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Circadian Rhythm in Brain Gamma Aminobutyric
Acid Levels in the Cockroach, Leucophuea muderae
Llepartments of Biology and Chemistry, Western Kentucky University,
Bowling Green, Kentucky 42101
Brain levels of y-aminobutyric acid (GABA) were determined using high performance liquid chroinatography coupled with fluorometeric detection at 3-h intervals throughout a
24-h time period in roaches acclimated to a photoperiodic cycle of 12 h of light and 12 h of darkness at 25 1?: 2°C to establish whether or not the levels of this inhibitory neurotransmitter vaned
temporally. Brain levels of GABA did vary temporally, with highest levels occurring a t midday.
Therefore, an additional experiment was conducted to determine if this rhythm persisted on a
circadian basis. Brain levels of GABA were determined a t two circadian times (CT)that corresponded t o the times during the daily cycle when levels were highest and lowest in animals
held under constant darkness. The differences in GABA levels observed at these two times of
day in animals held under a lightldark cycle persisted on the second cycle under conditions of
constant darkness, indicating that the rhythm of brain GABA levels may persist on a circadian
basis. Q 1996 WiIey LISS, Inc.
Invertebrates offer excellent models in which to
study circadian mechanisms involved in timing
the occurrence of bioch,emical, physiological, and
behavioral events and how the circadian system
is organized. Cockroaches, particularly Leucophaea maderae, have keen studied extensively in
this regard (for reviews see Page, '89a, b, '90). Circadian rhythms in lcicomotor activity (Nishiitsutsuji-Uwo and Pittendrigh, '68), eye sensitivity
t o light (Wills et al., 'G),retinula cell morphology (Ferrell and Reitcheck, '931, cytochrome oxidase activity (Lavialle el; al., '891, and neural output
from optic lobes measured in vitro and in vivo
(Colwell and Page, '90) have been characterized in
this species. The paceniaker(s) that regulates the
expression of locomotor (activity(Nishiitsutsuji-Uwo
and Pittendrigh, '68; Page, '82, '83) and eye sensitivity to light (Wills et al., '85) rhythms consists
of a pair of oscillators, each of which has been
localized t o the lobula neuropil within each optic
lobe. These oscillators are mutually coupled and
together regulate the expression of locomotor activity and eye sensitivity to light rhythms via neural pathways. In addition, this pacemaker(s) is
(are) photically entrained via a neural pathway
from the compound eyes (for review see Page, '90).
That a single pacemalker locus can regulate a
number of separate processes is consistent with
data from mammals (Rusak and Zucker, '79;
Moore, '79). The supratchiasmatic nucleus (SCN)
has been implicated in regulating a wide range of
rhythmic processes in mammals, for example.
One explanation for the endogenous mechanism
controlling the temporal organization of circadian
rhythms involves synchronized neural output via
efferent pathways from the optic lobe pacemakers t o broad areas of the nervous system. It is
envisioned that altered neural output temporally
organizes the expression of behavioral, physiological, and metabolic rhythms via its widespread influence on central nervous system activity (Page,
'89a, '90). The specific responses to this output at
intermediate neural and local effector tissue levels might determine the temporal expression of
behavioral and physiological events. Evidence in
support of this idea comes from experiments in
which neural activity was monitored from the cut
end of the optic tract of cultured optic lobes isolated from L. maderae (Page, '89a,b). Electrical
recording data from efferent neuronal pools indicate that output from the oscillators controlling
rhythms of locomotor activity is greatest during
subjective day and lowest during subjective night.
Received January 24, 1996; revision accepted June 28, 1996.
Address reprint requests to Blaine R. Ferrell, Department of Biology, Western Kentucky University, 1 Big Red Way, Bowling Green,
KY 42101.
It would seem that the neural output from the tory neurotransmitter prevalent in the central neroptic lobe oscillators measured in L. maderae vous system of vertebrates (Moore and Speh, '93)
might be inhibitory in light of the fact that increased neural output occurs at a time coincident
with decreased locomotor activity (Page, '89a). Additional evidence that optic lobe neural output is
inhibitory comes from electrical recordings taken
from cervical connectives in intact roaches. Peak
impulse activity occurred during the animals' subjective night. Severing the optic tract, thus preventing neural output from the optic lobe oscillator
from influencing the cervical connectives, abolished this rhythm and the impulse frequency increased tenfold over subjective daytime levels.
