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Department of Psychology (T.D., K.T.N., A.L.E., L.R.W., R.L.S., S.F.M.), University of Colorado, Boulder, Colorado 80309-0345; Clinical Neuroendocrinology Branch (J.L., M.-L.W., P.W.G.), National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1284; and Developmental Neuroendocrinology Branch (G.P.C., E.W.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1284
Address all correspondence and requests for reprints to: Terrence Deak, Campus Box 345, Department of Psychology, University of Colorado, Boulder, Colorado 80309-0345. E-mail: tdeak{at}clipr.colorado.edu
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Abstract |
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-helical CRH attenuates conditioned fear responses, we sought
to test antalarmin in this regard. In addition, it remains unclear as
to whether this is a result of receptor blockade during conditioning or
during testing. Thus, we explored whether CRH mediates the induction or
expression of conditioned fear (freezing in a context previously
associated with 2 footshocks; 1.0 mA, 5 sec each). Furthermore, because
rats previously exposed to inescapable shock (IS; 100 shocks, 1.6 mA, 5
sec each), demonstrate enhanced fear conditioning, we investigated
whether this effect would be blocked by antalarmin. Antalarmin (20
mg/kg·2 ml ip) impaired both the induction and expression of
conditioned fear. In addition, antalarmin blocked the enhancement of
fear conditioning produced by prior exposure to IS. Despite the marked
behavioral effects observed in antalarmin-treated rats, antalarmin had
no effect on IS-induced rises in ACTH or corticosterone. However,
antalarmin did block the ACTH response produced by exposure to 2
footshocks. |
Introduction |
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-helical CRH9–41 and D-Phe CRH12–41,
can blunt or block these stress-induced alterations in behavior and
autonomic activity (12, 13, 14, 15). Many of these effects can be obtained by
infusing CRH or it’s antagonists into nonhypothalamic sites, such as
the locus coeruleus and amygdala (16, 17, 18, 19), and these effects
persist in hypophysectomized and dexamethasone-treated subjects (12).
These facts, together with the wide extrahypothalamic distribution of
high-affinity CRH receptors (20, 21) and CRH-like immunoreactivity
(22, 23, 24), suggest that CRH functions as a neurotransmitter, as well as
a hormone, and that it mediates stress-related behavioral responses by
action at extrahypothalamic sites (25, 26). The critical role of brain CRH in mediating stress-related phenomena (along with the possible importance of brain CRH) in a number of human disorders, such as depression, posttraumatic stress disorder, and bulimia (27, 28, 29, 30), has motivated the recent development of a nonpeptide CRH receptor antagonist capable of readily crossing the blood-brain barrier. The compound, first synthesized by Chen (31), is a pyrrolopyrimidine and has been called CP-154,526 (32) and antalarmin (33). It has high affinity for the CRH receptor, with selectivity for the Type 1 receptor, CRHR-1. The compound, here to be called antalarmin, blocked or blunted the effects of CRH on adenylate cyclase in membranes from rat cortex and pituitary, plasma ACTH increases in response to iv CRH, locus coeruleus electrical activity in response to icv CRH, and the potentiation of the startle reflex by icv CRH (32). In addition, antalarmin blunted the increase in startle produced by a light that had been paired with footshock (32) and a carageenin-induced sc inflammation (33).
The purpose of the present experiments was both to further explore the
effects of this nonpeptide CRH antagonist and to investigate the role
of CRH in several phenomena. One phenomenon was fear conditioning. The
term fear conditioning refers to the fact that both discrete and
contextual cues that are present during exposure to a stressor such as
footshock come, themselves, to elicit behavioral and physiological
responses, such as freezing, inhibited appetitive behavior, potentiated
startle, increased autonomic, HPA activity, etc. (34). Brain CRH
systems have been shown to be important in mediating the fear responses
observed in fear-conditioning experiments. Rats and other organisms
freeze when placed in an environment in which they have previously
received an aversive stimulus, such as footshock; and freezing has been
shown to be a measure of fear conditioned to the environment by the
aversive stimulus (35). It is to be noted that freezing is not simply
an absence of movement but rather an active defensive response
consisting of no movement beyond that required for respiration
(including the absence of vibrissae movement), typically accompanied by
a hunched posture and muscular rigidity. icv -helical CRH reduced
the freezing that occurred when rats were exposed to the environment in
which they had previously received footshock (24 h earlier) (36), as
well as the potentiation of startle produced by a light that had
previously been paired with shock (15). In these experiments, the CRH
antagonist was administered before the behavioral testing, rather than
before the fear conditioning (the exposure to shock in the apparatus,
the pairing of the light with shock), which occurred 24 h or more
earlier. Thus, it is clear that CRH receptor blockade reduces the
expression of fear, but it is not known whether it would blunt the
conditioning or development of the conditioned fear. One purpose of the
present experiments was to determine whether the effect reported by
Kalin and Takahashi (36), using -helical CRH, would be duplicated by
antalarmin. An additional goal was to determine whether antalarmin
would reduce the development of conditioned fear and its
expression.
