The Role of the 5-HT 1B Receptor in the Therapeutic Effects of Antidepressant Drugs

1. The Role of the 5-HT1B Receptor in the Therapeutic Effects of Antidepressant Drugs Elizabeth Benge*, Leanne Hellstern* & Aileen M. Bailey, Ph.D.*, Angy Kallarackal+, Scott Thompson, Ph.D.+ *St. Mary’s College of Maryland;+ University of Maryland, Baltimore Introduction 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5-HT 1B receptors, the activation of which leads to potentiation of postsynaptic glutamatergic receptors (Cai et al., unpublished data).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the effects of fluoxetine, suggesting that they are necessary for the therapeutic effects of antidepressants (Bailey, unpublished data).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. Results • 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. • 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. Method Subjects & Procedures 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. • 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. • 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 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. • Figure 5. Latency to eat food in the novelty-suppressed feeding task. • No effect of Group, F (1,6) < 1, p >0.05. • No effect of Drug, F (1,6) < 1, p > 0.05. • No Group x Drug interaction, F (1,6) = 1.1, p > .05. Krishnan & Nestler (2008) 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. 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. • 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 • 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.