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BIOLOGY
OF
REPRODUCTION
47,
262-267
(1992)
Delta-9-Tetrahydrocannabinol
Luteinizing
Attenuates
Electrochemical
Stimulation
of the Medial
LEE
Departments
of Obstetrics
and
Gynecology
Durham,
Hormone
Release
Preoptic
Induced
by
Area1
1YREY2
and Neurobiology,
North
Carolina
27710
Duke
University
Medical
Center
ABSTRACT
Despite
diverse
exert
differential
GnRH
pathway.
surges
evoked
blocking
of ovulation
in the
These
drugs
(350
intensity
(P
or the
(P
in
distinguish
of ova
from
THC
Thus,
the preoptic-to-tuberal
within
before
<
The
constituent
in humans
[21 and
of marijuana
experimental
though
the sites
evidence
system,
known,
nervous
consistently
evoke
hibition
[3, 5, 8,9],
lated
the
from
reduced
LH
may
other
incubated
a view
consonant
with
GnRH
concentration
During
THc-induced
ovulation-blocking
preoptic
area
drugs
ilar,
ThC-induced
basal
nor
increase
treatment
evoked
most
Accepted
April
Received
October
‘This
work
W responses
easily explained
from
3244,
Durham,
(p
<
blockade
THC
release
LII
0.001),
peak
0.05)
not
was
and
levels
in-
total
and
in the
inci-
atthbutable
to
do not
mechanism,
overtly
affect
likely
which
the
Ui
response
includes
inhibitory
is inhibited
is thought
of GnRH
re-
the National
Institute
Department
of
other
efficacy
to that
for ovusuch
Blocking
mc
simdis-
is consistent
with those
selected
GnRH
by POA
pathway
stimulation
[14]. To deterduring
ThC
with that pattern,
LH responses
elicited
during
atropine
blockade,
as a classic
agents
representative
compared
of the
earlier
AND
set
were
the
of ovu-
[14].
METhODS
were
purchased
(Raleigh,
NC)
as
Drugs
of greater
solution
by
diately
before
the
than
95%
National
use,
the
purity
of 10 mg/kg
ml.
and
NC 27710.
262
body
weight
was
Institute
ethanol
trogen
and the mc
residue
composed
of 10% propylene
0.9% NaCl solution.
Rats were
on Drug
Obstetrics
the preoptic-to-tuberal
if LH release
induced
taken by saline lavage,
were used to document
estrous
cycle
regularity;
only rats exhibiting
at least two consecutive
4day cycles or two consecutive
5-day cycles
immediately
preceding
the then
current
cycle
were
selected
for experiments.
At the time of use, rats weighed
an average
of 269
± 23 g (SD).
of the medial
that is adequate
clear that the
is equivalent
to
adults.
Rats were
housed
in air-conditioned
animal
quarters
under
14 h of fluorescent
illumination
daily (05001900 h), and food (Purina
Rat Chow,
Ralston
Purina,
St Louis,
MO) and water
were
provided
ad libitum.
Vaginal
smears,
Abuse.
2Correspondence:
Lee Tyrey, Ph.D., Box
Gynecology,
Duke University
Medical
Center,
<
young
mc
that are remarkably
by blocking
action
DA 02006
(p
Female
rats of the crl:cD(SD)BR
strain
from Charles
River Breeding
Laboratories
instimu-
18, 1991.
by grant
LII
ovulation-
no difference
revealed
MATERIALS
14. 1992.
was supported
concentration
that
drugs
a different
lation-blocking
in hypothalamic
stimulation
LH surge
it is not
scheme,
a classic
blocked
treatments
oviducts
during
blocking
latter
blocks
the
[3, 7]. Al-
treatment
[12].
ovulatory
blockade,
as with
However,
after mc
drug
LH
response
blockade
contrasted
mc
In rats,
with a variety
of other
drugs
commonly
used
blockade.
Despite
their
diverse
pharmacology,
permit
a feature
psy-
mc
drugs,
direct
(POA)
evokes
an
for ovulation
[131.
of POA stimulation
noted
latory
after
to
observed
hypothalamic
that
with
(ATR),
uniformly
period
both
of the
mine
LH secretion
pituitaries
the
is consistent
by atropine
been
the final
sites.
involve
action
remain
unwithin
the central
injections
of GnRH
by mc added
to the medium
[10, 11]. Thus,
to suppress
LH secretion
through
inhibition
lease,
primary
[3-5].