A second phenomenon explored was learned helplessness. This term refers to the fact that rats and other organisms, exposed to inescapable (uncontrollable) shock (IS), later fail to learn to escape in a different environment in which escape is possible, whereas animals originally exposed to exactly equal amounts and intensities of escapable shock (controllable), later learn normally (37). Exposure to IS also leads to potentiated fear conditioning in a different environment 24 h later (38). The potential involvement of CRH in these phenomena has not been studied, but it is of interest because the IS paradigm and the behavioral sequelae that occur have been argued to constitute an animal model of depression (39).
Finally, the ability of antalarmin to blunt the pituitary-adrenal response to stressors has not been previously explored. Antalarmin has been shown to blunt ACTH and corticosteroid (CORT) responses to CRH administration, but its efficacy, with regard to stressors, is unknown. This was also tested in the present experiments.
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Materials and Methods |
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Drug
Antalarmin was dissolved in a sterile, lipid soluble fat
emulsion (Liposyn II, Abbott Laboratories , Chicago,
IL) and was administered ip (20 mg/kg·2 ml). Two hours before
experimentation, rats were injected with antalarmin or equivolume
vehicle.
Procedures
Fear conditioning. During fear conditioning, subjects were
individually placed in shuttleboxes measuring 46.0 x 20.7 x
20.0 cm. The end walls were aluminum, and the sidewalls and tops were
clear Plexiglas. The floor was constructed of stainless steel rods, 0.3
cm in diameter and spaced 1.4 cm apart. An aluminum wall, with a
5.5 x 7.5 cm archway cut out of it, divided the shuttleboxes into
two equal compartments. The shuttleboxes were housed within sound- and
light-attenuating enclosures equipped with a ventilation fan and a 28-V
houselight. The front of each enclosure was left open during behavioral
observation. Scrambled shocks were delivered to the grid floors by
shockers modeled after the Grason Stadler Model 700. During the fear
conditioning session, the subjects were first allowed a 5-min
acclimatization period in the shuttleboxes. This was followed by two
5-sec shocks of 1.0 mA in intensity. There was 1 min between the two
footshocks. The subjects were removed from the shuttleboxes 30 sec
after the last shock.
Testing for the amount of fear conditioned to the cues of the shuttleboxes occurred 24 h later. The rats were placed in the shuttleboxes, and freezing was assessed for 20 min. The experimenter observed each rat, every 8 sec to a signal, and scored it as freezing or not freezing. To be scored as freezing, a rat had to have all four paws on the grids, and there had to be an absence of all movement of the body and vibrissae beyond that required for respiration. The experimenter was always unaware of group membership. Interrater reliability on this measure is greater than .90.
Blood sampling procedure
If blood samples were taken after conditioning or testing, the
rat was removed from the apparatus and gently restrained in a towel. If
blood samples were to be taken during the IS session, a tail nick was
made without disturbing the subject, because it’s tail protruded from
the rear of the apparatus. A small nick was made in a lateral tail vein
with a scalpel (no. 15 blade), and the tail was gently stroked until a
volume of approximately 300–400 µl of whole blood was obtained in
microfuge tubes precoated with EDTA. All samples taken from animals in
their home cages were obtained within 2 min of approaching the cage.
Samples were spun in a refrigerated centrifuge immediately, and plasma
was aliquoted and stored at -20 C until the time of assay.
