EFFECTS OF PERINATAL STRESS AND DRUG ABUSE ON ANXIETY-LIKE
MA dose on SAP parameter seen in non-stressed group, i.e. there were no differences between acute MA and SA groups in any of postnatally stressed groups (Figure 2).
Discussion
The present data showed that prenatal treatments have no effect on anxiety-like behavior of adult male rats measured in both tests which is in agreement with previous studies with similar methodology (6). Acute MA dose in adulthood significantly decreased parameters of anxiety-like behavior which also support some previous studies.
However, there are data suggesting that higher dose of MA or its repeated administration have an anxiogenic effect (6). All postnatal stressors used in the present study decreased parameters of anxiety-like behavior. Available data describing the effects of postnatal stress on anxiety-like behavior are diverse. Our data are consonant with study Yang et al. (2019) (8) which showed that rats exposed to early life stress revealed decreased anxiety-like behavior and Borges-Aguiar et al. (2018) (9) where 3h daily maternal separation during whole lactation period failed in affecting anxiety of the adult rats exposed to either EPM or OF. The reduction or lack of anxiogenic effects in postnatally stressed rats in adulthood is also in accordance with other studies which used different tests to investigate anxiety-like behavior (e.g. fear conditioning, social interaction, restraint stress) (9). Despite the fact that severe stressful events may result in detrimental effects, perinatal low to moderate stressors may induce protective effects in adulthood. For example, brief daily separation of pups from their mother during the early postnatal period can reduce the effects of chronic stress on HPA axis reactivity (8). Our previous data showed increased plasma levels of ACTH and decreased plasma levels of CORT in postnatally stressed (S, SW) groups of rats after acute stress exposure compared to unstressed controls (7). Long-term postnatal stress may thus lead to lower sensitivity of ACTH receptors in adrenal cortex as a result to adaptation to subsequent stressful experiences. Chronic stress in early life periods thus may prepare the nervous, immune and endocrine systems to cope with stressful situations later in life (7, 8). Interestingly, rat-offspring postnatally exposed to social stressor (S) showed no differences in total time spent in the central ring, corners and by grooming after acute MA administration compared to SA counterparts. It seems that maternal separation changes the sensitivity to acute MA in adulthood. Combination of stress and use of MA have not been studied in detail. It should be noted that the effects of stress depend on the intensity, type and length of the stressors. It was shown that diverse stress of low to moderate intensity may induce positive or negative effects. The animal can become more resilient to the stressor and stress may even attenuate MA neurotoxicity (10).
Conclusion
Our results indicate that early postnatal stress and single acute MA injection in adulthood decrease parameters of anxiety-like behavior of adult male rats regardless of prenatal exposure. Moreover, early postnatal stress affects the effect of acute MA administration.
Summary
Drug abuse during pregnancy is a growing, world-wide problem. Statistical data show that a considerable number of drug addicted women switch from other hard drugs to MA during their pregnancy. The reason is assumed to be that MA reduces pregnancy related weight gain and fatigue. MA easily crosses the placental barrier and cause changes in the developing fetus that can have long-lasting consequences. Previous studies demonstrated that MA use during pregnancy can impair the development of central nervous system of affected pups. Moreover, preclinical studies have found that maternal injections during pregnancy, regardless of injected substance, induce long-term impairment of stress responsiveness in adult offspring. The offspring of drug addicted mothers are often neglected and exposed to neonatal stressors. And stressful events during neonatal period are believed to be closely associated with the development of psychological alterations and psychiatric disorders such as depression and anxiety. The aim of this study was to evaluate the effect of long-term perinatal stressors and drug exposure on anxiety-like behavior of adult male rats in Open filed (OF) and Elevated plus maze (EPM). Dams were divided into three groups according to drug treatment during pregnancy: controls (C); saline - SA (s.c., 1 ml/kg); MA (s.c., 5 mg/kg). Litters were divided into four groups according to postnatal stressor: non-stressed controls (N); maternal separation (S); maternal cold water stress (W); and maternal separation plus maternal cold water stress (SW).
45 minutes prior the testing, one half of adult male rats obtained injection (s.c.) of MA and the second half injection of SA. The prenatal MA/stress exposure had no effect on anxiety-like behavior of adult male rats. Acute MA dose in adulthood increased time spent in the central ring, decreased time spent in the corners and time spent in immobility and grooming. Also postnatal stress increased time spent in the central ring, decreased time spent in the corners and immobility compared to non-stressed controls. All groups of rats exposed to postnatal stressors spent significantly less time in closed arms in the EPM compared to non-stressed group of male rats. Overall, our results indicate that early postnatal stress and single acute MA injection prior testing decrease parameters of anxiety-like behavior of adult male rats regardless of prenatal exposure. Moreover, early postnatal stress affects the effect of acute MA administration. Stress can be adaptive or maladaptive depending on type, severity and
length of exposure. Chronic low to mild stress in early life periods thus may prepare the nervous, immune and endocrine systems to cope with stressful experiences later in life.
Acknowledgement
The work was supported by grant projects: GACR 18-03806S from Grand Agency of the Czech Republic, GAUK 1442120, 260533/SVV/2020 and Progres Q35 from Charles University.
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Additional information
Year of Graduation (Master’s degree): 2014 Year of beginning Ph.D. studies: 2014
Topic of Ph.D. dissertation: Drug abuse and perinatal stress
Role of the author and co-authors in preparing and carrying out the research included in the presentation: Anna Kroupová as PhD student performed all the experiments, video-analysis and statistical analysis. She wrote the present manuscript. Tutor and co-author, prof. Romana Šlamberová, is a supervisor of Anna Kroupová. She is also head of the department and the laboratory where this study has been conducted. She designed and coordinated the study and is involved to the present manuscript.
Figure 1. The effect of postnatal stress and acute MA administration on anxiety-like behavior in Open field test. Values are means ± SEM. C = controls; SA = saline; MA = methamphetamine. N = non-stressed controls;
S = maternal separation; W = maternal cold water swimming stress; SW = maternal separation plus maternal cold water swimming stress. Acute SA = single direct saline injection prior testing; acute MA = single direct methamphetamine injection prior testing. *p<0.05, **p<0.01, ***p<0.001 significant difference in one group of x-axis. # p<0.05, ## p<0.01, ### p<0,001 significant difference between the group in the legend and its N-controls.
(C-controls in case of rearing).
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Figure 2. The effect of postnatal treatment and acute MA administration on anxiety-like behavior in Elevated plus maze test. Values are means ± SEM. C = controls; SA = saline; MA = methamphetamine. N = non-stressed controls; S = maternal separation; W = maternal cold water swimming stress; SW = maternal separation plus maternal cold water swimming stress. Acute SA = single direct saline injection prior testing; acute MA = single direct methamphetamine injection prior testing. *p<0.05, **p<0.01, ***p<0.001 significant difference in one group of x-axis. # p<0.05, ## p<0.01, ### p<0,001 significant difference between the group in the legend and its N-controls.
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