LH release
to override
and,
in vitro,
neither
LH secretion
maximum
stimulation
by THC
[5,6] and
proestrus
of mc
action
In vivo,
not
have
above
pathway.
[11, inhibits
LH pulses
surge
at
and mechanisms
favors
primary
not the pituitary.
both
tat
animals
acutely
suppresses
episodic
preovulatory
gonadotropin
critical
after
Inspection
by extension,
and,
blockade
(mc),
Delta-9-tetrahydrocannabinol
action
blockade
surges
rats.
INTRODUC11ON
choactive
during
proestrous
LII
However,
0.05).
determined
GnRH
in the rat
blocking
(THC)
elicited
the
evoked
discharged.
ATh
ovulatory
those
THC-blocked
of histologically
ovulation
suggesting
compared.
stimulation
lower
thus
delta-9-tetrahydrocannabinol
with
been
were
number
by
treatment
of stimulation
or locus
stimulation.
have
mg/kg)
for blocking
used
stimulation,
contrasted
Preoptic
0.01)
<
commonly
blockade
were
rats.
extent
results
to preoptic
action
the
release
LI-I
variation
other
or ATh
sham-stimulated
with
tegrated
drugs
to preoptic
if ovulatory
stimulation
which
mg/kg)
in
increasing
determine
with
(10
ovulation
dence
To
actions,
on the LII response
by preoptic
agent
ThC
pharmacological
effects
on
was
supplied
Drug
evaporated
was emulsified
glycol
and 1%
treated
i.p. with
(b.w.)
in ethanol
Abuse.
in a total
Immeunder
ni-
in a vehicle
Tween-80
in
single
doses
volume
of 0.5
THC AUENUATION
Atropine
sulfate
by dissolving
MO)
(ATR)
was
freshly
in 0.9%
ml. AIR
kg b.w.,
was injected
s.c. in the
divided
approximately
and
sides
left
prepared
at each
to limit
the
St. Louis,
of 70 mg/
groin
in a dose
equally
between
volume
injected
Dosages
for THC and AIR treatments
provide
consistent
ovulatory
blockade
use
co.,
crystalline
ATR (Sigma
Chemical
NaCl solution
to a concentration
action,
fixation.
to
263
and then with
Serial
frontal
stained
with
10% formalin
in saline for in situ brain
sections
were
cut from frozen
brains
neutral
Serum
concentrations
ble-antibody
rials
supplied
[15-17].
3 reference
preparation.
cients
of variation
for
were
5.5% and 14.4%,
During
the morning
of proestrus,
animals
under
brief
ether
anesthesia
for placement
atrial
cannulae,
which
were
inserted
via the
jugular
(10
vein.
U/ml)
exit point
sampling.
That
medial
cannulae,
filled
to maintain
their
at the
of the
afternoon,
POA was
before
erage,
(SD).
were
The
1400
back
with
patency,
heparinized
were
neck
were
placed
of indwelling
right external
for
passed
later
s.c. to an
use
in blood
electrochemical
stimulation
(ECS) of the
delivered
unilaterally
to rats treated
just
h with
blocking
doses
of
mc
or AIR.
On
av-
stimulation
followed
drug treatment
by 71 ± 18 mm
Animals
were anesthetized
with ether
and their heads
fixed in the level skull position
(bregma
and lambda
in the same
horizontal
plane);
subsequently,
a stainless
steel
electrode,
insulated
except
at the tip, was lowered
into the
POA at 0.5 mm posterior
to bregma
and 0.5 mm lateral
to
the midline.
livered
to
the
Regulated
electrode
anodal
current
of 100 pA was dethrough
a constant
current
unit
(Grass
Instrument
Company,
Quincy,
MA) for durations
of
30, 60, or 90 sec, yielding,
respectively,
3000, 6000, or 9000
microcoulombs
(1iC).
Ear bars
of the stereotaxic
instrument
served
as the cathode.
