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Knockdown resistance to dichlorodiphenyl-trichloroethane and pyrethroid insecticides in the napts mutant of Drosophila melanogaster is correlated with reduced neuronal sensitivity.

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Archives of Insect Biochemistry and Physiology 10:293-302 (1989)
Knockdown Resistance to Dichlorodiphenyltrichloroethane and Pyrethroid Insecticides in
the napfsMutant of Drosophila
melanogaster I s Correlated With Reduced
Neuronal Sensitivity
Jeffrey R. Bloomquist, David M. Soderlund, and Douglas C. Knipple
Department of Entomology, New York State Agricultural Experiment Station, Cornell University,
Geneva
Resistance to pyrethroid insecticides and dichlorodiphenyltrichloroethane
(DDT) was investigated in t h e nap” ( n o action potential, temperature sensitive) mutant of Drosophila rnelanogaster. In surface contact bioassays, t h e
napfs strain s h o w e d threefold resistance t o deltamethrin a t t h e LC50 level
w h e n c o m p a r e d to susceptible Canton-S flies. Cross-resistance was also
observed t o DDT a n d t h e pyrethroids NRDC 157 [3-phenoxybenzyl [lR,cis]3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate],
fenfluthrin, and
MTI -800 [I-(3-phenoxy-4-fluorophenyl)-4-(4-ethoxyphenyl)-4-methylpentane]
.
The o n s e t of intoxication by pyrethroids in nap’ flies was markedly delayed,
a finding that is consistent with t h e existence of a resistance mechanism involving reduced neuronal sensitivity. Resistance at t h e level of t h e nerve was confirmed by electrophysiological recordings of spontaneous and evoked activity
in t h e dorsolongitudinal flight muscles of poisoned flies. Preparations from
nap” insects treated with fenfluthrin displayed longer latencies to t h e appeara n c e of spontaneous activity a n d also a n absence o r reduction in burst discharges compared to equivalent preparations from susceptible individuals.
These results are discussed in light of competing hypotheses concerning t h e
mechanism underlying knockdown resistance and reduced nerve sensitivity
in insects.
Key words: deltamethrin, fenfluthrin, sodium channel, electrophysiology
Acknowledgments: These studies were supported in part by CSRS Regional Research Project
NE-115. We thank Katherine Vega, an Independent Study participant from William Smith College (Geneva, NY) for her able technical assistance.
Received November 16,1988; accepted April 6,1989.
Address reprint requests to David M. Soderlund, Department of Entomology, NYS Agricultural
Experiment Station, Cornell University, Geneva, NY 14456.
Jeffrey R. Bloomquist’s present address is Department of Entomology, Virginia Polytechnic
Institute and State University, Blacksburg, VA 24061.
0 1989 Alan R. Liss, Inc.
294
Bloomquist et al.
INTRODUCTION
Drosophila rnelanogaster possesses several characteristics that should make it
an ideal insect species for studying insecticide resistance. Among these advantages are: the ability to generate a variety of resistant strains by chemical
mutagenesis; the ability to transform strains using P-element vectors; and the
ability to clone virtually any genetic locus using the well-developed molecular
genetic techniques afforded by this system [l]. Despite these advantages, D.
rnelanoguster remains an underutilized resource for exploring insecticide resistance problems.
The rich variety of defined genetic mutations induced in D. rnelanogaster by
chemical mutagenesis includes neurological mutants such as napts (no action
potential, temperature sensitive) [2]. Adult flies with the napts phenotype
display reversible temperature-sensitiveparalysis at 38°C that is correlated with
a reversible, temperature-sensitive blockage of nerve conduction [2]. Embryonic napfSneurons in culture are resistant to the cytotoxic action of the sodium
channel activator veratridine [3]. In addition, resistance to veratridine and hypersensitivity to tetrodotoxin, a specific sodium channel blocker, have been
observed in feeding experiments with adult flies [4]. In napfSnerve membranes, the density of binding sites for [3H]saxitoxin(a radioligand that specifically labels sodium channels) is lower than in membranes prepared from
wildtype flies [5,6]. This reduction in the number of [3H]saxitoxinbinding sites
is persuasive evidence for a reduction in the density of voltage-sensitive sodium
channels in napts nerve membranes, which has been claimed to be a sufficient mechanism to explain both temperature-sensitive paralysis [71 and altered
neurotoxin sensitivity [4] in naptsflies.
