Postnatal development of neurotransmitter systems and their relevance to extinction of conditioned fear

Kim, Jee Hyun; Perry, Christina; Ganella, Despina E.; Madsen, Heather B.

doi:10.1016/j.nlm.2016.10.018

Cited by 32 publications

(24 citation statements)

References 277 publications

(429 reference statements)

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“…During adolescence, there are dramatic changes in dopamine receptor expression in the mPFC, with a transient relative dominance of D1R against D2R activity (Andersen et al, 2000; Kim et al, 2017). This is particularly relevant for the emergence of anxiety disorders; computational models predict PFC D1R signaling to be activated by CS conditioning whereas PFC D2R signaling to be activated by CS extinction (Seamans and Yang, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, there is a well-established imbalance between dopamine receptor 1 vs. 2 (D1R vs. D2R) signaling during adolescence, which leads to inefficiency in prefrontal cortical processing that is required for cue inhibition (Andersen et al, 2000; Kim et al, 2017). Specifically, there is a relative dominance of D1R compared to D2R activity in the medial prefrontal cortex (mPFC) during adolescence compared to adulthood (Tarazi et al, 1998; Seamans and Yang, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Aripiprazole Facilitates Extinction of Conditioned Fear in Adolescent Rats

Ganella

Lee-Kardashyan

Luikinga

et al. 2017

Front. Behav. Neurosci.

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Anxiety disorders are the most common type of mental disorder during adolescence, which is at least partly due to the resistance to extinction exhibited at this age. The dopaminergic system is known to be dysregulated during adolescence; therefore, we aimed to facilitate extinction in adolescent rats using the dopamine receptor 2 partial agonist aripiprazole (Abilify™), and examine the behavioral and neural outcomes. Adolescent rats were conditioned to fear a tone. The next day, rats received extinction 30 min after a systemic injection of either 5 mg/kg aripiprazole or vehicle, and then were tested the following day. For the immunohistochemistry experiment, naïve and “no extinction” conditions were added and rats were perfused either on the extinction day or test day. To assess the activation of neurons receiving dopaminergic input, c-Fos, and dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32) labeled neurons were quantified in the amygdala and the medial prefrontal cortex (mPFC). Systemic treatment with aripiprazole at the time of extinction significantly reduced freezing at test the next day. This effect was not observed in rats that were fear conditioned but did not receive any extinction. Aripiprazole's facilitation of extinction was accompanied by increased activation of neurons in the mPFC. Taken together, aripiprazole represents a novel pharmacological adjunct to exposure therapy worthy of further examination. The effect of aripiprazole is related to enhanced activation of mPFC neurons receiving dopaminergic innervation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Aripiprazole Facilitates Extinction of Conditioned Fear in Adolescent Rats

Ganella

Lee-Kardashyan

Luikinga

et al. 2017

Front. Behav. Neurosci.

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“…Differing contribution of AMPARs to the extinction learning process have been reported. Although AMPAR antagonists in the amygdala have no effect on extinction acquisition (Kim et al, 2017), electrophysiological experiments have demonstrated that fear extinction learning corresponds to a loss of calcium-permeable AMPA receptors (GluR1-containing) in the BLA (Clem and Huganir, 2010). As previously reported, auditory fear conditioning is accompanied by enhanced synaptic plasticity at auditory input synapses in the BLA, and extinction reverses both the enhanced synaptic efficacy and the conditioning-induced enhancement of surface AMPAR expression (Lin et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Fear Extinction in the Basolateral Amygdala by Dopamine D2 Receptors Accompanied by Altered GluR1, GluR1-Ser845 and NR2B Levels

Shi

Fan

Xue

et al. 2017

Front. Behav. Neurosci.

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The amygdala, a critical structure for both Pavlovian fear conditioning and fear extinction, receives sparse but comprehensive dopamine innervation and contains dopamine D1 and D2 receptors. Fear extinction, which involves learning to suppress the expression of a previously learned fear, appears to require the dopaminergic system. The specific roles of D2 receptors in mediating associative learning underlying fear extinction require further study. Intra-basolateral amygdala (BLA) infusions of a D2 receptor agonist, quinpirole, and a D2 receptor antagonist, sulpiride, prior to fear extinction and extinction retention were tested 24 h after fear extinction training for long-term memory (LTM). LTM was facilitated by quinpirole and attenuated by sulpiride. In addition, A-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor glutamate receptor 1 (GluR1) subunit, GluR1 phospho-Ser845, and N-methyl-D-aspartic acid receptor NR2B subunit levels in the BLA were generally increased by quinpirole and down-regulated by sulpiride. The present study suggests that activation of D2 receptors facilitates fear extinction and that blockade of D2 receptors impairs fear extinction, accompanied by changes in GluR1, GluR1-Ser845 and NR2B levels in the amygdala.

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“…Chambers, Taylor, & Potenza, ; Flores, Morales‐Medina, & Diaz, ; Spear, ; Volkow & Morales, ). Although the biological bases for this vulnerability are uncertain, they could be related to the natural maturation of the brain during adolescence (Andersen, Thompson, Rutstein, Hostetter, & Teicher, ; Ganella, Drummond, Ganella, Whittle, & Kim, ; Gogtay et al, ; Kim, Perry, Ganella, & Madsen, ; Rakic, Bourgeois, Eckenhoff, Zecevic, & Goldman‐Rakic, ; Sowell, Thompson, & Toga, ).…”

Section: Introductionmentioning

confidence: 99%

Postnatal developmental trajectory of dopamine receptor 1 and 2 expression in cortical and striatal brain regions

Cullity

Madsen

Perry

et al. 2018

J of Comparative Neurology

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Healthy brain function requires a balance between the activity of dopamine receptor 1 (D1) and dopamine receptor 2 (D2). Alterations in this balance increase the risk for numerous developmental brain disorders. Indeed, D1 and D2 expression fluctuates throughout maturation, although there is conflicting evidence regarding the precise changes that occur. Here, we used stereology to investigate the developmental changes in the number of D1‐ or D2‐expressing neurons in the prelimbic cortex, infralimbic cortex (IL), insula cortex, dorsal striatum, and ventral striatum of female and male mice with green fluorescent protein‐tagged D1 or D2. Postnatal day 17, 25, 35, 49, and 70 were examined to cover juvenility to adulthood. In all regions, analysis of D1 density compared to D2 density within each sex seldom detected effects or interactions involving age. However, D1:D2 density ratio changed across age depending on sex. In the IL, D1:D2 density ratio increased in females from adolescence, whereas it was stable in males. In the insula cortex, D1:D2 ratio initially increased in males but decreased in females from juvenility to preadolescence. The ratio then increased in males and females from adolescence to adulthood, with males showing a more dramatic increase. In both the dorsal and ventral striatum, the ratio increased from adolescence. In all regions, females had a higher ratio compared to males throughout maturation except in the insula cortex at P25. These comprehensive observations are novel, and highlight how the maturational changes in the expression of these receptors may contribute to developmental disorders.

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Postnatal development of neurotransmitter systems and their relevance to extinction of conditioned fear

Cited by 32 publications

References 277 publications

Aripiprazole Facilitates Extinction of Conditioned Fear in Adolescent Rats

Aripiprazole Facilitates Extinction of Conditioned Fear in Adolescent Rats

Regulation of Fear Extinction in the Basolateral Amygdala by Dopamine D2 Receptors Accompanied by Altered GluR1, GluR1-Ser845 and NR2B Levels

Postnatal developmental trajectory of dopamine receptor 1 and 2 expression in cortical and striatal brain regions

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