Sham-stimulation
procedures
were
identical,
trode
was
except
positioned
no current
in the
was
samples
(0.2 ml) were
immediately
before
and
after
ume
or sham
replaced
saline
flushed
was separated
temperature)
Terminal
ing under
kg b.w.,
release.
stimulation.
immediately
through
the
by high-speed
elec-
via the indwelling
at 30, 60, 90, and 120 mm
cannula.
After
centrifugation
sample
vol(10 U/mI)
clotting,
(90 sec
serum
at room
and stored
at -20#{176}Cfor subsequent
assay.
laparotomies
were
performed
the next mornheavy pentobarbital
anesthesia
(Nembutal,
50 mg/
i.p.) in order
to evaluate
ovarian
Oviductal
ampullae
were
excised
lation
[14].
The heads
a solution
to mark
the
drawn
One half of each
with heparinized
microscopically
for ova. On
presence
of 9 or more
tubal
with
after
POA.
Blood
cannulae
ES
was
passed
sites
the
ova
responses
to LI-I
and
searched
basis
of experience,
was considered
full
and
the
ovu-
were
examination.
(Baltimore,
animals
were
were
expressed
as a repeated
Samples
assayed
within
the same
asin terms
of the rat LH-RP-
were
grouped
level,
and
(ANOVA),
measure.
according
time
with
Hartley’s
test
by each
level
were
test
performed
using
Integrated
was
used
to
or at specific
of freein-
times
after
with respective
control
levels
pairwise
post hoc comparisons
the
Newman-Keuls
LH responses,
rule)
under
the curve
sampling
times
within
[18]
single
degree
LH concentrations
of stimulation
compared
[19]. Other
sampling
for
time defined
and when
heterogeneity
transformation
was peroverall
effects
of blocking
and ECS were tested
by planned
contrasts
within
the ANOVA.
stimulation
by Dunnett’s
to blocking
of blood
sampling
Fmax
evaluate
homogeneity
of variance,
was
indicated,
logarithmic
data
formed
before
the ANOVA.
Main
were
MD).
mateand
Intraassay
and interassay
coeffirepetitive
assays
of a rat serum
pool
respectively.
LH concentrations
duced
by dou-
Analysis
drug,
stimulation
analysis
of variance
drug
dom
determined
using
methods
and
Institute
of Diabetes
Diseases
Kidney
from
individual
say, and results
Statistical
saline
microscopic
of W
Digestive
Procedures
for
radioimmunoassay
by the National
equal
potencies.
For each
drug,
the dose
chosen
was the
minimum
that would
promote
full blockade,
lesser
doses
allowing
ovulation
in an increased
proportion
of animals
Experimental
red
Radioimmunoassay
site.
were
selected
with approximately
RELEASE
W
and
of 350 mg/
the right
at a single
OF
defined
profiling
animals,
procedure
by the
area
[20].
(trapezoid
LH concentrations
over
were
subjected
to two-way
ANOVA after classification
by blocking
drug and stimulation
level. Tests of main effects
and post hoc comparisons
were
performed
as described
above,
and trends
in the integrated
LH response
with increasing
stimulation
were tested
by orthogonal
polynomial
partitioning
of the ANOVA
treatment
sum of squares.
The proportion
lation
was compared
er’s
exact
test
tables
were
lating
rats
of rats ovulating
in response
among
treatment
groups
for 4-cell
larger.
was
The
contrasted
tables,
and
number
the
Chi-square
of ova
among
to stimuusing
Fishtest
discharged
groups
when
by ovu-
by two-way
AN-
OVA.
When
when
comparisons
were
limited
to two groups,
such
contrasting
ECS locations
between
drug
treatments,
the Student’s
t-test
relation
coefficient
tween
was
was
used. When
relevant,
Pearson’s
calculated
to test for correlation
as
corbe-
measures.
RESULTS
of ECS rats were
of 2% potassium
of iron
deposition
perfused
via the ventral
ferrocyanide
by
the
aorta
in 0.9%
Prussian
saline
blue
re-
Treatment
with
either
AIR
or ThC
critical
period
uniformly
blocked
jected
to sham
stimulation.
Serum
before
the
ovulation
LH did
proestrous
in
not
rise
rats
after
subthe
264
TYREY
TABLE
1.
Ovulation
blocked with
stimulation.