IS
ISs were administered while the subjects were restrained in
Plexiglas tubes, 17.5 cm long and 7.0 cm in diameter. The rat’s tail
extended from the rear of the tube and was taped to a plexiglas rod.
Shock was administered to the tail through fixed electrodes and was 1.6
mA in intensity. One hundred 5-sec shocks were administered on a
variable intertrial interval ranging from 30–90 sec. These are the
minimal parameters necessary to produce learned helplessness effects
(40).
Fear and escape testing after IS
Twenty-four hours after IS or control treatment, the subjects
were placed in shuttleboxes as described above. Freezing was measured
for 10 min. The subjects then received 2 escapable footshocks in the
shuttleboxes in which each shock could be terminated by the rat’s
crossing to the other compartment. Shock intensity was 0.8 mA. There
was 1 min between the shocks. Freezing was then measured for 20 min, as
described above. This was followed by 3 further escape trials requiring
a single crossing of the shuttleboxes (FR-1). These trials were then
followed by 25 trials that required a back-and-forth crossing of the
shuttleboxes (FR-2) to terminate footshock. It is these FR-2 trials
that typically reveal an IS-induced escape deficit (e.g.
Ref. 41). Shocks terminated automatically after 30 sec if an escape
response had not occurred.
Assays
ACTH. Plasma levels of ACTH were determined by RIA,
according to the procedure outlined by INCSTAR Corp.
(catalog no. 24130; Stillwater, MN).
Corticosterone
Total plasma CORT levels were measured by RIA using rabbit
antiserum (antibody B21–42; Endocrine Sciences, Inc.,
Tarzana, CA). This antiserum has very low cross-reactivity with other
glucocorticoids and their metabolites. The assay sensitivity was 1
µg/dl.
Interassay and intraassay coefficients of variation for both ACTH and CORT were all less than 9%.
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Results |
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The results are shown in Fig. 1
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group that had not received shock on day 1 (No Shock-Veh/Veh) provides
a baseline of freezing against which to assess fear conditioning.
Clearly, there was virtually no freezing in the apparatus unless shock
had been given the previous day. The two footshocks conditioned a large
amount of fear to the cues of the apparatus. The maximun freezing score
possible is 15 (freezing was observed every 8 sec, and the data are
presented in 2-min blocks), and the Shock-Veh-Veh group showed maximal
freezing, which extinguished over the 20-min testing period. Antalarmin
produced a potent reduction of the conditioning, both when given before
the footshock session on day 1 and when administered before the day-2
test. Further, these effects summated, so that the most potent
reduction occurred in the group (Shock-Ant/Ant) that had received
antalarmin before both conditioning and testing. These conclusions are
confirmed by ANOVA [F(4, 35) = 17.1293, P <
0.0001].
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There was no observable freezing before the shocks in the shuttlebox;
and so, data from before the first shock are not shown. Figure 2a shows freezing for the 20-min testing
period. There was conditioning of fear in all of the groups. A
comparison of the group given prior IS and vehicle (Shock-Veh) with the
group that remained in their home cage on day 1 and received vehicle
(No Shock-Veh) indicates the typical potentiation of fear conditioning
by prior IS. Antalarmin eliminated this potentiation, as well as
reducing the overall level of fear conditioning, as in the prior
experiment [F(1, 27) = 10.459, P <
0.01].
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As in previous experiments (42), IS did not alter escape responding
when only a single crossing of the shuttlebox was required. However, a
large escape deficit appeared on the double-crossing (FR-2) trials
[F(1, 26) = 46.447, P < 0.0001]. The maximum possible
latency was 30 sec, and the 20-sec latencies that occurred were
produced by the majority of animals that had received IS failing
completely to escape. Antalarmin had no effect whatsoever on either the
escape deficit produced by IS or on escape behavior in control subjects
[F(4,104) = .510, P > 0.05]. Escape proceeded
normally.
CORT after IS
Blood samples were collected, as described in Subjects and
Methods, from the animals in the above experiment before IS,
immediately after the shock session, 60 min later, and 24 h later
(before the shuttlebox test). Plasma CORT levels are shown in Fig. 2c.
The IS produced a large increase in CORT, which was still present, in
reduced magnitude, 60 min later. Antalarmin showed no tendency to blunt
this CORT response [F(3,81) = 0.6, P > 0.05].
