Safety and Efficacy of Combined Low-Dose Lithium and Low-Dose Aspirin: A Pharmacological and Behavioral Proof-of-Concept Study in Rats

doi:10.3390/pharmaceutics13111827

. 2021 Nov 1;13(11):1827.

doi: 10.3390/pharmaceutics13111827.

Safety and Efficacy of Combined Low-Dose Lithium and Low-Dose Aspirin: A Pharmacological and Behavioral Proof-of-Concept Study in Rats

Rachel Shvartsur^{1

2}, Galila Agam², Alla Shnaider³, Sarit Uzzan², Ahmad Nassar², Adi Jabarin², Naim Abu-Freha⁴, Karen Meir⁵, Abed N Azab^{1

2}

Affiliations

¹ Department of Nursing, School for Community Health Professions, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel.
² Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel.
³ Department of Nephrology, Soroka University Medical Center, Beer-Sheva 84101, Israel.
⁴ The Institute of Gastroenterology and Hepatology, Soroka University Medical Center, Beer-Sheva 84101, Israel.
⁵ Department of Pathology, Hadassah Medical Center and Faculty of Medicine, The Hebrew University, Jerusalem 91120, Israel.

PMID: 34834241
PMCID: PMC8619680
DOI: 10.3390/pharmaceutics13111827

Safety and Efficacy of Combined Low-Dose Lithium and Low-Dose Aspirin: A Pharmacological and Behavioral Proof-of-Concept Study in Rats

Rachel Shvartsur et al. Pharmaceutics. 2021.

. 2021 Nov 1;13(11):1827.

doi: 10.3390/pharmaceutics13111827.

Authors

Rachel Shvartsur^{1

2}, Galila Agam², Alla Shnaider³, Sarit Uzzan², Ahmad Nassar², Adi Jabarin², Naim Abu-Freha⁴, Karen Meir⁵, Abed N Azab^{1

2}

Affiliations

¹ Department of Nursing, School for Community Health Professions, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel.
² Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel.
³ Department of Nephrology, Soroka University Medical Center, Beer-Sheva 84101, Israel.
⁴ The Institute of Gastroenterology and Hepatology, Soroka University Medical Center, Beer-Sheva 84101, Israel.
⁵ Department of Pathology, Hadassah Medical Center and Faculty of Medicine, The Hebrew University, Jerusalem 91120, Israel.

PMID: 34834241
PMCID: PMC8619680
DOI: 10.3390/pharmaceutics13111827

Abstract

Despite established efficacy in bipolar disorder patients, lithium (Li) therapy has serious side effects, particularly chronic kidney disease. We examined the safety and behavioral effects of combined chronic low-dose aspirin plus low-dose Li in rats to explore the toxicity and therapeutic potential of this treatment. Rats were fed regular or Li-containing food (0.1% [low-dose, LLD-Li] or 0.2% [standard-dose, STD-Li]) for six weeks. Low-dose aspirin (1 mg/kg) was administered alone or together with Li. Renal function and gastric mucosal integrity were assessed. The effects of the combination treatment were evaluated in depression-like and anxiety-like behavioral models. Co-treatment with aspirin did not alter plasma Li levels. Chronic STD-Li treatment resulted in significant polyuria and polydipsia, elevated blood levels of creatinine and cystatin C, and increased levels of kidney nephrin and podocin-all suggestive of impaired renal function. Aspirin co-treatment significantly damped STD-Li-induced impairments in kidney parameters. There were no gastric ulcers or blood loss in any treatment group. Combined aspirin and LLD-Li resulted in a significant increase in sucrose consumption, and in the time spent in the open arms of an elevated plus-maze compared with the LLD-Li only group, suggestive of antidepressant-like and anxiolytic-like effects, respectively. Thus, we demonstrate that low-dose aspirin mitigated the typical renal side effects of STD-Li dose and enhanced the beneficial behavioral effects of LLD-Li therapy without aggravating its toxicity.