AIR
incidence
or THC
number
of ova
discharged
to different
levels
ATR-blocked
Stimulation
E
and
and subjected
(C)
by rats
of POA
THC-blocked
Ovulating
Ovab
Ovulating
Ova
01
0
C
-
0/10
10.7
10.2
±
4.7
±
0/10
3/10
6/10
±
±
1.6
6/10
12.2
±
3.0
2.4
3000
6/10
14.2
±
-j
6000
6/10
12.2
9000
10/10
10.8
E
0
Number
Co
0
30
60
90
0
120
30
60
90
(Fig. 1), and no ova were
present
in ovithe next
morning
(Table
1). In contrast,
unambiguous
W surges
whether
the block-
ing drug was AIR or mc
groups,
serum
LH increased
maximum
(p
concentrations
< 0.001;
Fig.
within
30 mm
were
achieved
1). In both drug
(p < 0.01), and
90 mm
after
ECS
0.01).
However,
the peak
at 90 mm depended
intensity
of stimulation,
concentrations
increasing
level of stimulation
(p < 0.01).
In general,
peak
upon
with
con-
<
area
are displayed
in Figure
2 as quadratic
intensity;
however,
among
stimulated
in ECS intensity
produced
markedly
creases
in LH (p
<
0.05;
Fig.
2, inset).
functions
animals,
inlinear
in-
Consistent
with
the
effect
on LH peak
levels,
the integrated
response
across
stimulation
levels
was diminished
in Il-IC-blocked
animals,
relative
to that in the AIR group
(p < 0.01).
Interaction
between
drug
by linear
plot
tical significance
treatment
and ECS level,
slopes
(Fig. 2, inset),
did
(p = 0.075).
visually
suggested
not achieve
statis-
Neither
the
incidence
of 12.1
released
are sumrats dis-
1.1 (SE) ova, while
15 of 30
11.1 ± 1.7 ova per ovulation.
±
of ovulation
nor
sizes
surrounded
ritative
the
number
of ova
discharged
differed
significantly
between
drug
treatments.
Although
the number
of animals
ovulating
tended
to increase
with the level of ECS, the change
in incidence
was
not significant
statistically
(p = 0.074).
ova/number
stimulated.
(± SE) per ovulating
of stimulation
by a region
from
of its cross-sectional
that,
were
determined
for each
by a central
the
day
ECS animal.
coagulated
after
stimulation,
of neuronal
perikarya.
the region
of presumptive
deposited
area
rat.
sites
prepared
marked
a relative
absence
zone
delineates
stimulation
ment
tubal
ova
brain
sections
ECS sites were
iron
in the
[21],
center
and
plane
The
ir-
measurewas
used
as an index
of the bulk of POA stimulated.
Area measurements
correlated
with the level of ECS (r = 0.64, p < 0.001),
the average
size increasing
linearly
(p < 0.001)
with
increasing
intensity
of stimulation
(Table
2). No difference
in
cross-sectional
area
different
blocking
To compare
perpendicular
the
base
ECS
was
of the
brain
noted
between
drugs.
site locations
distances
of the
and
from
groups
between
coagulated
the
adjacent
treated
treatment
with
groups,
central
focus
from
wall
of the
third
700
600
E
0)
C
400
I
-J
E
200
Cl)
100
0
0
Ovulatory
responses
to ECS-evoked
LH release
marized
in Table
1. Overall,
22 of 30 AIR-blocked
charged
an average
mc-blocked
rats
and
exhibited
neuron-free
centrations
in THC-blocked
rats were
lower
than those
in
rats blocked
with AIR (p < 0.01).
The overall
response
to ECS was evaluated
by integrating serum
LH concentrations
over the sampling
range.
Integrated
responses
across
stimulation
levels
within
drug
treatments
of ECS
crements
displaying
of tubal
from
serial
In general,
FIG. 1. Mean serum LH concentrations
after sham or electrochemical
stimulation
(ECS) of the medial
preoptic
area in proestrous
rats blocked
with AIR or THC. Standard
errors exceeding
the size of data point symbols
are indicated
by vertical
lines. ECS provoked
LH surges
(p < 0.001) for
which maximum
concentrations
varied with the intensity
of stimulation
(p
< 0.01).
Sham stimulation
was without
effect.