ACTH and CORT during the IS session
Numerous explanations for the failure of antalarmin to blunt the
CORT response after IS are possible. One hundred inescapable tailshocks
is a very potent stressor, and a ceiling effect may have prevented an
effect from being detected. In addition, ACTH has often been argued to
be a more sensitive measure of HPA activation. Thus, in the next
experiment, ACTH and CORT were measured from blood samples taken after
5, 50, and 100 shocks, as well as 30 min after the session. Because the
subject’s tail protrudes from the rear of the tube, repeated samples
can be readily obtained. In terms of controls, HCC would be
problematic, because they would have to be repeatedly removed from
their cages for blood sampling. The controls here were instead confined
to the loose restraining tubes in which the ISs are administered. This
was done in the animal’s colony rooms to minimize disturbance. We have
found that this loose restraint during the inactive part of the rats
light-dark cycle in the colony rooms produces little or no ACTH or CORT
increase. Baseline values were obtained 2 days before the experiment.
Four groups were employed. Two were restrained and 2 received ISs. One
of each was given antalarmin, 120 min before treatment; and one of each
received vehicle.
Figure 3a shows that ACTH values did
indeed remain at baseline in the restrained controls. ACTH was elevated
after 5 shocks, reached maximum by 50 shocks, remained at this level at
100 shocks, and was still elevated 30 min later. Antalarmin had no
effect on ACTH in controls. Antalarmin did not reduce the ACTH response
to IS, even after only 5 shocks. Furthermore, an effect of antalarmin
did not emerge 30 min after treatment, at which point the ACTH values
were submaximal [F(4,84) = 0.566, P > 0.05]. The
results for CORT (Fig. 3b) mirror those for ACTH [F(4,84) = 0.998,
P > 0.05].
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) was increased by
the 2 footshocks, relative to merely being placed in the apparatus
(comparison of Shock-Veh/Veh with No shock-Veh/Veh). Antalarmin given
before the footshock session did blunt the ACTH response to the
footshocks and, indeed, brought ACTH to control levels [F(2, 22) =
9.7464, P < 0.001]. A similar pattern was also
observed for CORT; however, this trend was not significant
(P > 0.05). No reliable conditioned increase in ACTH
or CORT was observed on day 2; and so, any effect of antalarmin could
not be examined (data not shown). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-helical CRH, antalarmin reduced
the freezing that occurred when the subjects were placed into the
environment in which footshocks had occurred 24 h earlier. This
freezing is generally regarded as a reflection of fear conditioned to
the contextual cues of the shock environment because it only occurs if
the organism has been previously shocked in that particular environment
(35). Freezing does not occur if the rat has been shocked in a
different environment. Thus, the present results suggest that
antalarmin is capable of interfering with the expression of fear that
has been conditioned to a set of contextual environmental cues. The present data extend knowledge concerning CRH systems by revealing that blockade of CRH receptors with antalarmin interferes with the development of fear conditioning, as well as with the expression of fear. Antalarmin given before fear conditioning, rather than before the later testing, reduced the fear measured 24 h later. Prior studies have not separated these two possibilities because CRH antagonists have typically been administered before the testing, rather than before the stressor. Furthermore, in those few experiments in which a CRH antagonist was given before the stressor, the behavioral testing occurred immediately or very soon after the stressor (43). Thus, CRH receptors were occupied by the antagonist, during both the stressor and the behavioral testing for fear; and so, the impact of the drug on the conditioning process itself could not be assessed. In the present experiment, subjects who had been given antalarmin before the footshocks showed diminished freezing when exposed to the shock environment 24 h later. It might be noted that these results also counter the argument that the drug merely inhibits freezing itself rather than influencing fear, because here the drug was not present when freezing was measured.
