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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

Administration of the dopamine D3 receptor agonist 7-OH-PIPAT produced strong detrimental effects, specifically on go measures. mRT was longer than vehicle at all the doses tested (p < 0.01) and the highest dose was also different from all the other conditions (p < 0.01). Go accuracy was lower at 1 mg/kg (p < 0.01 compared with all the other conditions) and at 0.3 mg/kg (p < 0.01) compared with vehicle (Veh). **p < 0.01
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Fig7: Administration of the dopamine D3 receptor agonist 7-OH-PIPAT produced strong detrimental effects, specifically on go measures. mRT was longer than vehicle at all the doses tested (p < 0.01) and the highest dose was also different from all the other conditions (p < 0.01). Go accuracy was lower at 1 mg/kg (p < 0.01 compared with all the other conditions) and at 0.3 mg/kg (p < 0.01) compared with vehicle (Veh). **p < 0.01

Mentions: 7-OH-PIPAT administration (Fig. 7) had no effect on SSRT (F(3,54) = 1.17, ns). The drug, however, had a strong effect to slow mRT (F(3,54) = 31.24, p < 0.01). Pairwise analyses showed that all doses slowed mRT compared with vehicle (p < 0.01) and that at the highest dose (1 mg/kg) mRT was slower compared with all the other conditions (p < 0.01). 7-OH-PIPAT also affected stop accuracy (F(3,54) = 3.10, p < 0.05), but pairwise comparisons did not detect significant differences between doses. Repeated measures ANOVA showed that 7-OH-PIPAT administration significantly affected go accuracy (F(2,30) = 34.11, p < 0.01). According to post-hoc pairwise comparisons, 1 mg/kg impaired go accuracy compared with all the other conditions (p < 0.01), 0.3 mg/kg also being different from the vehicle condition (p < 0.01). There was no effect of the drug on SDGoRT (F(2,42) = 0.77, ns), but a main effect was detected for PES (F(2,36) = 7.31, p < 0.01; Table 2). In this case, the highest dose (1 mg/kg) increased PES compared with the vehicle (p < 0.01) and the 0.1 mg/kg (p < 0.05) conditions. Also, 0.3 mg/kg increased PES compared with 0.1 mg/kg (p < 0.05), but not compared with vehicle. ANOVA revealed a significant effect on NP/TO (F(2,31) = 4.25, p < 0.05) and RCL (F(2,41) = 3.87, p < 0.05); only in this latter case, pairwise comparisons showed that the highest dose (1 mg/kg) slowed the rats compared with the vehicle condition (p < 0.05), but failed to find a significant difference between doses for NP/TO.Fig. 7


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)

Administration of the dopamine D3 receptor agonist 7-OH-PIPAT produced strong detrimental effects, specifically on go measures. mRT was longer than vehicle at all the doses tested (p < 0.01) and the highest dose was also different from all the other conditions (p < 0.01). Go accuracy was lower at 1 mg/kg (p < 0.01 compared with all the other conditions) and at 0.3 mg/kg (p < 0.01) compared with vehicle (Veh). **p < 0.01
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3824307&req=5

Fig7: Administration of the dopamine D3 receptor agonist 7-OH-PIPAT produced strong detrimental effects, specifically on go measures. mRT was longer than vehicle at all the doses tested (p < 0.01) and the highest dose was also different from all the other conditions (p < 0.01). Go accuracy was lower at 1 mg/kg (p < 0.01 compared with all the other conditions) and at 0.3 mg/kg (p < 0.01) compared with vehicle (Veh). **p < 0.01
Mentions: 7-OH-PIPAT administration (Fig. 7) had no effect on SSRT (F(3,54) = 1.17, ns). The drug, however, had a strong effect to slow mRT (F(3,54) = 31.24, p < 0.01). Pairwise analyses showed that all doses slowed mRT compared with vehicle (p < 0.01) and that at the highest dose (1 mg/kg) mRT was slower compared with all the other conditions (p < 0.01). 7-OH-PIPAT also affected stop accuracy (F(3,54) = 3.10, p < 0.05), but pairwise comparisons did not detect significant differences between doses. Repeated measures ANOVA showed that 7-OH-PIPAT administration significantly affected go accuracy (F(2,30) = 34.11, p < 0.01). According to post-hoc pairwise comparisons, 1 mg/kg impaired go accuracy compared with all the other conditions (p < 0.01), 0.3 mg/kg also being different from the vehicle condition (p < 0.01). There was no effect of the drug on SDGoRT (F(2,42) = 0.77, ns), but a main effect was detected for PES (F(2,36) = 7.31, p < 0.01; Table 2). In this case, the highest dose (1 mg/kg) increased PES compared with the vehicle (p < 0.01) and the 0.1 mg/kg (p < 0.05) conditions. Also, 0.3 mg/kg increased PES compared with 0.1 mg/kg (p < 0.05), but not compared with vehicle. ANOVA revealed a significant effect on NP/TO (F(2,31) = 4.25, p < 0.05) and RCL (F(2,41) = 3.87, p < 0.05); only in this latter case, pairwise comparisons showed that the highest dose (1 mg/kg) slowed the rats compared with the vehicle condition (p < 0.05), but failed to find a significant difference between doses for NP/TO.Fig. 7

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