A neurochemical yin and yang: does serotonin activate and norepinephrine deactivate the prefrontal cortex?

Fitzgerald, Paul J.

doi:10.1007/s00213-010-1856-1

Cited by 30 publications

(25 citation statements)

References 125 publications

(140 reference statements)

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“…In fact, increasing evidence from studies using 5-HTT knock-out mice suggests that having the short allele results in decreased 5-HT neurotransmission based on long-term developmental effects of reduced 5-HT reuptake on cell number, firing rate, and postsynaptic receptor sensitivity (Lira et al, 2003;Kim et al, 2005). Assuming, thus, that healthy control subjects carrying the short/short genotype have lower 5-HT activity and a reduced clearance rate after activation than long/long controls, our results are consistent with previous studies showing decreased cognitive functioning in participants with lower 5-HT levels (Murphy et al, 2002;Porter et al, 2003;Rogers et al, 2003;Allen et al, 2006;Fitzgerald, 2011). However, this interpretation is speculative because there is no consensus on the effects of 5-HTTLPR on 5-HT neurotransmission in humans so far.…”

Section: Discussionsupporting

confidence: 82%

“…Hence, pharmacological compounds targeting 5-HT neurotransmission might be a promising treatment option of WM deficits in cocaine addiction. In addition, our results regarding the 5-HTTLPR and the VNTR In2 polymorphisms in healthy controls seem to confirm the hypothesis (Fitzgerald, 2011) that increased 5-HT activity improves cognitive functioning (in our case WM). Finally, the discovered gene × environment interaction (ie, cocaine use moderated genotype effects) indicates that the complexity of the 5-HT systems requires us to discover other relevant factors to fully understand the involvement of 5-HT in WM processing.…”

Section: Discussionsupporting

confidence: 75%

“…Increasing evidence from rodent and human studies suggests that the serotonin (5-HT) system has an important role in WM processing (Fitzgerald, 2011). For instance, altering 5-HT synthesis by tryptophan depletion revealed that 5-HT transmission positively correlates with activity in the prefrontal cortex (PFC) and with WM performance (Porter et al, 2003;Allen et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Serotonin Transporter and Tryptophan Hydroxylase Gene Variations Mediate Working Memory Deficits of Cocaine Users

Havranek

Vonmoos

Müller

et al. 2015

Neuropsychopharmacol

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Cocaine users consistently develop working memory (WM) impairments but the mediating molecular mechanisms are unknown so far. Recent evidence suggests that the serotonin (5-HT) system is altered by chronic cocaine use, while also being involved in WM processing. Thus, we investigated the effects of genetic variations impacting 5-HT activity and of peripheral 5-HT transporter (5-HTT) mRNA expression on WM performance in cocaine users and stimulant naive controls. Two hundred twenty participants (126 cocaine users, 94 controls) were assessed with visuospatial, spatial, and verbal WM tasks, genotyped for the length polymorphism in the promoter region of the 5-HTT (5-HTTLPR), the variable number of tandem repeats in the second intron of the 5-HTT (VNTR In2), two single-nucleotide polymorphisms (rs4570625 and rs1386497) in the tryptophan hydroxylase-2 (TPH2) gene and quantified for peripheral 5-HTT mRNA expression in whole-blood samples. Several significant gene × environment interactions between 5-HT genotypes and cocaine use on WM emerged: in cocaine users, the long/long (5-HTTLPR), 9+10/9+10 (VNTR In2) and C/C (TPH2 rs1386497) genotypes were risk alleles for WM impairments, whereas in healthy controls these polymorphisms were associated with improved WM performance. Analogously, high 5-HTT mRNA levels were associated with worse executive WM performance in cocaine users but with increased performance in controls. These gene × environment interactions suggest that the 5-HT system has an important role in the development of cognitive deficits in chronic cocaine users. Hence, pharmacological compounds targeting 5-HT neurotransmission might be promising for the treatment of cognitive deficits in cocaine dependence.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

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Serotonin Transporter and Tryptophan Hydroxylase Gene Variations Mediate Working Memory Deficits of Cocaine Users

Havranek

Vonmoos

Müller

et al. 2015

Neuropsychopharmacol

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“…These drugs are commonly used in various psychiatric disorders, such as depression and attention deficit h y p e r a c t i v i t y d i s o r d e r ( A D H D ) [2][3][4][5] . B o t h noradrenergic and serotonergic activity have been associated with cognitive functions, including learning and memory 6,7 . It has been suggested that noradrenaline plays a crucial role in memory processes 8 and that optimal levels of noradrenaline improve these and are necessary for memory consolidation 9 .…”

Section: Introductionmentioning

confidence: 99%

Improving Effect of Atomoxetine and Reboxetine on Memory in Passive Avoidance Task

