current binding sitemodel rationalizes the structure-activity relationships of pyrethroids relative to DDT, Types Iand II action, and the open- and closed-channel conformations (39). Some of the residues on thehelices that form the putative binding contacts are not conserved between insects and vertebrates,consistent with their contribution to species specificity (103, 122).

Other Sites

Four other sites in insect Na+ channels are targets for insecticidal botanicals (veratridineand isobutylamides) or synthetic insecticides (oxadiazines and metaflumizone) without cross-resistance, in any case, to pyrethroids and DDT. Veratridine, an active ingredient of sabadilla(Schoenocaulon officinale), was an early probe to study the Na+ channel, but attempts to simplify thestructure and improve the insecticidal activity and safety (139) have thus far been unsuccessful.The isobutylamides or lipid amides are based on natural product prototypes (e.g., pellitorine fromPiper nigrum) and can be quite potent but have not achieved the required balance of potency,stability, and safety to make them outstanding insecticide candidates (45). The oxadiazine indox-acarb is an effective proinsecticide that is enzymatically hydrolyzed to the active agent (77, 147).Metaflumizone is a triketone with excellent systemic aphicidal activity (118).


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OPIDN:organophosphate-induced delayedneuropathy

NTE: neuropathytarget esterase

OTHER NERVE AND MUSCLE TARGETS

Octopamine Receptor Agonists

Octopamine and the octopamine receptor in insects, analogous to dopamine and the dopaminergicsystem in mammals, are coupled to second messengers to elevate cyclic AMP, leading to neuroexci-tation (57) (Figure 1). Formamidines acting as octopamine mimics block the receptor and providebroad-spectrum insecticidal activity (59, 60). Chlordimeform, bioactivated by N-demethylation,was the most important insecticide of this type until its carcinogenic activity was discovered andit was replaced by amitraz (59, 64).

Homopteran Feeding Blockers

Two insecticides act as selective homopteran feeding blockers. Pymetrozine is thought to bind atan ACh site of some nAChRs that is different from that of the neonicotinoids or spinosad (95).Flonicamid blocks the A-type K+ rectifying current at the presynaptic nerve terminal neurons,leading to prolonged depolarization and uncontrolled neurotransmitter release (55).

Ryanodine Receptor Modulators

Ryanodine and 9,21-dehydroryanodine, the active ingredients of the botanical insecticide Ryania(no longer used), bind at the Ca2+-activated Ca2+ channel (109). [3H]ryanodine binding providesa convenient assay for the ryanodine receptors (RyRs) of mammalian nerve and muscle and insectmuscle (82, 109, 144). The ryanodine site is similarly sensitive in insects and mammals and alarge series of analogs was prepared, but high insecticidal potency combined with low mammaliantoxicity was not adequately achieved (65, 66). However, the hydrolysis products ryanodol and9,21-dehydroryanodol are selective for insects compared with mammals (144) and appear to actat a K+ channel site (141). The newest major class of insecticides is the diamides (flubendiamide,chlorantraniliprole, and cyantraniliprole), which selectively activate insect but not mammalianmuscle on binding to a new and yet uncharacterized site on RyRs, leading to uncontrolled Ca2+

release (Figure 1), thereby conferring strong selectivity for insects (36, 44, 120).

Genetic Engineering

Pest insect control with baculoviruses takes several days, allowing unacceptable crop damage (10).Baculoviruses expressing selected spider and scorpion toxins act much faster but have not yetfound practical applications (72).