These findings are consistent with an inhibitory
role for neural output from optic lobe oscillators
(Colwell and Page, '90). These findings are also
consistent with results from studies in nocturnal
and diurnal mammals (Inouye and Kawamura,
'79; Kurumiya and Kawamura, '88), in which neural activity in the suprachiasmatic nucleus, the
putative circadian pacemaker, is greatest during
subjective daytime, whereas the neural activity
is lowest at this time of day elsewhere in the
brain. The suggestion that neural output from the
oscillators is general and inhibitory is tempered
by the findings in Limulus polyphemus (Kass and
Barlow, '92) and a cricket (Tomioka and Chiba,
'92) that increased efferent neural activity recorded from excised brains occurs on a circadian
basis with heightened activity during subjective
night. Furthermore, there may be different neural pools conveying different circadian information, as found in the cricket, Gryllus bimaculatus,
where increased neural activity occurred during subjective days or subjective nights in different neuronal pools monitored simultaneously
(Tomioka and Chiba, '92). Evidence from electrical recordings from single interneurons associated
with the visual system in another cockroach,
Blaberus giganteus (Bult and Mastebroek, '93)
indicates that three visual interneuron types express circadian activity, each with their maximal activity occurring at a different time of day.
Although neural output from the pacemaker has
been examined in L . maderae (Colwell and
Page, '901 and other arthropods (Kass and
Barlow, '92; Tomioka and Chiba, '86, '92; Bult
and Mastebroek, '93), its effect on the temporal pattern of specific neurosecretions, which
could have broad effects on neural and general
tissue activity, has not been investigated in this
model organism.
Gamma aminobutyric acid (GABA) in an inhibi-
and invertebrates (Takeuchi, '76; Pfeiffer-Linn and
Glantz, '91), with high levels in the optic lobes
(Pfeiffer-Linn and Glantz, '91; Garcia and Arechiga,
'86). GABA occurs at high levels in nuclei associated with the circadian pacemaker and appears
to be the principal neurotransmitter of the circadian system in mammals (Moore and Speh, '93).
Furthermore, pharmacological studies have implicated GABA in the photic entrainment mechanism
of the clock in mammals (Ralph and Menaker, '89).
Because of the analogous organization of the circadian system in mammals and L. maderae and
the presence of high levels of GABA in the central nervous systems of both groups, characterization of a daily and circadian rhythm in brain
GABA levels seemed a good place to begin in
determining whether or not GABA plays a role
in the circadian system of this model organism.
Results of this study indicate GABA does play
a role in that it varies temporally on a circadian basis indicative of endogenous control by
a pacemaker.
Adult male L. maderae were transferred from
a rearing colony in our laboratory maintained under a 12-h light/l2-h dark cycle at room temperature to environmental chambers set at the same
photoperiod conditions and a constant temperature of 25 -c 2OC. Light onset occurred at 0600 h.
Roaches from which brains were to be excised
were placed in clear plastic containers (19.0 cm
[Ll x 14.0 cm [HI x 10.5 cm [WI). Representative
roaches were placed in running wheels equipped
with magnetic reed switches wired to an EsterlineAngus event recorder. Each revolution of the wheel
produced two dashes on a paper strip-chart moving at a constant rate. These animals were used
t o monitor entrainment and circadian times during conditions of constant darkness. All animals
were acclimated at least 10 days prior t o brain
Animals were removed from plastic cages in the
environmental chambers either under room light
conditions during daytime hours or under dim red
light (i.e., safelight) during nighttime or constant
darkness conditions. At each sampling time, three
t o four animals were flash frozen in -70°C petro-
leum ether in order to immediately stop any bioPreparation of standards
chemical reactions. The animals were then removed
Standards were 0.2, 0.5, 1.0, or 2.0 pg/mL
from the petroleum ether and placed in a freezer. GABA 4.5 pg/mL AVA in methanol. Standards
Brains were maintained frozen until they were were stored in a -70°C freezer until HPLC analyhomogenized. A frozen roach was taped t o a Petri sis could be carried out.
dish with its head protruding through an opening. The Petri dish was placed under a dissecting
HPLC, column, and fluorometric
microscope and a flap oT cuticle encompassing both
detection conditions
antennae was removed using a razor blade scalThe assay for GABA was a slight modification
pel and iridectomy scissors, The exposed brain was
that used in vertebrates (Sunol et al., '88). A
then removed by sectioning the left optic nerves,
(5000) HPLC and a CI8reverse phase collifting the left optic lobe with forceps, and peeling
dimensions of 22 cm x 4.6 mm and 5
the brain toward the right side while transecting
size (Supelco) was used for the assay.
all tissues connected to the brain.
