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Noradrenergic versus dopaminergic modulation of impulsivity, attention and monitoring behaviour in rats performing the stop-signal task: possible relevance to ADHD.

Bari A, Robbins TW - Psychopharmacology (Berl.) (2013)

Bottom Line: The results are described in terms of the effects of modulating specific receptor subtypes on various behavioural measures such as response inhibition, perseveration, sustained attention, error monitoring and motivation.No relevant effects were obtained after targeting DA D1, D2 or D4 receptors, while both a D3 receptor agonist and antagonist improved post-error slowing and compulsive nose-poke behaviour, though generally impairing other task measures.Our results suggest that the use of specific pharmacological agents targeting α2 and β noradrenergic receptors may improve existing treatments for attentional deficits and impulsivity, whereas DA D3 receptors may modulate error monitoring and perseverative behaviour.

View Article: PubMed Central - PubMed

Affiliation: Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, CB2 3EB, UK, andbari@gmail.com.

ABSTRACT

Rationale: Deficient response inhibition is a prominent feature of many pathological conditions characterised by impulsive and compulsive behaviour. Clinically effective doses of catecholamine reuptake inhibitors are able to improve such inhibitory deficits as measured by the stop-signal task (SST) in humans and other animals. However, the precise therapeutic mode of action of these compounds in terms of their relative effects on dopamine (DA) and noradrenaline (NA) systems in prefrontal cortical and striatal regions mediating attention and cognitive control remains unclear.

Objectives: We sought to fractionate the effects of global catecholaminergic manipulations on SST performance by using receptor-specific compounds for NA or DA. The results are described in terms of the effects of modulating specific receptor subtypes on various behavioural measures such as response inhibition, perseveration, sustained attention, error monitoring and motivation.

Results: Blockade of α2-adrenoceptors improved sustained attention and response inhibition, whereas α1 and β1/2 adrenergic receptor antagonists disrupted go performance and sustained attention, respectively. No relevant effects were obtained after targeting DA D1, D2 or D4 receptors, while both a D3 receptor agonist and antagonist improved post-error slowing and compulsive nose-poke behaviour, though generally impairing other task measures.

Conclusions: Our results suggest that the use of specific pharmacological agents targeting α2 and β noradrenergic receptors may improve existing treatments for attentional deficits and impulsivity, whereas DA D3 receptors may modulate error monitoring and perseverative behaviour.

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Related in: MedlinePlus

Nafadotride (D3 antagonist) significantly increased SSRT at 3 mg/kg compared with vehicle administration (p < 0.05). The same dose produced longer mRT (p < 0.01 compared with vehicle) and lower go accuracy (p < 0.01 compared with all the other conditions). At the dose of 0.3 mg/kg mRT was faster than both 1 (p < 0.05) and 3 mg/kg (p < 0.01). *p < 0.05; **p < 0.01
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Fig8: Nafadotride (D3 antagonist) significantly increased SSRT at 3 mg/kg compared with vehicle administration (p < 0.05). The same dose produced longer mRT (p < 0.01 compared with vehicle) and lower go accuracy (p < 0.01 compared with all the other conditions). At the dose of 0.3 mg/kg mRT was faster than both 1 (p < 0.05) and 3 mg/kg (p < 0.01). *p < 0.05; **p < 0.01

Mentions: Repeated-measures ANOVA revealed a main effect of nafadotride on SSRT (F(3,45) = 3.49, p < 0.05; Fig. 8); pairwise comparisons showed that the highest dose (3 mg/kg) significantly slowed SSRT compared with vehicle controls (p < 0.05). A main effect of the drug on mRT was also found (F(2,35) = 11.78, p < 0.01). Post-hoc analyses revealed that 3 mg/kg of nafadotride slowed mRT compared with both vehicle (p < 0.01) and 0.3 mg/kg (p < 0.01), while mRT at 1 mg/kg was slower only compared with the 0.3 mg/kg dose (p < 0.05). No effects of nafadotride were detected on stop accuracy (F(3,45) = 2.26, ns) and SDGoRT (F(3,45) = 2.58, p = 0.065, ns). Go accuracy was affected by the drug (F(1,22) = 21.57, p < 0.01) only at the highest dose (3 mg/kg) at which it was lower compared with all the other conditions (p < 0.01). There was a main effect of the drug on PES (F(3,45) = 5.39, p < 0.01; Table 2), with the highest dose (3 mg/kg) making the animals significantly slower after a stop error (p < 0.05). ANOVA revealed a significant effect of the drug on NP/TO (F(3,45) = 13.7, p < 0.01), but not on RCL (F(2,24) = 0.015, ns). Pairwise comparisons showed that, at the highest dose (3 mg/kg), NP/TO was significantly lower than in all the other conditions (p < 0.05).Fig. 8


Noradrenergic versus dopaminergic modulation of impulsivity, attention and monitoring behaviour in rats performing the stop-signal task: possible relevance to ADHD.

