Adolescent exposure to cocaine increases anxiety-like behavior and induces morphologic and neurochemical changes in the hippocampus of adult rats
Introduction
Adolescence represents an important period for neuronal maturation, and adolescent brain is highly sensitive to neurobiological changes induced by internal and external stimuli, such as cocaine abuse (Paule, 2005, Realini et al., 2009). Epidemiologic and preclinical evidence suggests that adolescents are vulnerable to substance abuse (Chambers et al., 2003, Schramm-Sapyta et al., 2009, Wong et al., 2013). In humans, experiencing drug abuse during adolescence increases the risk of psychiatric disorders and addiction in adulthood (Realini et al., 2009, Rutherford et al., 2010, Staff et al., 2010, Hanson et al., 2011, Moss et al., 2014). Yet, the molecular mechanisms underlying these risks are still unclear.
The hippocampus is known to participate in a variety of addictive-related behaviors, such as enhanced drug-cue memories and drug-seeking (Rogers and See, 2007, Lasseter et al., 2010, Noonan et al., 2010). Importantly, the hippocampus continues to undergo structural and functional changes throughout adolescence into adulthood. Thus, exposure to drugs such as cocaine during adolescence may impair hippocampal maturation and result in long-lasting changes in hippocampal neuronal function. Hippocampi are thought to be functionally subdivided into dorsal (posterior in primates) and ventral (anterior in primates) regions (Fanselow and Dong, 2010, Strange et al., 2014). Dorsal hippocampus (dHP) is thought to be mainly involved in spatial cognitive functions (White and Gaskin, 2006, Sannino et al., 2012). While, ventral hippocampus (vHP) has a preferential role in emotional processing related to stress, fear, and anxiety (Trivedi and Coover, 2004, Albrecht et al., 2013). Drugs of abuse affect behavior and brain function differently in adolescents and adults, and the hippocampus is highly sensitive to drug abuse during the developmental period (Collins and Izenwasser, 2004, Izenwasser, 2005). However, knowledge is lacking about morphologic and neurochemical changes that may occur in adult hippocampus after adolescent cocaine exposures.
In this study, we tested the hypothesis that repeated exposure of cocaine to adolescent rats may elicit morphologic and neurochemical changes in adult hippocampus, which may contribute to cognitive and emotional dysfunction in adult rats. To test this hypothesis, we first investigated animal behaviors, especially those related to spatial cognitive functions and anxiety, in adult rats with a cocaine exposure history during adolescence. We also examined morphologic structure, oxidative and antioxidant status, apoptotic and inflammatory status, and expressions of various addiction-associated proteins in dHP and vHP of adult rats.
Section snippets
Experimental procedures
All experiments were performed in accordance with the Nanjing Medical University Guide for the Care and Use of Laboratory Animals, China, and were approved by the Nanjing Medical University Institutional Animal Care and Use Committee. All efforts were made to minimize the number of animals used and to minimize their suffering.
Adolescent cocaine exposure did not affect spatial learning and memory behaviors in adult rats by MWM tests
In the MWM test, ELs decreased progressively in both groups over the four consecutive days of testing (p < 0.01, ANOVA, n = 8 rats/group, Fig. 2A), indicating a cumulative learning process. However, there are no significances on the ELs between the saline and cocaine groups in each day (p > 0.05, Fig. 2A). Likewise, on P86, the probe test showed no significant differences in spatial memory retention between the two groups (p > 0.05, Fig. 2B).
Adolescent cocaine exposure increased anxiety-like behaviors in adult rats by EPM tests
In the EPM tests, there was no significant difference on the
Discussion
Adolescence represents a critical developmental period for the brain, with a heightened vulnerability to cocaine abuse. It has been proposed that psychostimulant exposure during adolescence may disturb the developmental proceed and consequently result in maladaptive modifications in the brain (Cao et al., 2007), which might contribute to later increased susceptibility for psychiatric problems. Yet, few animal studies have been performed to investigate the long-term effects of adolescent cocaine
Conclusion
The current study shows repeated cocaine exposure to rats during their adolescent period results in increased anxiety-like behaviors in their adulthood. Changes in morphologic and neurochemical properties in adult hippocampus induced by adolescent cocaine exposure might contribute to this behavioral impairment. These results may help to better understand the molecular mechanisms underlying the susceptibility for psychiatric disorders and addiction behaviors in adults following adolescent drugs
Conflict of interest
The authors declare no conflict of interest relating to this study.
Acknowledgements
This work was supported by the National Natural Science Foundation of China, China (No. 81571303, No. 81371467, No. 81000572, No. 81301305) and Natural Science Foundation of Jiangsu Province, China (No. 10KJB180005). The authors thank Claire Levine, MS, ELS, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, for editing the manuscript.
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These authors contribute equally to this work.