A reduction in the number of DDT* and pyrethroid binding sites has been
proposed as a mechanism of reduced neuronal sensitivity underlying the kdr
resistance phenotype in houseflies [8].Since the voltage-sensitive sodium channel is the principal site of action of these compounds [9], the naptSstrain of D.
rnelanogaster appears to be an appropriate model for assessing the role of reduced
target site density in resistance in vivo and in reduced neuronal sensitivity in
physiological assays. Kasbekar and Hall [lo] recently reported that the napts
strain is resistant to pyrethroids and that the resistance to fenvalerate in this
strain was genetically inseparable from the naptSlocus. In this paper, we report
a modest level of cross-resistance to the lethal effects of DDT and a limited
group of structurally diverse pyrethroids in this strain. We also document substantial resistance to the rapid paralytic ("knockdown") effects of some pyrethroids that is correlated with reduced sensitivity of the nervous system.
MATERIALS AND METHODS
Chemicals
Deltamethrin and its noncyano analog, NRDC 157*, were provided by J.
Martel, Roussel-Uclaf, Romainville, France. DDT was purchased from Chem
dichlorodiphenyltrichloroethane; MTI-800 = 1-(3-phenoxy-4= 3-phenoxybenzyl [IR,cisl
-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate.
*Abbreviations used: DDT
=
fluorophenyl)-4-(4-ethoxyphenyl)-4-methylpentane; N R D C 157
Knockdown Resistance in D. melanogaster
295
Service (West Chester, PA). MTI-800 was a gift from N. Janes, Rothamsted Experimental Station (Harpenden, England) and fenfluthrin was supplied by J. Scott,
Cornell University (Ithaca, NY).
Insects
Colonies of D. melunoguster were reared in continuous cultures at 23°C using
established procedures. Wildtype (Canton-S)flies obtained from R. MacIntyre,
Cornell University, served as the reference susceptible strain. Flies of the nap"
strain were the kind gift of S. Benzer, California Institute of Technology (Pasadena, CA). We confirmed that holding these flies at 38°C caused paralysis in
both sexes, which was reversed by lowering the temperature.
Bioassays
Adult females of both strains were exposed to insecticides in a surface contact bioassay used previously to document resistance to DDT in field collected
strains of D. melunogusfer [ll]. Solutions of insecticide in acetone (0.5 ml) were
applied to the walls and bottom of 50 ml Erlenmeyer flasks and the solvent
evaporated to give a uniform residue. Control flasks received identical treatment with solvent only. Twenty adult female flies were introduced into each
flask, and the flasks were stoppered with cotton kept moist with sucrose solution. Initial toxicity measurements with deltamethrin were performed after
ether anesthesia. Similar results were also obtained with COzanesthesia, which
was then used in all subsequent toxicity determinations. Paralysis was assessed
at 60 min intervals for the first 4 h of exposure, at 8 h after exposure, and at 24
h after exposure. Those individuals unable to maintain posture and walk normally were considered paralyzed. Flies paralyzed at 24 h did not subsequently
recover and were considered dead. Results are presented as the pooled percent paralysis or mortality from at least two replicate experiments in which
the responses of the two strains were compared under identical conditions
and were corrected for paralysis or mortality in controls (S5% in all experiments). Computerized probit analysis of mortality data for deltamethrin was
performed using the POLO program [12].
Electrophysiology
Methods for measuring activity in the fibrillar flight muscles of D. melunoguster
were essentially those of Tanouye and Wyman [13]. Briefly, adult females were
anesthetized by chilling and fixed in soft wax. Sharpened steel stimulating
electrodes were placed in the cervical region of the head and thorax near the
central nervous system. Stimuli were delivered as rectangular pulses 0.1-0.3
ms in duration at a rate of 0.3 Hz. Responses in single dorsolongitudinal muscle fibers were recorded with a micropipette inserted through the cuticle into
the dorsal thoracic insertions of the muscles. Micropipettes were filled with a
saline containing (mM) NaCl(130), KC1(5), CaCI2(1.8),MgC1' (4), and HEPES
(5), pH 7.2. Flies were treated on the abdomen with 8 ng of fenfluthrin dissolved in 0.25 pl of acetone. Disruption of normal motor nerve function was
measured as the latency to both the appearance of evoked burst discharges
and the onset of spontaneous activity.
296
Bloornquist et al.
