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The Role of the 5-HT1B Receptor in the
Therapeutic Effects of Antidepressant Drugs
*
Benge ,
*
Hellstern
Elizabeth
Leanne
& Aileen M. Bailey,
*
+
+
Ph.D. , Angy Kallarackal , Scott Thompson, Ph.D.
*St.
Mary’s College of
+
Maryland;
University of Maryland, Baltimore
Introduction
Results
110
1.6
1.4
100
1.2
Percent Sucrose
Intake (g suc/g body wgt)
Major depression is a pervasive and debilitating mental disorder, the
etiology of which is widely unknown. The most common form of
antidepressant medications include the selective-serotonin reuptake
inhibitors (SSRIs), which increase synaptic serotonin levels. The synaptic
effects of these drugs are immediate but the therapeutic effects are not
experienced for several weeks, suggesting the role of unknown
downstream events in the treatment of depression. The hippocampus
also appears to play a role in depression. Individuals with depression
show decreased hippocampal volume, changes in hippocampal metabolic
activity, and impaired hippocampal dependent memory (Gould et al.,
2007; MacQueen et al., 2003; Mayberg et al., 2000). The CA1 region of
the hippocampus contains a dense population of 5-HT 1B receptors, the
activation of which leads to potentiation of postsynaptic glutamatergic
receptors (Cai et al., unpublished data). The role of 5-HT 1B receptors in
the treatment and etiology of depression is unknown. It appears that they
may mediate the effects of antidepressants by regulating synaptic
serotonin levels when transporters are blocked (Cai et al.). Additionally,
antagonizing 5HT 1B receptors blocks the effects of fluoxetine, suggesting
that they are necessary for the therapeutic effects of antidepressants
(Bailey, unpublished data). Thus, we examined the ability of the 5-HT1B
receptor to mimic the effects of fluoxetine using a social defeat stress
model of depression.
1
0.8
0.6
Control
0
Baseline
Week 1
Week 2
50
Week 3
Baseline
Figure 1. Sucrose intake during the pre-drug
injection phase.
• Significant effect of Time, F (3,27) = 3.39,
p = 0.032.
• No Group effect, F (1,9) = 2.29, p = 0.16.
• Significant interaction, F (3,27) = 4.15,
p = 0.015.
Week 1
Week 2
Control - Saline
1.6
Control - Anpirtoline
0.2
0.1
0
Control - Saline
Control Anpirtoline
SDS - Saline
SDS - Anpirtoline
-0.2
-0.3
-0.4
Intake (g suc/g body weight)
1.4
0.3
Week 3
Figure 2. Sucrose preference during the
pre-drug injection phase.
• Significant effect of Time, F (3,27) =
3.19, p = 0.04.
• No Group effect, F (1,9) = 3.18, p = 0.11.
• No interaction, F (3,27) = 1.21, p > 0.05.
0.5
Absolute Change in Intake
Control
60
0.2
SDS - Saline
1.2
SDS - Anpirtoline
1
0.8
0.6
0.4
0.2
Subjects & Procedures
-0.5
0
-0.6
12 Male C57BL6 mice experienced social defeat stress and received IP
injections of anpirtoline. Seven male CD1retired breeder mice produced
the social defeat stress. All procedures had SMCM IACUC approval.
Week 3
Figure 3. Change in absolute sucrose intake
following the first injection of anpirtoline.
• No Group effect, F (1, 4) = 1.3, p > 0.05.
• No Drug effect, F (1,4) = 0.5, p > 0.05.
• No interaction, F (1,4) = 5.2, p = .08.
Week 4
Week 5
Week 6
Figure 4. Sucrose intake during anpirtoline
administration (weeks 4-6).
• Significant Group effect, F (1, 5) = 13.23,
p =0.015.
• Significant Group x Drug interaction, F (1,5) =
25.16, p = .004
800
Figure 5. Latency to eat food in the noveltysuppressed feeding task.
700
Krishnan & Nestler (2008)
Latency to Eat (sec.)
Social Defeat Stress (SDS). Mice were
individually placed into the home cage of a
CD1 mouse. The animals interacted for 5
minutes. Submissive behavior and the
number of physical attacks were recorded.
After five minutes, a barrier was placed
between the mice and they remained
separated for an hour. Control animals were
placed in a neutral cage with a non-cage
mate C57Bl6 mouse separated for one
hour. SDS continued 6 times a week for 6
weeks.
70
SDS
0.4
Method
80
SDS
0.4
-0.1
90
600
500
• No effect of Group, F (1,6) < 1, p >0.05.
400
300
•No effect of Drug, F (1,6) < 1, p > 0.05.
200
100
0
Control - Saline
Sucrose Preference Test (SPT). SPT was used to measure anhedonia in
the test mice. All C57Bl6 mice were deprived of food and water for 9
hours. The mice were then separated into individual cages and each
given one previously weighed bottle of water and one previously weighed
bottle of 2% sucrose solution. After 15 hours, the mice were returned to
their home cages and given free access to food and water. The
discrepancy in the pre- and post- test bottle weights, indicating amount of
consumption, and preference for sucrose, were recorded once per week.
Novelty-Suppressed Feeding Test. Testing was completed in a 60x60x28
cm open field during the light phase. Food and water were removed from
the C57BL6 mice’s cages for 24 hours before the test. A pellet of regular
chow was placed in the middle of the open field. Animals were individually
placed in the lower left corner of the open field. Latency to chew the pellet
was recorded. Once the mouse began chewing, the food pellet was
removed and the animal was placed in a home cage where a new,
weighed food pellet was placed. After five minutes and again after 10
minutes, the food was weighed to determine the amount consumed.
Control - Anpirtoline
SDS - Saline
SDS - Anpirtoline
•No Group x Drug interaction, F (1,6) = 1.1, p >
.05.
Conclusions
• Prior to anpirtoline injections, the SDS and control animals did not differ in sucrose preference
or sucrose intake.
• Anpirtoline did not produce any acute changes in sucrose intake.
• SDS animals developed a significant decrease in sucrose intake following 5 weeks of social
defeat stress (see Figure 4). SDS animals given anpirtoline (M = 1.24, SD = .1) show a
significantly higher sucrose intake than SDS animals given saline (M = .52, SD = .02) at week
5, t (3) = 11.99, p = .002.
• Novelty-suppressed feeding is a known hippocampal dependent task. Although no significant
differences were found, the means in the SDS animals mimic those found in other studies
investigating the effects of chronic stress in animals.
References
Drug Injections. Half of the C57BL6 mice received IP injections of
anpirtoline (1mg/kg), a 5-HT1B receptor agonist. The remaining mice
received IP injections of saline. Injection quantities were calibrated based
on the individual animal’s weight. Injections were given twice a day, once
at 9:00am and once at 5:00pm, daily for three weeks.
• Bailey & Gaylor (unpublished data). The Role of 5-HT1B receptors in the therapeutic action of antidepressant drugs.
• Cai, X., Kallarackal, A.J., Lee, H., Huganir, R.L., & Thompson, S.M. (under review). Selective potentiation of TA-CA1 excitatory
synapses by serotonin and its deregulation in depression.
• Gould, et al. (2007). American Journal of Psychiatry, 164, 516-519.
• Krishnan, V., & Nestler, E. (2008). The Molecular neurobiology of depression. Nature, 455, 894-902.
• MacQueen et al. (2003). Proceedings of the National Academey of Sciences of the United States of America, 100(3), 1387-1392.
• Mayberg et al. (2000). Neuropharmacology, 43, 1230-1237.