Keywords: aspirin; bipolar disorder; inflammation; lithium; nephrotoxicity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Li blood levels in aspirin + Li-treated rats. Rats were fed regular food (control) or Li-containing food [0.1% (LLD-Li), 0.2% (STD-Li)] for 42 days. Low-dose ASA (1 mg/kg, ip) was administered alone or together with Li. Blood was collected on days 0 and 42 of treatment, plasma separated, and Li levels determined as described in Materials and Methods. Li levels were undetectable in all groups on Day 0 and thus are not presented in the Figure. Results are the means ± SEM of a single representative experiment out of two demonstrating a similar pattern with 9–12 rats per group in the depicted experiment. * p < 0.0001 vs. Control, # p < 0.0001 vs. LLD Li. Two-way ANOVA: ASA effect: F_1,59 = 0.1849, p = 0.6687; Li effect: F_2,59 = 328.6, p < 0.0001; aspirin x Li interaction: F_2,59 = 0.1608, p = 0.8519. Post hoc Fisher’s LSD: Control vs. LLD-Li or STD-Li—p < 0.0001, LLD-Li vs. STD-Li—p < 0.0001, LLD-Li vs. LLD-Li + ASA—p = 0.4687, STD-Li vs. STD-Li + ASA—p = 0.9644. Abbreviations: ASA—acetylsalicylic acid, LLD—low-low dose, Li—lithium, STD—standard dose, UD—undetectable.

**Figure 2**
Water consumption and urinary output in aspirin + Li-treated rats. Rats were fed regular food (control) or lithium-containing food [0.1% (LLD) or 0.2% (STD)] for 42 days. Low-dose aspirin (1 mg/kg, ip) was administered alone or together with Li. At indicated days, 24 h water consumption (a,b) and urinary output (c,d) were measured as described in Materials and Methods. Results are means ± SEM of a single representative experiment out of two demonstrating a similar pattern with 9–12 (day 21) or 6 (day 42) rats per group in the depicted experiment. (a) Water consumption day 21, two-way ANOVA: ASA effect, F_1,59 = 7.938, p = 0.007; Li effect, F_2,59 = 635.4, p < 0.0001; aspirin x Li interaction, F_2,59 = 4.091, p = 0.021. Post hoc Fisher’s LSD test: Control vs. LLD-Li; Control vs. STD-Li, p < 0.0001; LLD-Li vs. STD-Li, p < 0.0001; LLD-Li vs. LLD-Li + ASA, p = 0.34; STD-Li vs. STD-Li + ASA, p = 0.0001. (b) Water consumption day 42, two-way ANOVA: ASA effect, F_1,30 = 2.689 × 10⁻⁵, p = 0.9959; Li effect, F_2,30 = 320.5, p < 0.0001; aspirin X Li interaction: F2,30 = 0.069, p = 0.9328. Post hoc Fisher’s LSD test: Control vs. LLD-Li, p = 0.015; Control vs. STD-Li, p < 0.0001; LLD-Li vs. STD-Li, p < 0.0001; LLD-Li vs. LLD-Li + ASA, p = 0.77; STD-Li vs. STD-Li + ASA, p = 0.83. (c) Urinary output day 21, two-way ANOVA: ASA effect, F_1,59 = 4.528, p = 0.037; Li effect: F_2,59 = 729.5, p <0.0001; aspirin X Li interaction, F_2,59 = 3.384, p = 0.04. Post hoc Fisher’s LSD test: Control vs. LLD-Li, p = 0.0002; Control vs. STD-Li, p < 0.0001; LLD-Li vs. STD-Li, p < 0.0001; LLD-Li vs. LLD-Li + ASA, p = 0.523; STD-Li vs. STD-Li + ASA, p = 0.0009. (d) Urinary output day 42, two-way ANOVA: ASA effect, F_1,30 = 0.0044, p = 0.9475; Li effect, F_2,30 = 241.2, p < 0.0001; aspirin X Li interaction, F_2,30 = 0.07569, p = 0.9273. Post hoc Fisher’s LSD test: Control vs. LLD-Li, p < 0.0001; Control vs. STD-Li, p < 0.0001; LLD-Li vs. STD-Li, p < 0.0001; LLD-Li vs. LLD-Li + ASA, p = 0.80; STD-Li vs. STD-Li + ASA, p = 0.895. Asterisks and symbols denote the following: *—p < 0.05 vs. control; #—p < 0.05 vs. LLD-Li; ^—p < 0.05 vs. STD-Li; $—p < 0.05 vs. LLD-Li + ASA. Abbreviations: ASA—acetylsalicylic acid, LLD—low-low dose, Li—lithium, STD—standard dose.