It might be argued that antalarmin did not interfere with the fear
conditioning process per se, but rather reduced the
aversiveness of the footshocks. If the footshocks were experienced as
less aversive, then of course reduced freezing would be expected to
develop to the environmental cues present. Indeed, there is very little
prior research directed at measurement of whether CRH antagonists alter
the unconditioned aversiveness of noxious stimuli, in addition to
blunting the organisms’s emotional reaction to the stimulus. The
aversiveness of a stimulus is generally assessed by measuring the
organism’s propensity to escape from the stimulus. Escape from
footshock was studied in the present experiments, and antalarmin had no
impact whatsoever on the escape responding to footshock measured in a
shuttlebox. Rats that had been administered the very same dose of
antalarmin before shuttlebox escape testing as was used in the fear
conditioning study escaped with normal latencies on both the
single-crossing and double-crossing trials. If the drug reduced the
aversiveness of the footshocks, then escape responding should have been
slowed. In fact, the results were (nonsignificantly) in the other
direction. Consistent with the finding that antalarmin failed to alter
responsivity to footshock, as assessed by escape behavior, icv
-helical CRH has been reported to have no effect on pain thresholds
(44). There is thus no support for the possibility that antalarmin
interfered with the development of freezing to the contextual cues in
which footshock occurred because it reduces the aversiveness of
footshock. Rather, antalarmin would seem to have acted on the fear
conditioning process itself.
Peripherally administered antalarmin has access to CRH receptors in
both the periphery and brain. However, it is not likely that the
reduction in fear produced by antalarmin was mediated by action on the
pituitary-adrenal system. This is because: 1) peripheral
immunoneutralization of CRH does not reduce fear behavior to stressors
(45); 2) inhibition of pituitary-adrenal responses to CRH by
dexamethasone does not blunt the behavioral changes produced by icv CRH
(12); and 3) icv -helical CRH sufficient to blunt fear responses to
stressors does not reduce the pituitary-adrenal response to the same
stressor (46).
The amygdala plays a key integrative role in both the development of fear conditioning and the expression of fear-related behavior. Lesions in basolateral regions of the amygdala (47) or microinjection of N-methyl-D-aspartate (NMDA) antagonists (48) in this region prevent the development of fear conditioning. In contrast, infusion of NMDA antagonists into the central nucleus of the amygdala does not retard fear conditioning (48). However, NMDA antagonists, injected either into the amygdala (49) or icv (50), have no effect on the expression of fear that has been previously conditioned. Lesions of the central nucleus, however, block the expression of fear conditioning (47). This pattern of data has led to the view that the association between the sensory cues that precede the stressor and the stressor itself are formed in basolateral regions of the amygdala and critically involves NMDA receptors. The information then flows to the central nucleus of the amygdala, which functions in the expression of fear as a final common path to initiate the behavioral and physiological manifestations of fear (34). NMDA receptors do not seem to play a role in this central nucleus expression mechanism.
The amygdala contains CRH immunoreactive cells and fibers (51), and
both the type 1 and type 2 CRH receptors are widely distributed in both
the basolateral region and central nucleus (52). Exposure to a stressor
has been reported to increase CRH mRNA in the amygdala (53), and
microinjection of -helical CRH into the central nucleus decreases
the expression of conditioned fear (43), as well as other
stressor-induced behavioral changes (46). Thus, previous research has
implicated NMDA-related processes in the basolateral amygdala in the
development (but not expression) of fear conditioning, and CRH in the
central nucleus, in the expression of fear. The potential role of CRH
in the development of fear conditioning has not been explored. The
present results suggest that CRH is important in both development and
expression of conditioned fear, and it would be of interest to
determine whether the critical site of CRH action in the development of
fear is the basolateral amygdala.
The impact of CRH antagonists on the behavioral consequences of IS has only recently received attention. Mansbach et al. (54) have recently demonstrated that CP-154,526 (antalarmin) blocked the escape deficit produced by prior exposure to inescapable footshock. The present data are clearly not in accord with those of Mansbach et al. (54). In fact, antalarmin had no effect whatsoever on the escape deficits produced by IS in the present experiment, despite the fact that the dose used here was in a dose range comparable with that of Mansbach et al. (54). This discrepancy may be a result of procedural differences between the two studies. Mansbach’s group induced learned helplessness by exposing rats to inescapable footshocks on 3 consecutive days and tested for escape deficits with footshock in the same chamber on the 4th day. On the other hand, the present experiment induced learned helplessness by a single exposure to inescapable tailshock, and escape responding was assessed in a novel environment 24 h later. Learned helplessness is not the only potential cause of poor escape learning; and so, the escape deficits observed by Mansbach et al. and the present studies may reflect different phenomena. Learned helplessness is generally inferred as the cause of poor escape learning, using some protocol or procedure only after the demonstration that the poor escape learning follows inescapable (uncontrollable) but not escapable (controllable) shock. Such sensitivity to stressor controllability has been demonstrated with the procedures and parameters used here (38, 42, 55) but has not been reported for the procedures and parameters used by Mansbach et al. (54). For example, habituation to footshock could also produce poor escape responding to footshocks when the rats are then tested in the same apparatus. The inescapable nature of the footshocks would increase the likelihood of this possibility.