TABLE 1. Toxicity of Four Pyrethroids and DTT to Canton-S and napts Flies
Dosage,
Fglflask
Compound
Deltamethrin
24 h mortality, %
Canton S
napfs
0.05
0.15
5.0
50.0
15.0
50.0
0.05
0.5
5.0
50.0
NRDC 157
MTI-800
Fenfluthrin
DDT
0
35
3
58
63
93
5
100
12
30
25
72
45
83
87
100
60
100
58
85
RESULTS
The napts strain displayed modest levels of cross resistance to the lethal
effects at 24 h of all the compounds tested in this study when compared to
the susceptible Canton-S strain (Table 1).These studies revealed little response
in naptS flies at concentrations of deltamethrin, NRDC 157, fenfluthrin, and
DDT that caused appreciable toxicity in the susceptible strain. However, differences between strains in their responses to MTI-800 were small at the concentrations tested. Probit analysis of a more extensive set of toxicity data for
deltamethrin (Table 2) showed that responses of these strains were statistically different and that the napts strain exhibited threefold resistance to this
compound at the LC5,, level. However, the dosage-response curves for the naptS
and Canton-S strains were not parallel, so that differences in their responses
to deltamethrin were most pronounced at low levels of toxicity but were not
evident at mortalities above 90%. In view of the low levels of resistance to
other compounds found in our screening assays (Table l),efforts to determine
LC50values and resistance ratios for these compounds were not pursued.
More dramatic differences between strains were noted in the time course of
intoxication. Deltamethrin at 0.15 &flask (Fig. 1)produced extensive knockdown of Canton-S flies during the second hour of exposure. In contrast, paralysis of napts flies were barely detectable during the first 4 h of exposure at the
same dosage, although at 24 h this treatment produced approximately 50%
mortality (Table 2). Fenfluthrin at 0.1 pg/flask (Fig. 2) also caused a timedependent increase in knockdown that approached 80% in the susceptible
Canton S strain after 3 h of exposure, but naptsflies were virtually unaffected
during the first 2 h of exposure to fenfluthrin and only 15% knockdown was
observed after 4 h. A similar pattern of knockdown resistance was observed
TABLE 2. Probit Analysis of the Lethal Effects of Deltamethrin on Adult Female Canton-S and
n a d s Flies*
Strain
Canton-S
naps‘”
n
LC,,,pg/flask
95% conf. limits
Slope
300
299
0.06
0.19
0.02-0.13
0.16-0.23
1.73
4.18
“Thedosage-response curves were found to be nonidentical and nonparallel (likelihoodratio tests,
P < .05 [12]).
Knockdown Resistance in D. melanogaster
0
1
2
4
3
297
5
Time, hr
Fig. 1. Time course of deltamethrin-dependent paralysis of Canton-S and napt' flies.
100
m Canton-S
80
s
-6
s
E
60
u)
p" 40
Fenfluthrln
0.1 pglflask
20
0
0
1
2
3
4
5
Time, h
Fig. 2.
Time course of fenfluthrin-dependent paralysis of Canton-S and nap" flies.
with MTI-800 at 15 pg/flask (Fig. 3), a dosage that produced little difference
between strains in assays of lethality at 24 h (Table 1).Knockdown by MTI-800
was approximately linear for the first 4 h of exposure to Canton-S flies, producing about 80% knockdown. The napfSstrain, however, displayed virtually
no sensitivity to the knockdown action of MTI-800 when tested under identical conditions. Similar results were also observed with NRDC 157 (data not
shown). However, the slow action of DDT resulted in a complete absence of
knockdown in either strain during the first 8 h of exposure.
Electrophysiological studies showed that the resistance to the knockdown
and lethal effects of pyrethroids displayed by the napfsstrain was correlated
with reduced sensitivity of the nervous system. Untreated preparations from
both napfs and Canton-S flies displayed single muscle action potentials in
298
Bloomquist et al.
100
=
Canton-S
I
MTI 800
15 pg/flask
-n-----o-
0
1
2
3
4
5
Time, h
Fig. 3. Time course of MTI 800-dependent paralysis of Canton4 and nap" flies
response to stimulus pulses (Fig. 4A). We also observed varying amounts of
spontaneous firing activity in these preparations immediately after recordings
were initiated, but this activity declined with time and was absent at the time
of treatment with insecticide solution. After treatment with fenfluthrin, preparations were monitored for the appearance of spontaneous activity and changes
in the evoked responses. In Canton-S flies (n=5), evoked burst discharges
like those shown in Figure 4B were observed after a variable latency. Four of
the preparations displayed consistent bursting 5,5.5,6, and 22 min after treatment, while another preparation showed only double-spike responses after
32 min of poisoning. However, the appearance of spontaneous trains of action
potentials in Canton-S preparations was more consistent, appearing 4 2 1min
B
CFig. 4. Responses in the dorsolongitudinal flight muscles to stimulation of the central nervous system in Canton-S and nap" flies. A: Single-muscle action potential typical of those
normally evoked by a single stimulus in Canton-S and nap" preparations before fenfluthrin
treatment. B: Typical burst discharges elicited by a single stimulus after treatment of a CantonS fly with 8 ng of fenfluthrin. C: Type of response observed in some nap" preparations treated
with fenfluthrin. See text for explanation.