Overall,
ECS was less effective in THC-blocked
rats than in rats blocked with AIR (p < 0.01).
sham
procedure
ducts
inspected
ECS provoked
rats
number
Locations
120
Time (mm)
(p
the
the
of
bMean
-
1.4
2.4
I
3000
Stimulation
6000
9000
level QiCoulombs)
FIG. 2. Mean serum
LH concentrations
integrated
over the sampling
range after sham or ECS of the medial
preoptic
area in proestrous
rats
blocked with AIR or THC. Standard
errors exceeding
the size of data point
symbols
are indicated
by vertical
lines. Responses
over the full range fit
quadratic
regression
lines (r = 0.99 for ATR and 0.98 for THC), but among
stimulated
animals
only (inset); changes
in response
with incremental
increases in ECS were remarkably
linear (p < 0.05). Relative to ATR animals,
integrated
responses
in THC-blocked
rats were diminished
across stimulation levels (p < 0.01). Interaction
between
blocking
drug and ECS level
approached,
but did not achieve,
statistical
significance
(p = 0.075).
THc
TABLE
different
2.
areas of stimulation
sites measured
in rats blocked with ATR or THC.
Cross-sectional
levels
of ECS
Cross-sectional
Stimulation
(pC)
ventricle
were
Longitudinal
gin of the
number
of intervening
or lateral
group
Although
placement
difference
was a lack
=
±
0.20
using
(mm2)
the
brain
sections.
the
POA
in LH response.
of correlation
either
peak
did
not
by restricting
with AIR
vertical
ranges
subsets,
(AIR
0.09
±
0.12
0.12
±
microscope
and the
estimated
scale.
caudal
marfrom
the
sites
was
in lon-
detected
be-
sites in mC-blocked
than
those
in the
rats
AIR-
may
in average
vertical
that positioning
of
have
contributed
to the
serum
LH concentration
-0.14,
(r =
the LH response
curve
(r = -0.18,
reassurance
that the difference
in
reflect
electrode
placement
was
statistical
analysis
to subsets
of animals
(n = 17) or mc (n = 23) for which
the
mean
1.11
±
placement
were
vertical
location
0.04 mm, mc
equivalent.
of ECS
=
1.06
0.27),
but differences
in peak
LH
0.01)
and area under
the LH response
remained
evident.
=
Between
sites did not
± 0.03
mm;p
concentration
curve
(p
(p <
0.001)
<
the
GnRH
into
ship
[26],
[27,28]
and the
blockade
control
anisms
has
of LH secretion
mediating
the
Moreover,
blocking
quantitative
influence
blocking
blockade,
both
the pharmacological
drugs
and the general
on
stimulus-evoked
action
remote
on the other
scheme.
The LH surge
sumptive
result
electrolytically
creases
in local
in the rat. Although
precise
pharmacological
blockade
suppression
of catecholammne
septal-preoptic-tuberal
pathway
a role [23].
of efficacious
that
ovulation
to pharmafor many years [22],
ability
of direct
brain
stimulation
to override
that
has served
to advantage
in probing
hypothalamic
largely
unexplained,
transmission
in the
gest
THC
of spontaneous
been
recognized
that
follows
from
the GnRH
hand,
appears
ECS
of the
mechremain
release
sug-
neurons
to differ
[14].
from
POA
linkage
it
study,
is unlikely
of
relation-
two
events
has
that
to the
mass
amount
of equal
of POA
of charge
intensities
released
blocked
with mc
than
AIR.
That
conclusion
in terms
of either
in those
followed
peak
con-
integrated
over the entire
samdrugs
were
administered
in the
with
full ovulatory
blockade
[15-
the
difference
that mc
to direct
the
by the
ECS
were
with
of U-I release
from
clude
sponse
between
quantitatively
centration
or concentration
pling
range.
Since
both
lowest
doses
consistent
17],
discharge
a causal
Nonetheless,
both
the increase
in
and the amplitude
of evoked
LH re-
related
current
and
suggests
through
Correlation
in
difference
dose
in responsiveness
potencies.