In addition to escape responding, fear conditioning after exposure to two footshocks was also assessed in the present experiments. It has been shown that freezing, measured immediately after footshock, reflects fear conditioned to the contextual cues by the footshocks, not a reaction to the shock itself (50). Consistent with the fear-conditioning experiment, antalarmin reduced the freezing observed after the two footshocks in control subjects. As in prior research, exposure to IS potentiated the fear conditioning occurring 24 h later. Antalarmin also blocked this potentiation of fear conditioning. The HCC and IS groups that had been given antalarmin did not differ, indicating that the potentiation of fear produced by IS was blocked. It is not possible to determine whether the critical point of drug action was during the IS, during the fear conditioning, or both.
Interestingly, antalarmin did not even slightly reduce the deficit in escape learning produced by prior IS, even though the drug was given before both IS and shuttlebox escape testing and reduced fear in the same subjects. This suggests that the IS-produced escape failure is mediated by a mechanism fundamentally different from fear and the potentiation of fear, one that does not involve CRH as a critical element. Of course, it is possible that a larger dose might have been effective, but the dose used potently reduced fear and was already far in excess of minimally effective dosage (32). Consistent with the present data, lesions of basolateral and central nuclei of the amygdala have produced the same pattern as did antalarmin (blockade of fear but not the escape deficit) (42). Thus, the mechanism responsible for escape deficits after IS would seem to be independent of the amygdala and CRH. Furthermore, escape itself was not influenced by antalarmin, suggesting some specificity with regard to stressor actions. Amygdala lesions also do not interfere with escape behavior (42); and so, CRH involvement in behavioral sequelae of stressors may be restricted to behaviors that are, at least partly, mediated by the amygdala. Indeed, the potential clinical usefulness of antalarmin may be enhanced by its specificity and failure to interfere with escape behavior, an outcome that might be undesirable.
Although antalarmin blocked one of the behavioral effects of IS, it had no detectable impact on the ACTH or CORT response to IS. It is perhaps not surprising that antalarmin did not reduce CORT or ACTH measured at the end of the IS session. Although CRH is thought to be the major secretagogue in stimulating ACTH secretion in response to stressors, arginine vasopressin (AVP), catecholamines, and possibly other factors also play a role (56). Perhaps 100 ISs is a stressor that is sufficiently potent, so that these other secretagogues drive the system to its maximum, leaving CRH receptor blockade ineffective. However, antalarmin did not reduce the ACTH or CORT response measured after only 5 ISs, nor did it alter the time course of recovery after the IS session. It cannot be argued that antalarmin is simply ineffective in regulating the pituitary-adrenal response to stressors, because the ACTH increase produced by two footshocks was prevented by the drug. Whether the critical determinant was the number of shocks, type of shocks, etc., cannot be determined from the present data. Although it has most frequently been argued that AVP plays a secondary role, potentiating the actions of CRH (57), there is increasing evidence that AVP and CRH production and release from parvocellular neurons within the PVN are under independent regulation (58). Thus, it is possible that, under certain circumstances, AVP may play a dominant role in mediating the pituitary-adrenal response to stressors.
In sum, the peripheral administration of antalarmin produced effects consistent with it’s ability to cross the blood-brain barrier. Both stress-induced behavioral changes that are mediated by central CRH receptors, as well as pituitary-adrenal responses that are mediated by peripheral CRH receptors, were blunted. The present results also further support the notion that there is considerable selectivity in the mechanisms that mediate both the behavioral and the endocrine consequences of stressor exposure.
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Acknowledgments |
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Footnotes |
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Received April 14, 1998.
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