Increased dopamine transporter function as a mechanism for dopamine hypoactivity in the adult infralimbic medial prefrontal cortex following adolescent social 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 (20mg/kg, ip.) to isolate infralimbic mPFC DA clearance to DAT, then administered the selective DAT inhibitor GBR-12909 (20 or 40mg/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.

Impact of juvenile chronic stress on adult cortico-accumbal function: Implications for cognition and addiction

“…However, repeated activation of restorative mechanisms may result in a hypofunctional state, especially if these continue to operate in the absence of further stress. This idea is supported by studies showing that deficits in adult mPFC dopamine caused by adolescent social defeat of rats can be prevented by pharmacological blockade of release-inhibiting D 2 autoreceptors in the mPFC during the defeat experience (Watt et al, 2014), and the finding that rats defeated in adolescence exhibit increased function of dopamine transporters in the mPFC (i.e., increased dopamine clearance) as adults (Novick et al, 2015). Such changes to regulatory mechanisms of neural activity suggest that chronic juvenile stress irreparably disrupts the normal trajectory of PFC development, and may explain why deficits in PFC function and cognition are evident in adulthood, well beyond the stress experience.…”

Adolescent social defeat alters N-methyl-d-aspartic acid receptor expression and impairs fear learning in adulthood

“…The adolescent social defeat procedure was conducted using a modified resident-intruder paradigm as described previously [13, 17, 18]. Briefly, at P35 (mid-adolescence [32]), male rats were placed in the cage of a larger, aggressive adult (>P90) Sprague Dawley resident male rat, which had been housed in isolation for 3 weeks and pre-selected for aggressive behavior against practice male adolescent intruders (practice intruders were not included in any subsequent experiments).…”

“…In addition, male rats defeated in adolescence show deficits in adult mesocortical dopamine (DA) function [13–18], a system at least partially regulated by NMDA receptor activation [3, 19, 20]. Thus, dysfunction of NMDA receptors may represent a potential mechanism by which adolescent social defeat leads to long term changes in behavior and neurochemistry.…”

Enhanced dopamine D2 autoreceptor function in the adult prefrontal cortex contributes to dopamine hypoactivity following adolescent social stress

“…These behavioral alterations are reminiscent of those seen in bullying‐associated neuropsychiatric disorders and indicate disrupted mPFC dopamine activity (Clark & Noudoost, ; Steketee, ; Yates et al., ). In line with this, adolescent defeat decreases dopamine activity in the adult (P56) mPFC (Watt et al., , ), which is mediated, in part, by increased DAT expression and function in the infralimbic region of the mPFC (Novick, Forster, Tejani‐Butt, & Watt, ; Novick et al., ). A role for altered D2 autoreceptor function in contributing to later cortical dopamine hypofunction is also implied, as pharmacological blockade of mPFC D2 autoreceptors during the adolescent defeat experience prevents the decrease in dopamine activity at P56 (Watt et al., ).…”

“…Further, this decrease in adult mPFC dopamine activity can be replicated in the absence of any social stress by repeated pharmacological activation of mPFC D2 autoreceptors during the same period of adolescence (P35‐39; Watt et al., ). Activation of D2 autoreceptors directly increases DAT‐mediated dopamine clearance (Cass & Gerhardt, ; Schmitz, Schmauss, & Sulzer, ), which may explain the observed increase in adult mPFC DAT function (Novick et al., ). Enhanced D2 autoreceptor inhibition of dopamine release combined with greater DAT‐mediated dopamine clearance may also increase presynaptic dopamine concentrations to enhance end‐product inhibition of TH activity and decrease dopamine synthesis (Almas, Le Bourdelles, Flatmark, Mallet, & Haavik, ; Galloway et al., ), which could also be potentiated by a loss of phosphorylation at several serine residues, particularly serine 40 (Salvatore, Waymire, & Haycock, ).…”