SECONDARY EFFECTS

Serine Hydrolase Secondary Targets

OP and MC pesticides inhibit not only AChE but also many other serine hydrolases in nervetissues, as quantified by enzymatic activity assays on specific substrates (27, 29) or activity-basedprotein profiling (87). The major focus in safety evaluations is on AChE inhibition, but there isalso concern about OP-induced delayed neuropathy (OPIDN) and interest in behavioral effectsassociated with disruption of the cannabinoid system (Figure 3). OPIDN involves axonopathyand peripheral paralysis and has affected approximately 50,000 people globally in the past eightdecades from compounds other than insecticides; there were also incidents with the insecticidesmipafox and leptofos. The target protein was designated neuropathy target esterase (NTE) (69)


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Alzheimer’s diseased

Basal forebrain

Neurofibrillarytangles

Amyloid-bearingplaques

Otherneurotransmitters

OP-induced delayed neuropathya

Parkinson’s diseasec

Delayedneurotoxicityaxonopathy

NTE

PR O

R'O XP

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R'O NTEP

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–O NTE

P

HOOH

O O

–O OCholine P

HO

OOC(CH2)nCH3

O O

–O OCholine

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Substantia nigra

Lewy bodyubiquitin protea-some systemα-synuclein

Otherneurotransmitters

GABAglutamate

Transporter

Receptor

Dopamine

HO

HO CH2CH2NH2

Rotenone

Heptachlor

Permethrin

Cannabinoid systemb

OP/MCinhibitors

2-AG AnandamideEndo-cannabinoids

Prostaglandinprecursor

MAGL FAAH Hydrolases

CannabinoidCB1 receptor

Activation

Arachidonicacid

Cholinergic neurons

nAChR Nicotine

AChE OP (metrifonate)

MC (Aricept®)

CholineCholineacetyltransferase

ACh

Figure 3Secondary targets of neurotoxic insecticides. (a) OP-induced delayed neuropathy from inhibition and aging of lysophosphatidyl cholinehydrolase (NTE). (b) OP- or MC-induced inhibition of MAGL and FAAH elevates endocannabinoid and lowers arachidonic acidlevels. (c) Parkinson’s disease of the basal ganglia involves primarily dopaminergic neurons. (d ) Alzheimer’s disease of the basalforebrain involves disrupting cholinergic and other neurons, leading to tangles and plaques. Abbreviations: ACh, acetylcholine; AChE,acetylcholinesterase; 2-AG, 2-arachidonyl glycerol; FAAH, fatty acid amide hydrolase; GABA, γ-aminobutyric acid; MAGL, monoacylglycerol lipase; MC, methylcarbamate; nAChR, nicotinic acetylcholine receptor; NTE, neuropathy target esterase; OP,organophosphate.

MAGL: monoacylglycerol lipase

and identified as a lysophosphatidyl choline hydrolase (112, 113, 143). Diminished NTE activityin mice links OP exposure to hyperactivity (148) but not necessarily to attention deficit disorderin humans. NTE deficiency in mice is embryo lethal (93, 116, 148) but when localized to thehippocampus gives vacuolation of neuronal bodies and dendrites (1).

The cannabinoid system consists of the CB1 and CB2 G protein–coupled cannabinoid recep-tors in the central and peripheral nervous systems, respectively, and two endocannabinoid ligands,anandamide and 2-arachidonyl glycerol, biosynthesized as needed and degraded by the serine hy-drolases fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL), respectively(Figure 3). This system is involved in appetite, pain, synaptic plasticity, mood, and the psychoac-tive effects of cannabis. Behavioral effects of some OPs suggested possible involvement of thecannabinoid system, and the serine hydrolases FAAH and MAGL were found to be sensitive tochlorpyrifos and profenofos in vivo in mice (25, 97). Potent OP irreversible inhibitors of MAGLand FAAH induce the full cannabinoid syndrome in mice associated with greatly elevated brainendocannabinoid levels and depleted free arachidonic acid (96). The current OP and MC insecti-cides as normally used do not appear to pose any cannabinoid-related toxicity problems. Selectiveand reversible carbamate FAAH and MAGL inhibitors have been designed with the goal of painrelief (88).


