Elsevier

Neuropharmacology

Volume 97, October 2015, Pages 194-200
Neuropharmacology

Increased dopamine transporter function as a mechanism for dopamine hypoactivity in the adult infralimbic medial prefrontal cortex following adolescent social stress

https://doi.org/10.1016/j.neuropharm.2015.05.032Get rights and content

Highlights

  • Adolescent defeat results in less prefrontal dopamine accumulation upon transporter blockade.

  • Lower dopamine accumulation suggests greater dopamine transporter function.

  • Targeting dopamine transporters may rectify negative effects of adolescent stress.

Abstract

Being bullied during adolescence is associated with later mental illnesses characterized by deficits in cognitive tasks mediated by prefrontal cortex (PFC) dopamine (DA). Social defeat of adolescent male rats, as a model of teenage bullying victimization, results in medial PFC (mPFC) dopamine (DA) hypofunction in adulthood that is associated with increased drug seeking and working memory deficits. Increased expression of the DA transporter (DAT) is also seen in the adult infralimbic mPFC following adolescent defeat. We propose the functional consequence of this increased DAT expression is enhanced DA clearance and subsequently decreased infralimbic mPFC DA availability. To test this, in vivo chronoamperometry was used to measure changes in accumulation of the DA signal following DAT blockade, with increased DAT-mediated clearance being reflected by lower DA signal accumulation. Previously defeated rats and controls were pre-treated with the norepinephrine transporter (NET) inhibitor desipramine (20 mg/kg, ip.) to isolate infralimbic mPFC DA clearance to DAT, then administered the selective DAT inhibitor GBR-12909 (20 or 40 mg/kg, sc.). Sole NET inhibition with desipramine produced no differences in DA signal accumulation between defeated rats and controls. However, rats exposed to adolescent social defeat demonstrated decreased DA signal accumulation compared to controls in response to both doses of GBR-12909, indicating greater DAT-mediated clearance of infralimbic mPFC DA. These results suggest that protracted increases in infralimbic mPFC DAT function represent a mechanism by which adolescent social defeat stress produces deficits in adult mPFC DA activity and corresponding behavioral and cognitive dysfunction.

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.

References (56)

  • P.J. Lyss et al.

    Degree of neuronal activation following FG-7142 changes across regions during development

    Brain Res. Dev. Brain Res.

    (1999)
  • M.S. Mazei et al.

    Effects of catecholamine uptake blockers in the caudate-putamen and subregions of the medial prefrontal cortex of the rat

    Brain Res.

    (2002)
  • A.M. Novick et al.

    Adolescent social defeat alters markers of adult dopaminergic function

    Brain Res. Bull.

    (2011)
  • P.V. Piazza et al.

    Dopaminergic activity is reduced in the prefrontal cortex and increased in the nucleus accumbens of rats predisposed to develop amphetamine self-administration

    Brain Res.

    (1991)
  • R.B. Rothman et al.

    GBR12909 antagonizes the ability of cocaine to elevate extracellular levels of dopamine

    Pharmacol. Biochem. Behav.

    (1991)
  • J. Sabeti et al.

    Chloral hydrate and ethanol, but not urethane, alter the clearance of exogenous dopamine recorded by chronoamperometry in striatum of unrestrained rats

    Neurosci. Lett.

    (2003)
  • L.P. Spear

    The adolescent brain and age-related behavioral manifestations

    Neurosci. Biobehav. Rev.

    (2000)
  • J.W. Tidey et al.

    Social defeat stress selectively alters mesocorticolimbic dopamine release: an in vivo microdialysis study

    Brain Res.

    (1996)
  • M.E. Wolf et al.

    Dopamine neurons projecting to the medial prefrontal cortex possess release-modulating autoreceptors

    Neuropharmacology

    (1987)
  • L.D. Wright et al.

    Periadolescent stress exposure exerts long-term effects on adult stress responding and expression of prefrontal dopamine receptors in male and female rats

    Psychoneuroendocrinology

    (2008)
  • J.R. Yates et al.

    Isolation rearing as a preclinical model of attention/deficit-hyperactivity disorder

    Behav. Brain Res.

    (2012)
  • E.D. Abercrombie et al.

    Differential effect of stress on in vivo dopamine release in striatum, nucleus accumbens, and medial frontal cortex

    J. Neurochem.

    (1989)
  • M. Akil et al.

    Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects

    Am. J. Psychiatry

    (1999)
  • A.F. Arnsten

    Stimulants: therapeutic actions in ADHD

    Neuropsychopharmacol

    (2006)
  • L. Arseneault et al.

    Bullying victimization in youths and mental health problems:“Much ado about nothing”?

    Psychol. Med.

    (2010)
  • M.J. Bannon et al.

    Pharmacology of mesocortical dopamine neurons

    Pharmacol. Rev.

    (1983)
  • C.D. Blaha et al.

    A critical assessment of electrochemical procedures applied to the measurement of dopamine and its metabolites during drug-induced and species-typical behaviours

    Behav. Pharmacol.

    (1996)
  • W.A. Cass et al.

    In vivo assessment of dopamine uptake in rat medial prefrontal cortex: comparison with dorsal striatum and nucleus accumbens

    J. Neurochem.

    (1995)
  • Cited by (23)

    • Corticosterone in the ventral hippocampus differentially alters accumbal dopamine output in drug-naïve and amphetamine-withdrawn rats

      2020, Neuropharmacology
      Citation Excerpt :

      After the second week of withdrawal from amphetamine or saline pre-treatment, rats were anesthetized with urethane (1.8 g/kg, ip.). Urethane is a long-acting anesthetic that does not affect endogenous dopamine clearance (Barr and Forster, 2011; Blaha et al., 1997; Novick et al., 2015; Sabeti et al., 2003). Rats were placed into a stereotaxic frame (Kopf, Tujunga, CA, USA) with incisor bar set at −3.5 mm and body temperature held at 37 °C ± 0.5 °C by a temperature-controlled heating pad (Harvard Apparatus, Holliston, MA, USA).

    • The impact of chronic stress during adolescence on the development of aggressive behavior: A systematic review on the role of the dopaminergic system in rodents

      2018, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      One study reported contrasting effects regarding monoamine content, turnover, and biosynthesis in both mesolimbic and mesocortical brain areas following adolescent social defeat, but did observe increased levels of social anxiety in adulthood (Vidal et al., 2007). Overall, these findings indicate that chronic stress taking place in adolescence generally results in a decreased dopamine activity/functioning in adult PFC through reduced dopamine levels and turnover, D2R’s, higher DAT expression and binding, and amphetamine-induced DA release (Burke et al., 2013, 2011; Novick et al., 2015, 2011; Watt et al., 2014, 2009; Wright et al., 2008). In addition, the specificity of the mesocortical pathway in the response to adolescent stress may be due to the increased sensitivity of the adolescent PFC to stress, as a consequence of increased glucocorticoid receptor expression during this period (Perlman et al., 2007), a prolonged and heightened corticosterone response to stress compared to adults (Romeo and McEwen, 2006), as well as a higher PFC dopamine response to stress compared to the striatum and NAcc (Abercrombie et al., 1989).

    • Adult forebrain NMDA receptors gate social motivation and social memory

      2017, Neurobiology of Learning and Memory
      Citation Excerpt :

      Dopamine has been widely studied for its roles in reward and motivational behaviors. For example, DA neurons showed a marked increase in calcium transients during social interactions (Gunaydin et al., 2014), whereas decreased dopamine activity in the prefrontal cortex has been indicated in the altered social behaviors following social defeat stress (Jin et al., 2015; Novick et al., 2015; Watt et al., 2014). Further, when the DA neurons in the VTA were optogenetically stimulated, the mice significantly increased the investigation of a novel conspecific while the investigation of a novel object remained unchanged (Gunaydin and Deisseroth, 2014).

    • The exercise-glucocorticoid paradox: How exercise is beneficial to cognition, mood, and the brain while increasing glucocorticoid levels

      2017, Frontiers in Neuroendocrinology
      Citation Excerpt :

      In addition, a human PET imaging study showed that 50 min of walking reduces DAT expression in the striatum in normal aged subjects, and in the striatum and mPFC of aged patients with Parkinson's disease (Ouchi et al., 2001). On the contrary, chronic stress upregulates DAT (Novick et al., 2011, 2015) and plasmalemmal NET (Miner et al., 2006) expression in the mPFC of young and adult male rats, respectively. The above conclusions also led us to examine another potential answer to the exercise-CORT paradox, the mineralocorticoid receptor (MR) and GR CORT receptors.

    View all citing articles on Scopus
    View full text