Thus,
rewe
con-
exerted
an action
that attenuated
the rePOA stimulation,
a result
that is in marked
contrast
to earlier
findings
blocking
drugs representing
[14]. In the work
reported
of invariant
LH responses
different
pharmacological
by Everett
and Tyrey
treated
phine),
(pentobarbital),
(chlorpromazine)
with a barbiturate
or an antiadrenergic
among
classes
[14], rats
an opiate
(morbefore
ECS
(7000
C)
presented
90-mm
LH levels
averaging
88-102%
of those elicited
in AIR-blocked
animals.
In the present
study,
ECS at levels
of 6000
or 9000
C,
bracketing
the earlier
stimulus,
resulted
in LH surges
in
averaged
only 53-60%
of those
trasts
relative
to AIR treatments
provide
evidence,
albeit
indirect,
mc
TI-IC-blocked
rats
that
after AIR blockade.
Conwithin
each
experiment
that LH suppression
by
differs
not only from that by AIR,
from that by other
drugs
included
but also quite
in the earlier
probcom-
set.
The relative
decrease
in LH response
to ECS after blockade with
mc was not attributable
to differences
in the
placement
or size of POA stimulation
sites. No statistically
significant
difference
in either
tion of the ECS site
Similarly,
the extent
cross-sectional
area
longitudinal
or
was detected
between
of tissue
involvement,
measurements,
did
lateral
loca-
drug
groups.
inferred
from
not
differ
between
neuromay play
diversity
absence
of
W
definitive
quantification
sulted
activity
circulation
LH in rats that
were
blocked
parison
susceptibility
blockade
neuronal
portal
are
the mechanism
is not clear.
the latter
determined
through
the electrode.
In the
less
that
increased
established.
activity
[24]
stimulated,
delivered
ably
DISCUSSION
The
cological
265
the
but
not been
multiunit
lease
Arguing
against
that possibility
between
vertical
placement
of the
merely
of ECS
=
±
1.39
1.86
No difference
of ECS
3), but
ventrally
0.60
0.001).
<
within
U-I response
sought
blocked
site
was
RELEASE
LH
between
group.
a calibrated
between
commissure
0.29) or area under
0.18).
Nonetheless,
those
differ
1.64
(Table
more
(p
ECS site and
p
0.14
0.19
modest,
the difference
of ECS sites raised
concern
stimulus
=
±
placement
drug groups
somewhat
blocked
p
±
OF
iron deposition
[24,25],
although
which
iron enhances
that activity
ThC-blocked
per treatment
measured
distance
anterior
gitudinal
the
0.97
1.30
SE of 10 measurements
±
tween
ranged
area
after
ATR-blocked
3000
6000
9000
Mean
A’ITENUATION
is the
pre-
of local “irritative”
action
of iron deposited
from
a steel
electrode
[21]. Transient
inneuronal
activity
have been associated
with
TABLE
3. Location
sections
taken from
of stimulation
rats blocked
sites determined
with ATR or THC.
from
serial
Distance
(mm)
brain
Directions
ATR-blocked
THC-blocked
Lateral
Vertical
Caudal
0.53
1.38
-0.09
0.56
1.03
-0.16
#{176}Laterallyfrom 3rd ventricle
daIly (-)
from caudal edge
bMean ±SE of 30 animals.
‘p
<
0.001
vs. ATR-blocked.
±
0b
±
0.06
0.06
±
wall, vertically
from base
of anterior
commissure.
of brain,
±
0.04
±
0.05’
0.05
±
and
cau-
266
1YREY
groups.
A difference
in
vertical
ECS
placement
was
tected,
account
but statistical
adjustment
for that difference
for the difference
in LH response.
Thus,
tential
for
GnRH
neuron
activation,
and
hence
de-
did
the
not
po-
GnRH
re-
lease, should
have been equivalent
for the two drug groups.
The more
limited
effectiveness
of POA stimulation
after mc
treatment
suggests,
action,
is exerted
way. This sets mc
block
the
its release
ing action
inferred
therefore,
that a drug effect,
if not direct
locally
within
the POA-to-pituitary
pathapart
from
AIR and other
drugs
that
That
distinction
for investigation
sive action.
provides
of mechanisms
rons
to GnRI-I
drug
action
to respond
discharge
cholamines
epinephrine
be
envisioned,
if electrolytically
through
but
tion.
an
iron
for
indirect
effect
drocannabinol.
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