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OP- and MC-induced teratogenesis by diazinon, carbaryl, and other insecticides in hen eggsinvolves inhibition of N-formylkynurenine hydrolysis by arylformamidase (121) and depletion ofNAD levels (110, 111). The importance of this secondary OP target in mice was later evaluated byidentifying the catalytic site (106) and defining the effect of gene inactivation on the kynureninepathway metabolites (43). Another OP-sensitive serine hydrolase is KIAA1363 with an acetylmonoalkylglycerol ether substrate that also serves as a chlorpyrifos oxon hydrolase (98, 99, 100).

Parkinson’s and Alzheimer’s Diseases

The increasing incidence of Parkinson’s and Alzheimer’s diseases worldwide associated with agingis attributed to genetic and environmental factors, including exposure to neuroactive insecticides(49, 54) The Parkinson’s signs of tremor, rigidity, slowness of movement, and postural instabilityresult from insufficient levels of dopamine in the substantia nigra of the midbrain leading to α-synuclein protein accumulation and formation of Lewy body inclusions. Some of the insecticidesproposed to contribute to these changes and the incidence of Parkinson’s disease are the NADHoxidase inhibitors rotenone and deguelin (4, 17, 129), the PCCAs heptachlor and dieldrin (9, 12),and the pyrethroid permethrin (9, 52). Alzheimer’s disease is progressive and irreversible, lead-ing to memory loss, language problems, unpredictable behavioral changes, and development ofamyloid plaques, neurofibrillary tangles, and loss of connections between neurons in brain tissue(51, 56). Choline acetyl transferase activity is low in Alzheimer’s, resulting in low ACh levels,and other neurotransmitters (GABA and glutamate) are also possibly involved. Mild to moder-ate Alzheimer’s signs can be relieved by nicotine and AChE inhibitors, including the importantAlzheimer’s drug Aricept R© and the candidate (but withdrawn) drug metrifonate (i.e., the super-seded OP insecticide trichlorfon) (13, 89), which delay ACh breakdown in the synaptic cleft,thereby enhancing cholinergic neurotransmission.

FUTURE PROSPECTS

Less Emphasis on Neurotoxicants

Almost all insecticides used in the 1940s to 1980s were neurotoxicants, but this had droppedto 79% of the total world market value by 1990. Between 1997 and 2010, there was a markedshift from OPs and MCs to neonicotinoids accompanied by a distinct trend toward a variety ofnon-neuroactive insecticides (Figure 4). After seven decades of continuing discoveries, there areindications that we may be coming to the end of the golden age (26) of neuroactive insecticideresearch. Exploring nature and sifting through chemical libraries have repeatedly ended up withinsecticides dependent on the same major targets (21). This is disappointing when new targets areneeded to circumvent cross-resistance mechanisms. Although insect growth regulators, includ-ing insect hormone analogs or agonists and inhibitors of chitin synthesis, can be highly potent,effective, and selective, they act slowly in stopping crop damage, thereby limiting their role inpest control. Inhibitors of Complex I and other sites in the respiratory chain, including selectedthioureas, organotins, and uncouplers of oxidative phosphorylation, are limited by low selectivitybetween insects and mammals (23, 95).

Insecticide Activation and Detoxification

Neurotoxicant selectivity and resistance are attributable not only to differences in the biochemicaltargets considered here but also to the relative rates of P450 oxidation, hydrolysis, and conjugation


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40

Cholinergic

AChE

OP MC neonic pyr

nAChR Other

30

20

Wor

ldw

ide

mar

ket (

%)

Years (1997 – 2010)

10

0

Na+channel

Figure 4Changes in use of insecticide classes between 1997 and 2010 showing decreases for organophosphates (OPs),methylcarbamates (MCs), and pyrethroids (pyr) and increases for neonicotinoids (neonic) and othercompounds. Abbreviations: AChE, acetylcholinesterase; nAChR, nicotinic acetylcholine receptor. Datashown for the years 1997, 2000, 2002, 2005, 2008, and 2010 from T.C. Sparks (personal communication) aresimilar to those from his coauthored paper (95).

leading to activation and detoxification in insects and mammals. Many neurotoxic insecticides arein fact proinsecticides, such as phosphorothionates and derivatized MCs, that undergo preferentialbioactivation in pests to the active metabolites. The use of proinsecticides makes it possible toalter the physicochemical properties, distribution, and persistence for improved efficacy, resistancemanagement, and safety.