Knockdown Resistance in D. melanogaster
299
(mean ? S.D.) after treatment. Identically treated preparations of napts flies
either displayed single evoked spikes for at least 30 min after treatment (2 of 4
preparations) or a truncated bursting response like that shown in Figure 4C.
These short responses appeared in two preparations 14 min and 17 min after
treatment and, unlike the consistent bursting observed in most Canton-S preparations, were interspersed with many single evoked spikes. Spontaneous activity in nap" preparations appeared 9.75 2 3.9 min (mean S.D.) after treatment.
The absent or reduced bursting in napts flies, along with the greater latency
for the onset of elevated spontaneous activity, provide evidence of reduced
sensitivity of the napts nervous system to exogenously applied pyrethroid.
*
DISCUSSION
Our findings confirm and extend those of Kasbekar and Hall [lo], demonstrating that the napts strain of D. melanogaster exhibits low levels of resistance to DDT as well as to a group of structurally diverse pyrethroids. The
compounds used in our experiments were chosen to exemplify the diversity
of insecticidal compounds known to act at the sodium channel. This group
included examples of compounds producing both type I (e.g., NRDC 157)
and type I1 (e.g., deltamethrin) symptomology [9], compounds having rapid
(e.g., fenfluthrin) or slow (e.g., DDT) action, and compounds expected to be
resistant to detoxicationby cytochrome P-450-dependentmonooxygenases(e.g.,
fenfluthrin [14] or carboxylesterases (e.g., DDT, M1'1800). We conclude from
our findings and those of other workers [lo] that the napts strain, like kdr
strains of the housefly [ 151, exhibits broad cross-resistance to insecticides acting at the sodium channel.
The levels of resistance found in this study are consistent with both the reduction in sodium channel density observed in the nap" strain [5,6] and the results
of biophysical studies of pyrethroid-sodium channel interactions, which suggest that less than 1%of sodium channels must be modified to compromise
normal function [16]. In nerves having reduced sodium channel density, the
modification of an equal number of target sites per unit area of nerve membrane would require modification of a greater fraction of the total complement
of sodium channels. This in turn would require a higher concentration of insecticide, which would be reflected both at the level of the nerve and at the level
of the whole organism as resistance. However, if the fraction of sodium channels that must be modified under normal circumstances is small [16], the twofold reduction in sodium channel density evident in [3H]saxitoxinbinding assays
with napts insects should confer approximately twofold resistance. This predicted value is in excellent agreement with low levels of resistance observed
in our bioassays. The fact that resistance is directly related to the number or
density of sodium channels provides further evidence that the pyrethroid/DDT
recognition site is intimately associated with the voltage-sensitive sodium channel itself. This finding validates the use of specific sodium channel radioligands,
such as [3H]saxitoxin, to assess whether alterations in binding site density
are involved in pyrethroid resistance in other species.
Although differences in the responses of the naptSand Canton-S strains to
the lethal effects of these insecticideswere small, much larger differences were
300
Bloomquist et al.
observed between these strains in their responses to the rapid paralytic actions
of some of the compounds tested. With deltamethrin, fenfluthrin, and MTI
800, the onset of paralysis in Canton-S flies was rapid, whereas little or no
paralysis occurred in parallel assays of napfSflies exposed to the same dosage
of toxicant. Striking differences in the onset of paralysis were evident even in
cases (e.g., MTI 800 at 15 pgflask) where differencesin mortality at 24 h between
strains were very small. The extent of resistance to the rapid paralytic effects
of these two compounds in the napfS strain is much greater than that previously reported for fenvalerate [lo]. This difference may simply result from
our use of rapidly-acting compounds for these assays. Alternatively, it is possible that our bioassay method, which involved exposure of flies to a uniform
residue on a glass surface [ll], provides a more precise estimate of rapid paralysis than that involving exposure to a treated filter paper disc [lo].