**Figure 3**
Plasma creatinine levels in aspirin + Li-treated rats. Rats were fed regular food (control) or Li-containing food (LLD-Li or STD-Li) for 42 days. Low-dose ASA (1 mg/kg, ip) was administered alone or as add-on to Li. On days 21 (a) and 42 (b) blood was collected, plasma separated, and creatinine levels determined as described in Materials and Methods. Presented are creatinine levels adjusted to rat’s body weight. The figure summarizes the combined results of two independent experiments demonstrating a similar pattern. Results are the means ± SEM of 9–12 rats per group. (a) Two-way ANOVA: ASA effect, F_1,64 = 0.6556, p = 0.6874; Li effect, F_2,64 = 10, p = 0.0002; aspirin x Li interaction: F_2,64 = 0.3770, p = 0.6874. Post hoc Fisher’s LSD test: Control vs. LLD-Li, p = 0.0274; Control vs. STD-Li, p = 0.0005; Control vs. STD-Li + ASA, p = 0.0064. (b) Two-way ANOVA: aspirin effect, F_1,112 = 1.031, p = 0.312; Li effect, F_2,112 = 14.79, p < 0.0001; aspirin X Li interaction: F_2,112 = 0.2559, p = 0.775. Post hoc Fisher’s LSD test: Control vs. LLD-Li, p = 0.045; Control vs. STD-Li, p = 0.0003; Control vs. STD-Li + ASA, p = 0.0006; LLD-Li + ASA vs. STD-Li + ASA, p = 0.0095. Asterisks and symbols denote the following: *—p < 0.05 vs. Control, $—p < 0.05 vs. LLD-Li + ASA. Abbreviations: ASA—acetylsalicylic acid, LLD—low-low dose, Li—lithium, STD—standard dose.

**Figure 4**
Plasma cystatin C levels in aspirin + Li-treated rats. Rats were fed regular food (control) or lithium-containing food [LLD-Li or STD-Li] for 42 days. Low-dose aspirin (1 mg/kg, ip) was given alone or together with Li. On day 42, rats were euthanized, blood collected, plasma separated, and cystatin C levels determined by ELISA as described in Materials and Methods. Presented are cystatin C levels adjusted to rat’s body weight. Results are the means ±SEM of a single representative experiment out of two demonstrating a similar pattern with 8 rats per group in the depicted experiment. Two-way ANOVA: ASA effect, F_1,40 = 5.801, p = 0.0207; Li effect, F_2,40 = 3.616, p = 0.036; aspirin x Li interaction: F_2,40 = 1.679, p = 0.1995. Post hoc Fisher’s LSD test: Control vs. LLD-Li, p = 0.0116; Control vs. STD-Li, p = 0.217; Control vs. LLD-Li + ASA, p = 0.0118; Control vs. STD-Li + ASA, p = 0.413; STD-Li vs. LLD-Li, p = 0.008; STD-Li vs. STD-Li + ASA, p = 0.0436. Asterisks and symbols denote the following: #—p < 0.05 vs. LLD-Li, ^—p < 0.05 vs. STD-Li. Abbreviations: ASA—acetylsalicylic acid, LLD—low-low dose, Li—lithium, STD—standard dose.

