Increased dopamine transporter function as a mechanism for dopamine hypoactivity in the adult infralimbic medial prefrontal cortex following adolescent social stress
Introduction
Social experiences during development profoundly influence physiology and behavior later in life. This holds true for adolescent bullying victimization, a common yet potent stressor associated with emergence of a wide range of neuropsychiatric disturbances both acutely and in adulthood (Arseneault et al., 2010). The relationship between bullying and later disorders appears to hold true even after controlling for previous psychiatric illness and family environment (Copeland et al., 2013). Effective treatment of these bullying-related disorders would be greatly facilitated if a common underlying neural mechanism could be identified, particularly one amenable to targeting by existing pharmacotherapies. Preclinical research indicates adolescent stress exposure can disrupt the developing medial prefrontal cortex (mPFC) dopamine (DA) system, altering DA neurotransmission to potentiate psychopathology-associated behaviors (Wright et al., 2008, Watt et al., 2014, Burke et al., 2011, Novick et al., 2013). This is also evident from the numerous psychiatric disorders promoted by bullying victimization, which are all characterized by deficits in cognitive function dependent on optimal mPFC DA activity (Robbins and Arnsten, 2009, Testa and Pantelis, 2009). A key regulator of mPFC DA activity is the DA transporter (DAT), which acts to clear synaptic DA and shows functional alterations in psychiatric disorders associated with adolescent bullying (Akil et al., 1999, Krause et al., 2003). Exposure to social aggression in adulthood alters rodent DAT expression, but only in subcortical regions (Filipenko et al., 2001, Lucas et al., 2004). In contrast, rats isolated from weaning show enhanced meosocortical DAT-mediated DA clearance in adulthood compared to those in an enriched environment, suggesting stress exposure encompassing the adolescent period may directly influence later mPFC DAT mechanics (Yates et al., 2012). However, whether adolescent experience of social aggression can similarly alter adult mPFC DAT function is unknown.
Recent research demonstrated that adolescent social defeat in male rats, as a model of teenage bullying, specifically increases DAT expression in the infralimbic region of the adult mPFC (Novick et al., 2011). This complimented previous studies revealing reductions in adult mPFC DA activity following adolescent social defeat, both basally and in response to amphetamine (Watt et al., 2009, Watt et al., 2014, Burke et al., 2013). Adolescent defeat also causes changes to adult behavior, including heightened locomotion responses to both amphetamine and novelty (Watt et al., 2009, Burke et al., 2013), enhanced seeking of drug-associated cues (Burke et al., 2011), and decreased working memory (Novick et al., 2013), all of which are potentiated by reduced mPFC DA activity (Piazza et al., 1991, Clinton et al., 2006). We hypothesize that the enhanced DAT expression in the infralimbic region of the adult mPFC following adolescent defeat may result in greater DA clearance, reducing availability of extracellular DA to cause deficient mPFC DA activity. Here, we tested this by using in vivo chronoamperometry to measure differences in infralimbic mPFC DA signal accumulation in response to DAT blockade. As predicted, adolescent defeat increases DAT function in the adult mPFC, as reflected by lower DA signal accumulation following DAT inhibition. Our findings suggest a mechanistic explanation by which exposure to negative social experiences in adolescence results in deleterious changes to adult behavior and cognition, and may offer a potential treatment target to guide development of more effective pharmacotherapies.
Section snippets
Animals
Eighty-one male weanling Sprague-Dawley rats (Postnatal day [P]21) were obtained from the University of South Dakota (USD) Animal Resource Center. All rats were pair-housed according to treatment (defeat or control) and kept at 22 °C on a reverse 12-hr light–dark cycle (lights off 10.00). Food and water were available ad libitum. Behavioral experiments were conducted between 11:00 and 15:00 under red lighting. All procedures were carried out in accordance with the National Institutes of Health
Results
The electrode recording surfaces ranged in location between 2.7 mm and 3.2 mm anterior to bregma and were placed within the entire mediolateral and dorsoventral aspects of the infralimbic region of the mPFC across all subjects (Fig. 2). There were no differences in electrode placement either between control and defeated rats (Fig. 2), or among drug treatment groups.
Within the vehicle (H2O) plus vehicle (DMSO/H2O 1:1) treatment groups (Fig. 3A), there was only a significant main effect of time (F
Discussion
Experience of social defeat in adolescence increased DAT function in the adult infralimbic mPFC, as reflected by less DA signal accumulation using chronoamperometric measurement following DAT blockade. Specifically, previously defeated rats receiving a combination of DMI plus GBR-12909 (20 mg/kg and 40 mg/kg) exhibited significantly lower DA accumulation across time compared to controls, suggesting that neither dose of DAT inhibitor was able to saturate the higher levels of adult infralimbic
Acknowledgments
We thank Dr. Charles Blaha for valuable advice on chronoamperometry experiments, Shaydie Engel for performing histology, and Dr. Lee Baugh and Kelene Fercho for assistance with statistical analyses. Work supported by NSF IOS 1257679 (MJW), NIDA RO1 DA019921 (GLF), NIH P20 RR015567 (COBRE), NIDA R15 DA035478 (MJW) and a Joseph F. Nelson and Martha P. Nelson Faculty Research Grant (MJW). The authors declare no competing financial interests.
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