Bari A, Robbins TW - Psychopharmacology (Berl.) (2013)

Nafadotride (D3 antagonist) significantly increased SSRT at 3 mg/kg compared with vehicle administration (p < 0.05). The same dose produced longer mRT (p < 0.01 compared with vehicle) and lower go accuracy (p < 0.01 compared with all the other conditions). At the dose of 0.3 mg/kg mRT was faster than both 1 (p < 0.05) and 3 mg/kg (p < 0.01). *p < 0.05; **p < 0.01
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3824307&req=5

Fig8: Nafadotride (D3 antagonist) significantly increased SSRT at 3 mg/kg compared with vehicle administration (p < 0.05). The same dose produced longer mRT (p < 0.01 compared with vehicle) and lower go accuracy (p < 0.01 compared with all the other conditions). At the dose of 0.3 mg/kg mRT was faster than both 1 (p < 0.05) and 3 mg/kg (p < 0.01). *p < 0.05; **p < 0.01
Mentions: Repeated-measures ANOVA revealed a main effect of nafadotride on SSRT (F(3,45) = 3.49, p < 0.05; Fig. 8); pairwise comparisons showed that the highest dose (3 mg/kg) significantly slowed SSRT compared with vehicle controls (p < 0.05). A main effect of the drug on mRT was also found (F(2,35) = 11.78, p < 0.01). Post-hoc analyses revealed that 3 mg/kg of nafadotride slowed mRT compared with both vehicle (p < 0.01) and 0.3 mg/kg (p < 0.01), while mRT at 1 mg/kg was slower only compared with the 0.3 mg/kg dose (p < 0.05). No effects of nafadotride were detected on stop accuracy (F(3,45) = 2.26, ns) and SDGoRT (F(3,45) = 2.58, p = 0.065, ns). Go accuracy was affected by the drug (F(1,22) = 21.57, p < 0.01) only at the highest dose (3 mg/kg) at which it was lower compared with all the other conditions (p < 0.01). There was a main effect of the drug on PES (F(3,45) = 5.39, p < 0.01; Table 2), with the highest dose (3 mg/kg) making the animals significantly slower after a stop error (p < 0.05). ANOVA revealed a significant effect of the drug on NP/TO (F(3,45) = 13.7, p < 0.01), but not on RCL (F(2,24) = 0.015, ns). Pairwise comparisons showed that, at the highest dose (3 mg/kg), NP/TO was significantly lower than in all the other conditions (p < 0.05).Fig. 8

Bottom Line: The results are described in terms of the effects of modulating specific receptor subtypes on various behavioural measures such as response inhibition, perseveration, sustained attention, error monitoring and motivation.No relevant effects were obtained after targeting DA D1, D2 or D4 receptors, while both a D3 receptor agonist and antagonist improved post-error slowing and compulsive nose-poke behaviour, though generally impairing other task measures.Our results suggest that the use of specific pharmacological agents targeting α2 and β noradrenergic receptors may improve existing treatments for attentional deficits and impulsivity, whereas DA D3 receptors may modulate error monitoring and perseverative behaviour.

View Article: PubMed Central - PubMed

Affiliation: Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, CB2 3EB, UK, andbari@gmail.com.

ABSTRACT

Rationale: Deficient response inhibition is a prominent feature of many pathological conditions characterised by impulsive and compulsive behaviour. Clinically effective doses of catecholamine reuptake inhibitors are able to improve such inhibitory deficits as measured by the stop-signal task (SST) in humans and other animals. However, the precise therapeutic mode of action of these compounds in terms of their relative effects on dopamine (DA) and noradrenaline (NA) systems in prefrontal cortical and striatal regions mediating attention and cognitive control remains unclear.

Objectives: We sought to fractionate the effects of global catecholaminergic manipulations on SST performance by using receptor-specific compounds for NA or DA. The results are described in terms of the effects of modulating specific receptor subtypes on various behavioural measures such as response inhibition, perseveration, sustained attention, error monitoring and motivation.

Results: Blockade of α2-adrenoceptors improved sustained attention and response inhibition, whereas α1 and β1/2 adrenergic receptor antagonists disrupted go performance and sustained attention, respectively. No relevant effects were obtained after targeting DA D1, D2 or D4 receptors, while both a D3 receptor agonist and antagonist improved post-error slowing and compulsive nose-poke behaviour, though generally impairing other task measures.

Conclusions: Our results suggest that the use of specific pharmacological agents targeting α2 and β noradrenergic receptors may improve existing treatments for attentional deficits and impulsivity, whereas DA D3 receptors may modulate error monitoring and perseverative behaviour.

Show MeSH
Related in: MedlinePlus