Methamphetamine exposure during gestation and lactation periods impairs the learning and memory of offspring mice, which is reversed by melatonin: the role of oxidative stress and acetylcholinesterase

Abstract

Background and purpose: Melatonin is a product of the pineal gland, which regulates the circadian cycle. Neurotoxicity is the most important side effect of methamphetamine (Met) abuse during pregnancy. This study aimed to explore the effect of Met exposure during gestation and lactation periods on the learning and memory of offspring mice. The protective effect of melatonin and the role of oxidative stress and acetylcholinesterase were also investigated.

Experimental approach: The pregnant mice were randomly divided into 2 groups. Saline or Met (5 mg/kg) was injected daily during pregnancy and lactation. After the lactation period, the offspring mice of each group were divided into 2 subgroups, and saline or melatonin (10 mg/kg) was orally (gavage) administered to the offspring mice from the post-delivery (PD) day 21 up to PD Day 60. The offspring mice were examined in the passive avoidance (PA) test. Finally, oxidative stress markers and acetylcholinesterase (AchE) activity were measured in the brains.

Findings/results: As a result, Met decreased delay and light time while increasing the frequency of entry and time in the dark region of PA. However, melatonin alleviated the impairing effect of Met on PA performance. Meanwhile, the administration of Met increased malondialdehyde while decreasing superoxide dismutase and thiol content. Furthermore, AchE activity was significantly increased in Met-treated mice. Melatonin reversed the levels of antioxidants, lipid peroxidation, and AchE activity in the brain.

Conclusion and implications: Together, these results suggested that melatonin may be a potential therapeutic agent for alleviating Met-induced memory impairment by restoring redox hemostasis and AchE.

Keywords: Acetylcholinesterase; Melatonin; Methamphetamine; Oxidative stress.

Fig. 1

The comparison of latency for entering the dark compartment and the total time spent in the dark compartment in the passive avoidance test among all groups. (A and E) 3, (B and F) 24, (C and G) 48, and (D and H) 72 h after receiving the shock. Data were expressed as mean ± SEM. ^*P < 0.05, ^**P < 0.01, and ^***P < 0.001 indicate significant differences compared to P/saline-O/saline group; ⁺P < 0.05, ⁺⁺P < 0.01, and ⁺⁺⁺P < 0.001 versus P/saline-O/melatonin group; ^#P < 0.05 and ^###P < 0.001 versus P/Met-O/saline groups. P, Pregnant mothers; Met, methamphetamine; O, offspring.

Fig. 2

The comparison of total time spent in the light compartment and the number of entries into the dark compartment in the passive avoidance test among all groups. (A and E) 3, (B and F) 24, (C and G) 48, and (D and H) 72 h after receiving the shock. Data were expressed as mean ± SEM. ^**P < 0.01 and ^***P < 0.001 indicate significant differences compared to P/saline-O/saline group; ⁺P < 0.05, ⁺⁺P < 0.01, and ⁺⁺⁺P < 0.001 versus P/saline-O/melatonin group; ^##P < 0.01 and ^###P < 0.001 versus P/Met-O/saline groups. P, Pregnant mothers; Met, methamphetamine; O, offspring.

Fig. 3

The comparison of MDA concentration in the (A) hippocampus and (B) cortex among all groups. Data were expressed as mean ± SEM. ^***P < 0.001 indicates significant difference compared to P/saline-O/saline group; ⁺⁺⁺P < 0.001 versus P/saline-O/melatonin group; ^##P < 0.01 and ^###P < 0.001 versus P/Met-O/saline groups. P, Pregnant mothers; Met, methamphetamine; O, offspring; MDA, malondialdehyde.

Fig. 4

The comparison of thiol concentration in the (A) hippocampus and (B) cortex among all groups. Data were expressed as mean ± SEM. ^**P < 0.01 indicates significant difference compared to P/saline-O/saline group; ⁺P < 0.05 versus P/saline-O/melatonin group; ^#P < 0.05 and ^##P < 0.01 versus P/Met-O/saline groups. P, Pregnant mothers; Met, methamphetamine; O, offspring.

Fig. 5

The comparison of SOD activity in the (A) hippocampus and (B) cortex among all groups. Data were expressed as mean ± SEM. ^***P < 0.001 indicates significant difference compared to P/saline-O/saline group; ⁺⁺P < 0.01 and ⁺⁺⁺P < 0.001 versus P/saline-O/melatonin group; ^###P < 0.001 versus P/Met-O/saline groups. P, Pregnant mothers; Met, methamphetamine; O, offspring, SOD, superoxide dismutase.

Fig. 6

The comparison of AchE activity in the (A) hippocampus and (B) cortex among all groups. Data were expressed as mean ± SEM. ^**P < 0.01 and ^***P < 0.001 indicate significant differences compared to P/saline-O/saline group; ⁺⁺P < 0.01 and ⁺⁺⁺P < 0.001 versus P/saline-O/melatonin group; ^##P < 0.01 and ^###P < 0.001 versus P/Met-O/saline groups. P, Pregnant mothers; Met, methamphetamine; O, offspring, AchE, acetylcholinesterase.