Elsevier

Neuroscience

Volume 313, 28 January 2016, Pages 174-183
Neuroscience

Adolescent exposure to cocaine increases anxiety-like behavior and induces morphologic and neurochemical changes in the hippocampus of adult rats

https://doi.org/10.1016/j.neuroscience.2015.11.041Get rights and content

Highlights

  • Adolescent exposure to cocaine increases anxiety-like behavior in adult rats.

  • Adolescent exposure to cocaine impairs pyramidal neurons and increases activities of astrocytes in adult hippocampus.

  • Adolescent exposure to cocaine alters status of synaptic transmission, apoptosis, and inflammation in adult hippocampus.

  • Adolescent exposure to cocaine changes the levels of addiction-related proteins in adult hippocampus.

Abstract

Repeated exposure to cocaine during adolescence may affect both physical and psychological conditions in the brain, and increase the risk of psychiatric disorders and addiction behaviors in adulthood. Adolescence represents a critical development period for the hippocampus. Moreover, different regions of the hippocampus are involved in different functions. Dorsal hippocampus (dHP) has been implicated in learning and memory, whereas ventral hippocampus (vHP) plays an important role in emotional processing. In this study, the rats that were exposed to cocaine during adolescence (postnatal days, P28–P42) showed higher anxiety-like behavior in the elevated plus maze test in adulthood (P80), but displayed normal spatial learning and memory in the Morris water maze test. Furthermore, repeated exposure to cocaine during adolescence lead to alterations in morphology of pyramidal neurons, activities of astrocytes, and levels of proteins that involved in synaptic transmission, apoptosis, inflammation and addiction in both dHP and vHP of adult rats. These findings suggest that repeated exposure to cocaine during adolescence in rats may elicit morphologic and neurochemical changes in the hippocampus when the animals reach adulthood. These changes may contribute to the increased susceptibility for psychiatric disorders and addiction seen in adults.

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.

References (78)

  • C. Florian et al.

    Hippocampal CA3-region is crucial for acquisition and memory consolidation in Morris water maze task in mice

    Behav Brain Res

    (2004)
  • G.J. Harry et al.

    Microglia in the developing brain: a potential target with lifetime effects

    Neurotoxicology

    (2012)
  • C.M. Hostetler et al.

    DeltaFosB is increased in the nucleus accumbens by amphetamine but not social housing or isolation in the prairie vole

    Neuroscience

    (2012)
  • H.C. Lasseter et al.

    Sub-region specific contribution of the ventral hippocampus to drug context-induced reinstatement of cocaine-seeking behavior in rats

    Neuroscience

    (2010)
  • A. Lopes et al.

    Gestational protein restriction induces CA3 dendritic atrophy in dorsal hippocampal neurons but does not alter learning and memory performance in adult offspring

    Int J Dev Neurosci

    (2013)
  • J.F. McGinty et al.

    Brain-derived neurotrophic factor and cocaine addiction

    Brain Res

    (2010)
  • H.B. Moss et al.

    Early adolescent patterns of alcohol, cigarettes, and marijuana polysubstance use and young adult substance use outcomes in a nationally representative sample

    Drug Alcohol Depend

    (2014)
  • R.E. Mrak et al.

    Glia and their cytokines in progression of neurodegeneration

    Neurobiol Aging

    (2005)
  • E.J. Nestler et al.

    The mesolimbic dopamine reward circuit in depression

    Biol Psychiatry

    (2006)
  • S. Ozsoy et al.

    Hippocampal volumes and cognitive functions in adult alcoholic patients with adolescent-onset

    Alcohol

    (2013)
  • G.L. Pereno et al.

    Timed changes of synaptic zinc, synaptophysin and MAP2 in medial extended amygdala of epileptic animals are suggestive of reactive neuroplasticity

    Brain Res

    (2010)
  • N. Realini et al.

    Neurobiological alterations at adult age triggered by adolescent exposure to cannabinoids

    Pharmacol Res

    (2009)
  • J.L. Rogers et al.

    Selective inactivation of the ventral hippocampus attenuates cue-induced and cocaine-primed reinstatement of drug-seeking in rats

    Neurobiol Learn Mem

    (2007)
  • H.J. Rutherford et al.

    Neurobiology of adolescent substance use disorders: implications for prevention and treatment

    Child Adolesc Psychiatr Clin N Am

    (2010)
  • K.Y. Salas-Ramirez et al.

    Prenatal cocaine exposure increases anxiety, impairs cognitive function and increases dendritic spine density in adult rats: influence of sex

    Neuroscience

    (2010)
  • S.E. Sillivan et al.

    Binge cocaine administration in adolescent rats affects amygdalar gene expression patterns and alters anxiety-related behavior in adulthood

    Biol Psychiatry

    (2011)
  • S.A. Sloan et al.

    Mechanisms of astrocyte development and their contributions to neurodevelopmental disorders

    Curr Opin Neurobiol

    (2014)
  • L.P. Spear

    The adolescent brain and age-related behavioral manifestations

    Neurosci Biobehav Rev

    (2000)
  • J.H. Tao-Cheng

    Activity-related redistribution of presynaptic proteins at the active zone

    Neuroscience

    (2006)
  • M.A. Trivedi et al.

    Lesions of the ventral hippocampus, but not the dorsal hippocampus, impair conditioned fear expression and inhibitory avoidance on the elevated T-maze

    Neurobiol Learn Mem

    (2004)
  • H.Y. Yang et al.

    Chronic morphine administration induces over-expression of aldolase C with reduction of CREB phosphorylation in the mouse hippocampus

    Eur J Pharmacol

    (2009)
  • A. Albrecht et al.

    Long-lasting increase of corticosterone after fear memory reactivation: anxiolytic effects and network activity modulation in the ventral hippocampus

    Neuropsychopharmacology

    (2013)
  • J.K. Andersen

    Oxidative stress in neurodegeneration: cause or consequence?

    Nat Med

    (2004)
  • A.S. Bahar et al.

    Memory-guided learning: CA1 and CA3 neuronal ensembles differentially encode the commonalities and differences between situations

    J Neurosci

    (2011)
  • J.J. Bajramovic

    Regulation of innate immune responses in the central nervous system

    CNS Neurol Disord: Drug Targets

    (2011)
  • V. Bashkatova et al.

    Memory impairments and oxidative stress in the hippocampus of in-utero cocaine-exposed rats

    NeuroReport

    (2005)
  • G. Bing et al.

    Long-term expression of Fos-related antigen and transient expression of delta FosB associated with seizures in the rat hippocampus and striatum

    J Neurochem

    (1997)
  • D.M. Buffalari et al.

    Treatment of cocaine withdrawal anxiety with guanfacine: relationships to cocaine intake and reinstatement of cocaine seeking in rats

    Psychopharmacology (Berl)

    (2012)
  • J. Cao et al.

    Adolescent maturation of cocaine-sensitive neural mechanisms

    Neuropsychopharmacology

    (2007)
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