**Figure 5**
Nephrin and podocin levels in aspirin + Li-treated rats. Rats were fed regular food (control) or lithium-containing food [LLD-Li or STD-Li] for 42 days. Low-dose aspirin (1 mg/kg, ip) was given alone or together with lithium. On day 42 the rats were sacrificed, kidneys excised and homogenized, and nephrin (a) and podocin (b) levels determined by ELISA as described in Materials and Methods. Results are the means ± SEM of a single representative experiment out of two demonstrating a similar pattern with 8 rats per group in the depicted experiment. * p < 0.05 vs. Control, # p < 0.05 vs. LLD-Li, ^ p < 0.05 vs. STD-Li. (a) Nephrin—two-way ANOVA: ASA effect: F_1,30 = 5.4, p = 0.027; Li effect: F_2,30 = 3.35, p < 0.05; Interaction: F_2,30 = 2.62, p = 0.089. Post hoc LSD: Control vs. STD Li, p ≤ 0.01; LLD Li vs. STD-Li, p ≤ 0.01; STD-Li + ASA vs. STD-Li, p = 0.003. (b) Podocin—two-way ANOVA: ASA effect: F_1,30 = 6.018, p = 0.02; Li effect: F_2,30 = 4.449, p = 0.02; Interaction: F_2,30 = 8.121, p = 0.0015. Post hoc LSD: Control vs. STD Li, p ≤ 0.0004; LLD-Li + vs. STD-Li, p ≤ 0.0004; STD Li + ASA vs. STD Li p < 0.0001. Abbreviations: ASA—acetylsalicylic acid, LLD—low-low dose, Li—lithium, STD—standard dose.

**Figure 6**
Kidney histopathology in aspirin + Li-treated rats. Rats were fed regular food (control) or lithium-containing food [LLD-Li or STD-Li] for 42 days. Low-dose aspirin (1 mg/kg, ip) was given alone or together with lithium. On day 42, rats were euthanized, kidneys excised, and longitudinally sectioned in half. Then, 2 μm sections were cut, stained with hematoxylin and eosin, and with Periodic acid–Schiff (PAS) and examined as described in Materials and Methods. Hematoxylin and eosin (A1–F1) and PAS stain (A2–F2) × 100 magnifications. Six samples from each group were randomly chosen for assessment. A1,2—Control, B1,2—LLD-Li, C1,2—STD-Li, D1,2—Aspirin, E1,2—LLD-Li + aspirin, F1,2—STD-Li + aspirin. Abbreviations: ASA—acetylsalicylic acid, LLD—low-low dose, Li—lithium, STD—standard dose. No discernible differences were found among the groups.

**Figure 7**
Gastric mucosal PGE2 levels in aspirin + Li-treated rats. Rats were fed regular food (control) or lithium-containing food [LLD-Li or STD-Li] for 42 days. Low-dose ASA (1 mg/kg, ip) was administered alone or together with Li. On day 42 rats were euthanized, stomachs excised, 100 mg of the gastric tissue homogenized and mucosal PGE2 levels determined by ELISA as described in Materials and Methods. Results are the means ± SEM of 18 rats per group. The figure summarizes the combined results of two independent experiments demonstrating a similar pattern. Two-way ANOVA: ASA effect, F1,101 = 7.83, p < 0.0001; Li effect, F_2,101 = 1.926, p = 0.151; aspirin x Li interaction: F2,30 = 0.1592, p = 0.8531. Post hoc Fisher’s LSD test: Control vs. LLD-Li, p = 0.419; Control vs. STD-Li, p = 0.14; Control vs. ASA, p = 0.018; Control vs. LLD-Li + ASA, p = 0.0004; Control vs. STD-Li + ASA, p = 0.0007; ASA vs. LLD-Li + ASA, p = 0.2037; ASA vs. STD-Li + ASA, p = 0.2576; LLD-Li vs. LLD-Li + ASA, p = 0.005; STD-Li vs. STD-Li + ASA, p = 0.044. Asterisks and symbols denote the following: *—p < 0.05 vs. Control, #—p < 0.05 vs. LLD-Li, ^—p < 0.05 vs. STD-Li. Abbreviations: ASA—acetylsalicylic acid, LLD—low-low dose, Li—lithium, STD—standard dose.

**Figure 8**
Blood hemoglobin and red blood cell levels in aspirin + Li-treated rats. Rats were fed regular food (control) or lithium-containing food [LLD-Li or STD-Li] for 42 days. Low-dose ASA (1 mg/kg, ip) was administered alone or together with Li. On the indicated days, blood was collected, and hemoglobin levels and red blood cell count were measured as described in Materials and Methods. Results are the means ± SEM of a single representative experiment out of two demonstrating a similar pattern with 6–8 rats per group in the depicted experiment. (a) Hemoglobin—One-way ANOVA: Day 0—p = 0.547; day 21—p = 0.07; day 42—p = 0.29. (b) RBC—One-way ANOVA: Day 0—p = 0.547; day 21—p = 0.07; day 42—p = 0.294. Abbreviations: ASA—acetylsalicylic acid, LLD—low-low dose, Li—lithium, STD—standard dose.

