Decreased prefrontal cortex dopamine activity following adolescent social defeat in male rats: role of dopamine D2 receptors

Abstract

Rationale Adverse social experience in adolescence causes reduced medial prefrontal cortex (mPFC) dopamine (DA) and associated behavioral deficits in early adulthood. Objective To determine whether mPFC DA hypofunction following social stress is specific to adolescent experience, and if this results from stress-induced DA D2 receptor activation. Materials and Methods Male rats exposed to repeated social defeat during adolescence or adulthood had mPFC DA activity sampled 17 days later. Separate experiments used freely-moving microdialysis to measure mPFC DA release in response to adolescent defeat exposure. At P40, 49 and 56 mPFC DA turnover was assessed to identify when DA activity decreased in relation to the adolescent defeat experience. Finally, non-defeated adolescent rats received repeated intra-mPFC infusions of the D2 receptor agonist quinpirole, while another adolescent group received intra-mPFC infusions of the D2 antagonist amisulpride before defeat exposure. Results Long-term decreases or increases in mPFC DA turnover were observed following adolescent or adult defeat, respectively. Adolescent defeat exposure elicits sustained increases in mPFC DA release, and DA turnover remains elevated beyond the stress experience before declining to levels below normal at P56. Activation of mPFC D2 receptors in non-defeated adolescents decreases DA activity in a similar manner to that caused by adolescent defeat, while defeat-induced reductions in mPFC DA activity are prevented by D2 receptor blockade. Conclusions Both the developing and mature PFC DA systems are vulnerable to social stress, but only adolescent defeat causes DA hypofunction. This appears to result in part from stress-induced activation of mPFC D2 autoreceptors.

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

“…The comparable DA accumulation response to DMI plus vehicle treatment in both controls and defeated rats suggests that NET-mediated DA transport in the adult infralimbic mPFC is not altered by adolescent social defeat, and so is unlikely to contribute to the differences observed following DAT blockade with GBR-12909. These results support the hypothesis that increased DAT expression in the adult infralimbic mPFC following adolescent defeat leads to functional increases in DAT-mediated clearance, which in turn may contribute to defeat-induced mPFC dopaminergic hypofunction (Watt et al, 2009, 2014; Burke et al, 2013) by lowering availability of extracellular DA. Increased DA uptake could also enhance end-product inhibition of tyrosine hydroxlase within terminals to directly reduce DA synthesis (Bannon and Roth, 1983) and produce the previously observed decrease in adult mPFC DA content following adolescent defeat (Watt et al, 2009).…”

“…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, 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).…”

“…Stressors preferentially activate mesocortical DA release (Abercrombie et al, 1989), which may be augmented during adolescence by enhanced mPFC neuronal responses to stress (Lyss et al, 1999). Adolescent rats exposed to threat of social defeat show increased extracellular DA release in the mPFC (Watt et al, 2014), similar to that shown by adult rats in response to social challenge (Tidey and Miczek, 1996). Such increased mPFC DA release during adolescent defeat would be expected to result in enhanced activation of DA type 2 (D2) autoreceptors located on mPFC DA terminals, which function to inhibit further DA release (Wolf and Roth, 1987) and restore DA homeostasis.…”

“…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).…”

Inhalation Administration of Valerena-4,7(11)-diene from <i>Nardostachys chinensis</i> Roots Ameliorates Restraint Stress-Induced Changes in Murine Behavior and Stress-Related Factors

“…In another report, social defeat stress initiated depression and decreased DA turnover in rats, and the D 2 antagonist, amisulpride, prevented these defeat-induced reductions in DA turnover. 24) Attenuation of dopaminergic neurons directly may lead to sedation of excitement behaviors and sympathetic activities. Therefore, it also seemed that D 2 -antagonist activity was involved in the effect of VLD.…”