The column was coupled to a Shimadzu fluorometric detector (RF-540) operated at an excitation
Tissue preparation for injection onto the
wavelength of 355 nm, emission wavelength of 440
HPLC column
and a bandwith of 10 nm. The mobile phase,
Each excised brain was placed in an Eveljham
acetonitrile (by volume) and 55% phosphate
tissue homogenizer chilled by ice (approximately
at a pH of 2.8, was delivered isocratically.
4"C), and 200 pL of methanol containing the surThe
phase was filtered and degassed using
rogate standard, aminovaleric acid (AVA, Sigma,
and moderate warming to encourSt. Louis, MO), was added, and the tissue was
of gas prior to HPLC analysis. A
homogenized for 30 sec. The homogenate was
and temperature setting
transferred t o a 1 mL inicrofuge tube and centriof
fuged at 15,366g for 30 min. The supernatant was
collected using a 1 cc: tuberculin syringe, the
Analysis of endogenous GABA levels
needle was replaced with a 45 pm syringe filter,
Peak heights were measured using calipers for
and the supernatant filtered into a clean 1.5 mL
centrifuge tube. The filtered extract was then both GABA and AVA on graphs generated by an
maintained frozen at --70°C until it was diluted integratodrecorder. A standard curve was gener1:4 (v/v, sample extract/mobile phase) in mobile ated from triplicate measurements of each stanphase immediately prior to injection onto the dard (Fig. 1)throughout each assay run and the
equation of the regression line determined. This
HPLC column.
Samples and standards were derivatized by curve plotted the GABAAVA ratio (y-axis) against
placing 10 pL of dilutedl sample (or standard) with the known GABA levels in the standard (x-axis).
50 FL of Borate (0.1 M boric acid solution, pH For brain samples (Fig. 21, the GABA:AVA ratio
10.51, 100 pL OPA (5.5 mg o-phthaldialdehyde, 40 was used to calculate the levels of GABA in the
pL ethanethiol, and 4 mL methanol, Sigma) in a brain. Levels were determined in six brains at
polypropylene microfuge tube, and allowed to re- each sampling interval during Experiment 1.Samact for 90 sec on a vortex mixer. The derivatization pling occurred at 3-h intervals throughout a 24-h
reaction was stopped bly adding 100 pL of glacial time period in which roaches were acclimated to
acetic acid. Immediately following the addition of a 12L:12D photoperiod cycle. A brain sample from
the glacial acetic acid. an aliquot of derivatized each of the eight sampling times was analyzed
sample (or standard) was injected into the HPLC under each assay run in order to ensure that any
system using a 25 pL injection loop. Each sample temporal variance in GABA levels was not the re(standard) was injected in triplicate and the in- sult of assay variability. The existence of a daily
jector loop rinsed with mobile phase several times variation in brain levels was determined using a
between injections. A d erivatized methanol blank one-way analysis of variance and Student-Newmanwas injected each day prior t o the injection of Keul's range test at the 95% confidence interval.
In Experiment 2, endogenous levels of GABA
samples t o check for contamination.
Several brain samples were spiked with an were determined in seven brains at each sampling
equal volume of the high GABA standard and in- time. Sampling times coincided with the times of
jected onto the HPLC to check for interference day that GABA levels were determined to be high
and low in Experiment 1.Brain samples were obfrom other analytes.
12.5 ng GABA: 112.5 ng AVA
U 60.0
2 4 6
Fig. 1. Representative chromatogram of a derivatized standard with GABA and AVA (aminovaleric acid).
tained at 1200 h and 1800 h from roaches acclimated to a 12L:12D photoperiodic schedule (light
onset at 0600 h) and at corresponding circadian
times from roaches during their second cycle under constant dark conditions. Data were analyzed
using a two-way analysis of variance and differences were identified using Student-NewmanKeul's range test.
