Date of Award
Master of Arts in Psychological Science
First Reader/Committee Chair
Serotonin has been found to regulate several cognitive and physiological functions, and its role in depression and other neuropsychiatric disorders has been a focus of research. More specifically, a wealth of research regarding serotonin focuses on serotonergic medications in the treatment of neuropsychiatric disorders, such as depression and anxiety, and stimulates the 5-HT1A and 5-HT1B receptors. Within the last decade, there has been an increase in prescriptions of psychotropic medication for children, however, the efficacy and adverse effects of these drugs have not been evaluated in younger populations. While antidepressants reduce symptoms of depression in adults, they are less effective in reducing symptoms in children, and can result in an increased risk of suicidal behavior or ideation, social impairments, and substance abuse. For this reason, there is an urgent need to better understand how the 5-HT1A, and 5-HT1B receptors work in different age groups to find treatments that are efficacious in pediatric populations. RU 24969 is a preclinical serotonergic drug that binds to the serotonin 5-HT 1A and 5-HT1B receptors, that possesses antidepressant qualities in animal models. Therefore, the purpose of the present study was to investigate whether RU 24969 treatment is unique to this preclinical drug or if it is primarily mediated by the stimulation of the 5-HT1A, 5-HT1B, or both receptors. A total of 128 male and 128 female Sprague-Dawley rats were used for this study. In examining the single-trial effects of each drug, Experiment 1A: rats were pretreated with saline (n = 32) or 0.1, 0.2, 0.4, or 0.8 mg/kg 8-OH-DPAT. After a 24 hr abstinence period, rats previously treated with saline received 0.1, 0.2, 0.4, or 0.8 mg/kg 8-OH-DPAT (n = 8 per group). Subjects initially treated with 8-OH-DPAT were injected with the same dose of 8-OH-DPAT again (n = 8 per group). In Experiment 1B: The procedure was identical to Experiment 1A, except higher doses of 8-OH-DPAT (1, 2, 4, or 8 mg/kg) were administered on PD 20 and PD 22. In Experiment 2: The procedure was identical to Experiment 1A, with the exception that CP 94253 (2.5, 5, 10, or 20 mg/kg) was administered instead of 8-OH-DPAT. In Experiment 3: rats were injected with saline or the combined treatment of 4 mg/kg 8-OH-DPAT plus 5 mg/kg CP 94253. Experiment 4: In examining the repeated effects of each drug during a PD 17–20 pretreatment phase, rats were injected with saline (n = 24) or 4 mg/kg 8-OH-DPAT, 5 mg/kg CP 94253, or DPAT+CP (n = 8 per drug group) and immediately placed in activity chambers. On PD 22, rats previously administered saline were injected with 8-OH-DPAT, CP 94253, or DPAT+CP (n = 8 per group), whereas rats initially given one of the drug treatments were given the same drug treatment again (n = 8 per group). Distance traveled and motoric capacity were measured during each 45-minute session, while axillary temperatures were measured immediately after each session. Our findings revealed (across all experiments), all drug groups (8-OH-DPAT, CP 94253, and DPAT+CP) increased locomotor activity and caused hypothermia on the first pretreatment day. In our single-trial studies (Experiments 1-3), only 8-OH-DPAT and CP 94253 caused tolerance to the hypothermic effects. Additionally, CP 94253 causes tolerance to motoric impairment, while DPAT+CP causes a sensitized motoric impairment. When given repeatedly (Experiment 4), 8-OH-DPAT caused locomotor sensitization and tolerance to axial temperatures. CP 94253 caused tolerance to locomotor activity and axial temperatures. Lastly, DPAT+CP caused locomotor sensitization and tolerance to axial temperatures. In summary, the effects observed through single and multi- trial paradigms with the direct agonists 8-OH-DPAT and CP 94253 administered alone and in combination differ from the mixed agonist RU 24969. This suggests that therapeutic effects observed with RU 24969 treatment are unique and may possibly stimulate receptors that are still undiscovered.
Taylor, Jordan, "REPEATED TREATMENT WITH 5-HT1A AND 5-HT1B RECEPTOR AGONISTS: EVIDENCE OF TOLERANCE AND BEHAVIORAL SENSITIZATION" (2023). Electronic Theses, Projects, and Dissertations. 1797.
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