**Figure 9**
Plasma TXA2 in aspirin + lithium-treated rats. Rats were fed regular food (control) or lithium-containing food [LLD-Li or STD-Li] for 42 days. Low-dose ASA (1 mg/kg, ip) was administered alone or together with Li. On day 42 rats were sacrificed, blood collected, serum separated, and TXA2 levels determined by ELISA as described in Materials and Methods. Results are the means ± SEM of a single representative experiment out of two demonstrating a similar pattern with 6–8 rats per group in the depicted experiment. Two-way ANOVA: ASA effect, F_1,40 = 4.204, p = 0.046; Li effect, F_2,40 = 5.071, p = 0.01; aspirin x Li interaction: F_2,40 = 3.312, p = 0.046. Post hoc Fisher’s LSD test: Control vs. LLD-Li, p = 0.107; Control vs. STD-Li, p = 0.077; Control vs. ASA, p = 0.048; Control vs. LLD-Li + ASA, p = 0.426; STD-Li vs. STD-Li + ASA, p = 0.0135; ASA vs. STD-Li + ASA, p = 0.0233; STD-Li vs. STD-Li + ASA, p = 0.044. Asterisks and symbols denote the following: *—p < 0.05 vs. Control, ^—p < 0.05 vs. STD-Li, §—p < 0.05 vs. ASA. Abbreviations: ASA—acetylsalicylic acid, LLD—low-low dose, Li—lithium, STD—standard dose.

**Figure 10**
Anxiety-like behavioral facets in aspirin + Li-treated rats. Rats were fed regular food (control) or Li-containing food [LLD-Li or STD-Li] for 42 days. Low-dose ASA (1 mg/kg, ip) was administered alone or together with Li. (a) On treatment day 14, rats were subjected to an EPMT for five minutes. (b) On day 35, rats were placed in an open field arena for 20 min and their locomotor activity was monitored. In both tests, rats’ behavior was videotaped and subsequently analyzed by a video-tracking system as described in Materials and Methods. (a) Results are the means ± SEM of a single representative experiment out of two demonstrating a similar pattern with 9–12 rats per group in the depicted experiment. Two-way ANOVA: ASA effect, F_1,60 = 13.38, p = 0.0005; Li effect, F_2,60 = 406, p = 0.016; aspirin x Li interaction: F_2,60 = 1.295, p = 0.2813. Post hoc Fisher’s LSD test: Control vs. LLD-Li, p = 0.1797; Control vs. STD-Li, p = 0.1491; Control vs. ASA, p = 0.0739; Control vs. LLD-Li + ASA, p = 0.0182; Control vs. STD-Li + ASA, p < 0.0001; STD-Li vs. STD-Li + ASA, p = 0.0011; LLD-Li + ASA vs. STD-Li + ASA, p = 0.0205. Asterisks and symbols denote the following: *—p < 0.05 vs. control, ^—p < 0.05 vs. STD-Li, $—p < 0.05 vs. LLD-Li + ASA. (b) Results are means ± SEM of a single representative experiment out of two demonstrating a similar pattern with 9–12 rats per group in the depicted experiment. Two-way ANOVA: ASA effect, F_1,60 = 1.069, p = 0.3052; One-tailed Li effect, F_2,60 = 2.804, p = 0.0329; aspirin x Li interaction: F_2,60 = 0.2523, p = 0.7778. Post hoc Fisher’s LSD test: Control vs. LLD-Li, p = 0.2228; Control vs. STD-Li, p = 0.7405; Control vs. ASA, p = 0.5316; Control vs. LLD-Li + ASA, p = 0.0296; Control vs. STD-Li + ASA, p = 0.6827. Asterisk denotes the following: *—p < 0.05 vs. Control. Abbreviations: ASA—acetylsalicylic acid, LLD—low-low dose, Li—lithium, STD—standard dose.