2 4 6
Fig. 2. Example of a chromatogram of a brain sample.
temperature conditions in Experiment 2 were
similar t o those determined in Experiment 1. In
addition, this difference persisted between measurements at circadian time (CT) 0600 h and CT
1200 h on the second day aRer light conditions were
changed to constant darkness (Fig. 4). Circadian
time 1200 h was the time of onset of activity in
animals maintained under constant conditions of
darkness (DD) and temperature, and was assumed
to be the equivalent of 1800 h (i.e., onset of activBrain GABA levels did vary with time of day in ity) in animals held under LD 12:12. The period
roaches acclimated t o LD 12:12 photoperiodic con- length of the locomotor activity cycle recorded unditions and 25 2 2°C in Experiment 1. Levels of der constant dark conditions was divided into 24
brain GABA at 1200 h were 896 36 nghrain, equal intervals in order to establish other circawhereas they were 544 2 13 nghrain at 1800 h dian times, such as CT 0600 h (i.e., subjective
(Fig. 3). Levels at other times of day sampled were midday).
similar to those measured at 1800 h.
Based on locomotor activity recordings of repThe difference in brain GABA levels determined resentative animals housed under the same envibetween 1200 h and 1800 h in animals acclimated ronmental conditions, it armears that roaches had
under a LD 12:12 photoperiodic cycle and constant been acclimated t o the light-dark cycle and did
Daily P a t t e r n of B r a i n GABA Levels
900a 800.rl
m 700-
6005000 400-
$ 300'"O]
o! :
-300 600
900 1200 1600 1800 2100 2400
Fig. 3. Daily pattern of brain GABA levels in cockroaches
acclimated to a 12 h lighUl2 h dark cycle (horizontal bar)
with light onset at 0600 h. "ean levels of brain GABA (dark
squares) were determined from measurements in six roaches
at each sampling time, each run in triplicate (S.E.M. = standard error of the mean).
free run under conditions of constant darkness
(Fig. 5).
GABA in other arthropods, brain levels of GABA
in L. maderae could be expected to range between
147 and 693 nghrain, values which include the
levels determined in this study. We are unaware
of any studies which have looked at the daily
rhythm of GABA in arthropods.
The temporal variation in brain GABA levels
appeared to continue on a circadian basis. Differences between the maximum and minimum levels determined in roaches held under LD 12:12
conditions persisted during the second cycle of constant dark conditions. The fact that GABA levels
peaked during subjective daytime, a time of day
when locomotor activity and eye sensitivity to light
are low, is consistent both with data regarding
neural output from the optic lobe oscillators (Page,
'89b; Colwell and Page, '90) and its inhibitory role
in the central nervous system of arthropods
(Takeuchi, '76; Pfeiffer-Linn and Glantz, '91). Interestingly, GABAergic neurons have been found
in the major brain nuclei associated with the generation and control of circadian rhythms in mammals (Hendrickson et al., '83; Card and Moore,
'84; Van den Pol and Tsujimoto, '85). Interaction
of the SCN with areas they innervate is largely
one of cyclic levels of inhibitory control (Moore and
Speh, '93). In that several correlates between the
circadian systems in mammals and L. maderue
Brain levels of GABA in L. maderae do vary with
time of day, with highest levels occurring at midday. Levels found at other times of day in L.
maderae (e.g., 544 to 689 ng) with a brain wet
weight of approximately 2.5 mg (Garrett et al.,
'91) are comparable to those found in mouse brain
cerebral cortex (i.e., 4.96 ng/2 mg wet weight;
Kapetanovjc et al., '87; Sunol et al., '88). Comparisons with brain 'levels reported in other
arthropods were difficulit to make in that reported
levels vaned widely and levels were reported relative to protein levels (Breer and Heilgenberg, '85;
Clarke and Donellan, '82; Fuchs et al., '89). Nevertheless, levels of GAB.A previously reported were
substantially higher compared with other neurotransmitter levels mentioned (Fuchs et al., '89)
consistent with the data reported herein. The ratio of 5-HT (5-hydroxyt~yptamine):GABA
for other arthropods ranged from 1:35 to 1:165.
The level of 5-HT measured in another cockroach,
Periplaneta americana (Evans, '80) was approximately 4.2 nghrain consistent with the level of 5HT reported in L. maderae (Garrett et al., '91).
Based on the range of ratios between 5-HT and
lsID 400
o m
1200 1800 Time (h)
Fig. 4. Mean brain levels of GABA measured at midday
(1200) and light offset (1800) in cockroaches acclimated t o a
12 h light/l2 h dark cycle (LD) and at subjective midday (CT
0600) and subject lights off (CT 1200) on day two after animals were transferred to constant dark conditions. Circadian
times (CT)0600 and 1200 h in animals maintained under
constant darkness (DD) were judged t o be times equivalent
to 1200 and 1800 h in animals acclimated to a 12 h light/l2
h dark cycle based on examination of locomotor activity pat-
terns of representative animals. The light and dark conditions are represented by the unshaded and shaded horizontal bar above the X axis. The zigzag line indicates the number
of cycles in brain GABA levels. The range of values is given
by the vertical lines and one standard deviation of the mean
by the shaded boxes. Means with different letters were found
to be significantly different at the 95%confidence level by a
two-way analysis of variance and Student-Newman-Keul's
range test.
have been found, the role of GABA in the circadian system certainly warrants further pharmacological and anatomical investigation.