Resistancemanagement:the attempt tominimize the buildupof resistance toinsecticides and otherpesticides throughvarious means

SUMMARY POINTS

1. The four major neuroactive insecticide targets (AChE, nAChR, GABAR, and Na+ chan-nels) have the following features in common: original recognition by a botanical insecti-cide or prototype; target site cross-resistance limiting their effectiveness; available modelsfor insecticide binding site interactions; alternative subsites for insecticides less involvedin cross-resistance phenomena.

2. Downsizing of research on insecticide chemistry and toxicology has limited the discoveryof new chemotypes and biochemical targets, but this is partially compensated for by newin vitro screens and testing of massive chemical libraries.

3. Neuroactive insecticides have helped clarify the role of secondary targets in OPIDN,cannabinoid-like effects, PD, and AD.


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FUTURE ISSUES

1. There is a continuing need for new chemotypes of neuroactive insecticides as the nextgeneration of “resistance busters.”

2. An increasing diversity of non-nerve targets will help to maintain control capabilities.

3. New centers of excellence in insecticide research will meet continuing and increasingdemands for safe and effective chemicals.

DISCLOSURE STATEMENT

The authors are not aware of any affiliations, memberships, funding, or financial holdings thatmight be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS

Financial support past and present from the U.S. National Institutes of Health and the WilliamMuriece Hoskins Chair in Chemical and Molecular Entomology (University of California,Berkeley) ( J.E.C.) and from the U.S. National Science Foundation (CHE-0840505) (K.A.D.)is gratefully acknowledged. We thank undergraduate researchers Alex Laihsu, Elodie Tong-Lin,and particularly Sean Kodani for excellent assistance and advice.

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EN58-Frontmatter ARI 5 December 2012 7:43

Annual Review ofEntomology

Volume 58, 2013 Contents

Life as a Cataglyphologist—and BeyondRudiger Wehner � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 1

Ecological Mechanisms Underlying Arthropod SpeciesDiversity in GrasslandsAnthony Joern and Angela N. Laws � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �19

Recurrent Evolution of Dependent Colony FoundationAcross Eusocial InsectsAdam L. Cronin, Mathieu Molet, Claudie Doums, Thibaud Monnin,

and Christian Peeters � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �37

The Impact of Molecular Data on Our Understanding of Bee Phylogenyand EvolutionBryan N. Danforth, Sophie Cardinal, Christophe Praz, Eduardo A.B. Almeida,

and Denis Michez � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �57

An Emerging Understanding of Mechanisms Governing Insect HerbivoryUnder Elevated CO2

Jorge A. Zavala, Paul D. Nabity, and Evan H. DeLucia � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �79

Neuroactive Insecticides: Targets, Selectivity, Resistance,and Secondary EffectsJohn E. Casida and Kathleen A. Durkin � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �99

Biological Pest Control in MexicoTrevor Williams, Hugo C. Arredondo-Bernal, and Luis A. Rodrıguez-del-Bosque � � � � 119

Nutritional Ecology of Entomophagy in Humans and Other PrimatesDavid Raubenheimer and Jessica M. Rothman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 141

Conservation and Variation in Hox Genes: How Insect Models Pioneeredthe Evo-Devo FieldAlison Heffer and Leslie Pick � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 161

The Juvenile Hormone Signaling Pathway in Insect DevelopmentMarek Jindra, Subba R. Palli, and Lynn M. Riddiford � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 181

viii

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The Adult Dipteran Crop: A Unique and Overlooked OrganJohn G. Stoffolano Jr. and Aaron T. Haselton � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 205