**Figure 11**
Rats were fed regular food (control) or lithium-containing food [LLD-Li or STD-Li]. On day 21 of the treatment rats were offered two bottles, one containing sucrose solution and one—regular drinking water as described in Materials and Methods. Sucrose consumption in each cage was calculated according to the body weight of the rats (three) in the cage. Results are the means ± SEM of a single representative experiment out of two demonstrating a similar pattern with 9–12 rats per group in the depicted experiment. Two-way ANOVA: ASA effect, F_1,48 = 1.711, p = 0.1738; Li effect, F_2,48 = 278.7, p < 0.0001; aspirin x Li interaction, F_2,48 = 1.711, p = 0.1915. Post hoc Fisher’s LSD test: Control vs. LLD-Li, p < 0.0001; Control vs. STD-Li, p < 0.0001; Control vs. ASA, p = 0.9362; Control vs. LLD-Li + ASA, p < 0.0001; Control vs. STD-Li + ASA, p < 0.0001; LLD-Li vs. STD-Li; LLD-Li vs. LLD-Li + ASA, p = 0.0254; STD-Li vs. STD-Li + ASA, p = 0.997; LLD-Li + ASA vs. STD-Li +ASA, p = 0.0019. Asterisks and symbols denote the following: *—p < 0.05 vs. Control, #—p < 0.05 vs. LLD-Li, $—p <, 0.05 vs. LLD-Li + ASA. Abbreviations: ASA—acetylsalicylic acid, LLD—low-low dose, Li—lithium, STD—standard dose.

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References

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[1] Fagiolini A., Forgione R., Maccari M., Cuomo A., Morana B., Dell’Osso M.C., Pellegrini F., Rossi A. Prevalence, chronicity, burden and borders of bipolar disorder. J. Affect. Disord. 2013;148:161–169. doi: 10.1016/j.jad.2013.02.001. - DOI - PubMed

[2] Fagiolini A., Forgione R., Maccari M., Cuomo A., Morana B., Dell’Osso M.C., Pellegrini F., Rossi A. Prevalence, chronicity, burden and borders of bipolar disorder. J. Affect. Disord. 2013;148:161–169. doi: 10.1016/j.jad.2013.02.001. - DOI - PubMed

[3] Ferrari A.J., Stockings E., Khoo J.P., Erskine H.E., Degenhardt L., Vos T., Whiteford H.A. The prevalence and burden of bipolar disorder: Findings from the Global Burden of Disease Study 2013. Bipolar Disord. 2016;18:440–450. doi: 10.1111/bdi.12423. - DOI - PubMed

[4] Ferrari A.J., Stockings E., Khoo J.P., Erskine H.E., Degenhardt L., Vos T., Whiteford H.A. The prevalence and burden of bipolar disorder: Findings from the Global Burden of Disease Study 2013. Bipolar Disord. 2016;18:440–450. doi: 10.1111/bdi.12423. - DOI - PubMed

[5] Belmaker R.H. Bipolar disorder. N. Engl. J. Med. 2004;351:476–486. doi: 10.1056/NEJMra035354. - DOI - PubMed

[6] Belmaker R.H. Bipolar disorder. N. Engl. J. Med. 2004;351:476–486. doi: 10.1056/NEJMra035354. - DOI - PubMed

[7] Kupfer D.J. The increasing medical burden in bipolar disorder. J. Am. Med. Assoc. 2005;293:2528–2530. doi: 10.1001/jama.293.20.2528. - DOI - PubMed

[8] Kupfer D.J. The increasing medical burden in bipolar disorder. J. Am. Med. Assoc. 2005;293:2528–2530. doi: 10.1001/jama.293.20.2528. - DOI - PubMed

[9] Grande I., Berk M., Birmaher B., Vieta E. Bipolar disorder. Lancet. 2016;387:1561–1572. doi: 10.1016/S0140-6736(15)00241-X. - DOI - PubMed

[10] Grande I., Berk M., Birmaher B., Vieta E. Bipolar disorder. Lancet. 2016;387:1561–1572. doi: 10.1016/S0140-6736(15)00241-X. - DOI - PubMed

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Safety and Efficacy of Combined Low-Dose Lithium and Low-Dose Aspirin: A Pharmacological and Behavioral Proof-of-Concept Study in Rats

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Safety and Efficacy of Combined Low-Dose Lithium and Low-Dose Aspirin: A Pharmacological and Behavioral Proof-of-Concept Study in Rats

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