Although the possibility that other analytes interfered with our GABA peaks exists, the fact that
peak shoulders were not produced by spiking
brain samples with known concentrations of
GABA, that the levels determined from spiking
brain samples fell within predicted levels, and that
this assay (Sunol et al., '88) had been verified using GC-MS in vertebrates t o include no other
analytes gave us confidence that we did in fact
measure endogenous GABA levels and that temporal variances are real. Freezing and thawing
experienced during our analysis should have had
no effect on GABA levels in that no effect on determinations of GABA levels in cerebrospinal fluid
samples that were analyzed using an HPLC/fluorometric assay (Manyam and Hare, '83) were observed due to repeated freezing and thawing of
The fact that maximum brain GABA levels occur shortly after the time of maximum neural output measured electrophysiologically from isolated
optic lobes in this species (Colwell and Page, '90)
is intriguing. In fact, the daily pattern of brain
GABA levels is similar to the pattern of multiunit neural activity recordings from the optic
TIME (hours)
Fig. 5. Locomotor activity pattern of a representative cockroach used to verify that the animals were entrained and
that brain samples were taken from cockroaches at the appropriate times under freerunning conditions. Lights were
left off beginning with the clay indicated by DD>. The dark-
ened regions on the lines for each day represent periods of
locomotor activity. Prior to the transition to constant darkness, animals were acclimated to a LD 1212 photoperiod
schedule with lights off a t 1800 h.
tracts of optic lobes in vitro (Page, '89). However,
the phase of the GABA rhythm is slightly delayed
compared with phase of the rhythm in neural activity. Neural activity (Page, '89) and brain GABA
levels peaked approximately 4 and 6 h after the
onset of light under LD 12:12 conditions, respectively. Both neural and GABA peaks were short
in duration and declined rapidly thereafter. Based
on the neural activity pattern, the pacemakerb)
function, and possibly GABA's, may not be through
continued suppression of neural activity throughout the day, but rather as a master temporal signal that resets rhythms of neurons elsewhere that
are responsible for the expression of individual
physiological, behavioral, and biochemical rhythms.
The coincidence between patterns in neural activity from the pacemaker and brain GABA levels
does not argue for a causal relationship between
neural output from the optic lobe pacemaker and
GABA levels, however, especially in light of the
fact that GABA levels were determined for whole
brains not just optic lobes. Therefore, caution
should be exercised in thawing conclusions regarding functional significance of varying GABA levels based on measurements of GABA in this study.
Furthermore, it is impossible from data in the
present study to know whether or not the elevated
GABA levels represenl; an increase in the release
of GABA from neurons or an accumulation of
GABA in inactive neurons through increased
synthesis and a decreased release for example.
However, based on comparisons of the patterns
of neural activity arid brain GABA levels, it
seems more plausible to suggest that elevated
GABA levels represent the accumulation of
GABA in less active neurons and not increased
Pharmacological and anatomical studies are
currently in progress to explore the role of GABA
in the circadian system in this model organism.
Studies involving labeling of GABAergic neurons
should help t o determine if they are localized in
the lobula neuropil, site of the putative pacemaker
in L. maderue, as GABAergic neurons are in mammals (Moore and Speh, '93). According to results
of studies employing agonistic and antagonistic
pharmacological agents carried out in hamsters,
GABA is involved in the regulation of circadian
responses to light and this regulation is mediated
by both GABA, and GABABreceptors (Ralph and
Menaker, '89; Smith et al., '90). A GABAergic systems involving both types of receptors can reset the
mammalian circadian clock. However, GABAergic
neural pathways may not be involved in the circadian timing system (Smith et al., '90). Similar
pharmacological work needs to be carried out in
L. maderue in order t o determine the role of GABA
in its circadian system.
We thank the Marcia Athey Fund of the Kentucky Academy of Science, the L.Y. Lancaster Memorial Lectureship Society, the Ogden Foundation,
and the Faculty Research Grants Committee at
Western Kentucky University for the funds t o
carry out this research.
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