Yüce

İlkaya

Karabekiroğlu

et al. 2014

Klinik Psikofarmakoloji Bülteni-Bulletin of Clinical Psychophar

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ÖZET:Atomoksetin ve reboksetinin pasif sakınma testinde bellek üzerindeki iyileştirici etkisi Amaç: Serotonin ve/veya noradrenalin geri alım inhibitörlerinin bellek üzerine etkileri çeşitli klinik ve preklinik çalışmalarda araştırılmıştır. Ancak, çelişkili sonuçlar bildirilmiştir. Bu çalışmada selektif noradrenalin geri alım inhibitörü olan atomoksetin ve reboksetinin; serotonin geri alım inhibitörü olan paroksetinin ve trisiklik antidepresan amitriptilinin farelerde bellek üzerindeki etkileri pasif sakınma testi ile karşılaştırılmalı olarak değerlendirilmiştir. Yöntem: Çalışmada 25-30 gr ağırlığında erkek Balb-C fareler kullanıldı. Reboksetin (10 mg/kg), atomoksetin (5 mg/kg), paroksetin (10 mg/kg) ve amitriptilin (10 mg/kg) tek başlarına ve skopolamin (1 mg/kg) ile kombinasyon şeklinde uygulandı. Belleği değerlendirmek için pasif sakınma testi kullanıldı. İlk gün farelerin kazanım süresi (acquisition time) ikinci gün (24 saat sonra) ise retansiyon süresi (retention time) kaydedildi. Tüm ilaçlar ve salin, retansiyon süresinin değerlendirilmesinden 30 dakika önce intraperitoneal olarak uygulandı. Bulgular: Tüm ilaçlar ve salin, tek başlarına uygulandıklarında retansiyon süresini bozmadılar. Ancak, skopolamin retansiyon süresini anlamlı ölçüde bozdu (p=0.003). Skopolamin ile kombine edildiğinde reboksetin, atomoksetin ve paroksetin retansiyon süresinde belirgin bir iyileştirici etki gösterdi. Amitriptilin, skopolamin ile kombine edildiğinde retansiyon süresi anlamlı ölçüde azaldı (p=0.013). Sonuç: Atomoksetin ve reboksetinin bellek bozukluğu üzerindeki iyileştirici etkisi noradrenalin gerialım inhibisyonuna bağlı olabileceği ileri sürülebilir. Bellek bozukluğu üzerinde paroksetinin iyileştirici etkisi artmış serotonerjik aktivite ile ilişkili olabilir. Amitriptilinin bellek bozukluğu üzerinde iyileştirici etkisinin olmaması antikolinerjik yan etkisi nedeniyle olabilir. Bu ilaçların iyileştirici etkilerinin mekanizmalarını açıklamak için aynı model ve hayvan türlerini kullanarak yapılacak daha ileri çalışmalara ihtiyaç vardır. Improving effect of atomoxetine and reboxetine on memory in passive avoidance task Objective: The effects of serotonin and/or noradrenaline re-uptake inhibitors on memory have been investigated in various clinical and pre-clinical studies. However, contradictory results have been reported. In this study, the effect of the selective noradrenaline re-uptake inhibitors atomoxetine and reboxetine, a tricyclic antidepressant, amitriptyline, and a selective serotonin re-uptake inhibitor, paroxetine, on learning and memory were examined alone or in combination with scopolamine in mice using a passive avoidance task. Methods: Male Balb-C mice (25-30 g) were used. Reboxetine (10 mg/kg), atomoxetine (5 mg/kg), paroxetine (10 mg/kg) and amitriptyline (10 mg/ kg) were investigated alone or in combination with scopolamine (1 mg/kg). A passive avoidance task was used to evaluate memory function. Acquisition time was recorded on the first day and retention time on the second (after 24 h). All drugs and sal...

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“…Seen in this way, serotonin may modulate the affective impact of punishment-related signals and also promote response inhibition (Cools et al 2007;Boureau and Dayan 2010). The paper by Fitzgerald (2011) provides an interesting development of this approach by examining the role of serotonin in prefrontal cortex in relation to noradrenaline.…”

mentioning

confidence: 99%

Serotonin revisited

Cowen

Lucki

2010

Psychopharmacology

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A neurochemical yin and yang: does serotonin activate and norepinephrine deactivate the prefrontal cortex?

Abstract: While all of the existing data do not unequivocally support the activation/deactivation hypothesis, there is a large body of support for it.

Cited by 30 publications

References 125 publications

Serotonin Transporter and Tryptophan Hydroxylase Gene Variations Mediate Working Memory Deficits of Cocaine Users

Serotonin Transporter and Tryptophan Hydroxylase Gene Variations Mediate Working Memory Deficits of Cocaine Users

Improving Effect of Atomoxetine and Reboxetine on Memory in Passive Avoidance Task

Serotonin revisited

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