Biology of Phlebotomine Sand Flies as Vectors of Disease AgentsPaul D. Ready � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 227

Ecdysone Receptors: From the Ashburner Model to Structural BiologyRonald J. Hill, Isabelle M.L. Billas, Francois Bonneton, Lloyd D. Graham,

and Michael C. Lawrence � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 251

Thelytokous Parthenogenesis in Eusocial HymenopteraChristian Rabeling and Daniel J.C. Kronauer � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 273

Red Turpentine Beetle: Innocuous Native Becomes Invasive Tree Killerin ChinaJianghua Sun, Min Lu, Nancy E. Gillette, and Michael J. Wingfield � � � � � � � � � � � � � � � � � � 293

Vision in Drosophila: Seeing the World Through a Model’s EyesAngelique Paulk, S. Sean Millard, and Bruno van Swinderen � � � � � � � � � � � � � � � � � � � � � � � � � � 313

Intrinsic Inter- and Intraspecific Competition in Parasitoid WaspsJeffrey A. Harvey, Erik H. Poelman, and Toshiharu Tanaka � � � � � � � � � � � � � � � � � � � � � � � � � � � 333

Biology and Management of Palm Dynastid Beetles: Recent AdvancesGeoffrey O. Bedford � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 353

Odorant Reception in Insects: Roles of Receptors, Binding Proteins,and Degrading EnzymesWalter S. Leal � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 373

Molecular Systematics and Insecticide Resistance in the Major AfricanMalaria Vector Anopheles funestusMaureen Coetzee and Lizette L. Koekemoer � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 393

Biology and Management of Asian Citrus Psyllid, Vector of theHuanglongbing PathogensElizabeth E. Grafton-Cardwell, Lukasz L. Stelinski, and Philip A. Stansly � � � � � � � � � � � � 413

Host Preferences of Blood-Feeding MosquitoesWillem Takken and Niels O. Verhulst � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 433

Biology of Invasive Termites: A Worldwide ReviewTheodore A. Evans, Brian T. Forschler, and J. Kenneth Grace � � � � � � � � � � � � � � � � � � � � � � � � � � 455

Spider-Venom Peptides: Structure, Pharmacology, and Potentialfor Control of Insect PestsGlenn F. King and Margaret C. Hardy � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 475

Ecdysone Control of Developmental Transitions:Lessons from Drosophila ResearchNaoki Yamanaka, Kim F. Rewitz, and Michael B. O’Connor � � � � � � � � � � � � � � � � � � � � � � � � � � � 497

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Diamondback Moth Ecology and Management: Problems, Progress,and ProspectsMichael J. Furlong, Denis J. Wright, and Lloyd M. Dosdall � � � � � � � � � � � � � � � � � � � � � � � � � � � � 517

Neural Mechanisms of Reward in InsectsClint J. Perry and Andrew B. Barron � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 543

Potential of Insects as Food and Feed in Assuring Food SecurityArnold van Huis � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 563

A History of Entomological ClassificationMichael S. Engel and Niels P. Kristensen � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 585

Ants and the Fossil RecordJohn S. LaPolla, Gennady M. Dlussky, and Vincent Perrichot � � � � � � � � � � � � � � � � � � � � � � � � � � 609

Indexes

Cumulative Index of Contributing Authors, Volumes 49–58 � � � � � � � � � � � � � � � � � � � � � � � � � � � 631

Cumulative Index of Article Titles, Volumes 49–58 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 636

Errata

An online log of corrections to Annual Review of Entomology articles may be found athttp://ento.annualreviews.org/errata.shtml

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AnnuAl Reviewsit’s about time. Your time. it’s time well spent.

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Annual Review of Statistics and Its ApplicationVolume 1 • Online January 2014 • http://statistics.annualreviews.org

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neuroactive insecticides: targets, selectivity, resistance

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