The delay in the onset of intoxication in the napfSstrain of D. melanogaster
is similar to that observed in kdr house flies [15]. This result is consistent with
a mechanism of resistance involving reduced target sensitivity but does not, in
itself, rule out the possible involvement of other mechanisms. However, two
other lines of evidence also point to a mechanism involving altered response
of the target tissue. First, resistance to fenvalerate in the napfSstrain is genetically inseparable from the napfSlocus itself [lo]. Since the napts mutation is
known to affect both the density of sodium channels and the normal functioning of nerves, this finding clearly implicates a neuronal mechanism rather
than one involving differences in penetration or metabolism of the insecticide. Second, the fact that resistance extends to compounds such as MTI 800,
DDT, and fenfluthrin also provides indirect evidence against the existence of
a mechanism in nap" flies that involves increased metabolic detoxication. Crossresistance to MTI 800 and DDT, compounds that lack carboxylester moieties,
unequivocally rules out the involvement of enhanced hydrolytic activity in resistance, but the lack of an effect of oxidative detoxication is less clearly delineated. Kasbekar and Hall [lo] obtained contradictory results using combined
treatments of piperonyl butoxide (an inhibitor of cytochrome P450-dependent
monooxygenases)and fenvalerate. This combination completely counteracted
the resistance to the lethal effects of fenvalerate in the napfSstrain but did not
completely remove the resistance to the rapid paralytic effects of this compound. Nevertheless, resistance of the napfS strain of D. melanogaster to
fenfluthrin, a compound not attacked by the cytochrome P450-dependent
monooxygenases that contribute to high levels of resistance to a variety of other
pyrethroids in the Learn-PyR strain of the housefly [14], provides additional
evidence that a mechanism other than enhanced oxidation may be involved
in this strain.
Direct evidence for reduced neuronal sensitivity to insecticides in the naptS
strain was obtained in physiological assays of the onset of altered neuronal
function in flies individually treated with fenfluthrin. Fenfluthrin was chosen
for physiological assays because it produces consistent burst discharges in equivalent dorsolongitudinal muscle preparations of the housefly 1171. The increased
latency of abnormal spontaneous and evoked activity in napfSflies was qualitatively similar to the type of responses observed when this assay is used to
define reduced neuronal sensitivity in kdr houseflies [14] and provides the
Knockdown Resistance in D. melanogaster
301
first physiological documentation of reduced neuronal sensitivity to pyrethroids
in D. rnelanogaster. However, the differences between wildtype (Canton-S)and
napfs strains in D. melanogaster are more subtle than those observed between
susceptible and kdr strains in the house fly, reflecting the low levels of resistance at the organismal level conferred by the napts mutation. The abnormal
evoked multiple potentials (e.g., Fig. 4C) that were observed in some napfS
preparations may represent the highest frequency bursting responses measurable for this strain, reflecting the prolonged refractory period of nap" nerves
[18]. Support for this interpretation also comes from our failure to observe
high-frequency bursting responses, such as that shown in Figure 48, to
fenfluthrin or any other pyrethroid in dorsolongitudinal muscles of intoxicated
napfs flies treated either by surface contact or topical application (J. R. Bloomquist, unpublished observations).
Although our findings identify the mechanism of resistance conferred by
the napfs mutation as "kdr-like", the napts strain does not appear to be an
appropriate mechanistic model for the kdr mechanism of the housefly. If a
reduction in target site density were the principal mechanism underlying the
kdr phenotype, the high levels of resistance observed in some allelic variants
at the kdr locus [19] should be correlated with substantial reductions in sodium
channel density. Although a reduction in sodium channel density in kdr houseflies has been reported [20], recent studies in this laboratory [21] and elsewhere [22,23] failed to document any differences in the density of binding
sites for [3H]saxitoxinin well-characterized susceptible and kdr or super-kdr
housefly strains. We conclude from these findings that a reduction in sodium
channel density is not specifically associated with the kdr mechanism. These
considerations argue against the reliance on any single well-characterized case
of reduced neuronal sensitivity as a mechanistic model for similar phenomena in other strains and species.
Although our study was restricted to the napfsstrain, three other temperature-sensitive paralytic mutants of D. rnelanogaster have been described that
also exhibit altered sodium channel properties: parafs (paralysis), seits (seizure), and tip-E" (temperature-induced paralysis, locus E) [24]. Of these
mutant strains, parats is of particular interest because the cloning and sequencing of this locus has revealed a significant structural homology with vertebrate sodium channel structural genes 1251. Moreover, a preliminary report
[26] suggests that different alleles of parats may exhibit either resistance or
hypersensitivity to pyrethroids. These findings suggest that strains of D.
rnelanogaster exhibiting altered neuronal function will continue to be valuable
resources for characterizing target site-mediated mechanisms of insecticide
resistance.
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