Rigidity and task switching problems - neurophysiological correlates

• 1. Increased tonic dopamine at D2R promotes rigidity
• 2. Noradrenaline reuptake inhibitors facilitate set-shifting
• 3. Beta blockers facilitate cognitive flexibility

1. Increased tonic dopamine at D2R promotes rigidity¶

Learning a response strategy to reinforcement occurs via phasic dopamine in the nucleus accumbens via D1 receptors.¹
Increased tonic dopamine release greatly reduces phasic dopamine release, which results in particularly stable neuronal activity. This is associated with increased rigidity.²](https://dianakuenne.de/p/steinhausen-u-a-hrsg-handbuch-adhs)

The absence of anticipated rewards correlates with reduced tonic dopamine release in the nucleus accumbens. As this disinhibits phasic dopamine, it may facilitate cortico-striatal information processing that mediates behavioral flexibility.³ The reduction in tonic DA stimulation of D2 receptors is essential to enable the switch to a new response strategy once goal attainment criteria are changed.¹ High dopamine and high D1R/D5R binding in the PFC cause increased LTP, persistence of mnemonic representations⁴ and may contribute to perseverative behavior and behavioral stereotypy, leaving patients unable to use new external cues to change ongoing behaviors.⁵

2. Noradrenaline reuptake inhibitors facilitate set-shifting¶

The learning and reversal of rules can be tested by extra-dimensional set shifting. The Intra-Extra Dimensional Set Shift (IED) is a computerized version of the Wisconsin Card Sorting Test and examines visual discrimination and the flexibility of attention set formation. ⁶

Noradrenaline facilitates changes in attention.⁷

• Lesions of the dorsal noradrenergic bundle selectively impair extradimensional set-shifting in rodents⁸
• the α2-adrenoreceptor antagonist idazoxan impairs extradimensional set-shifting in rats⁹
• the α2-adrenoreceptor antagonist atipamezole in rodent mPFC blocks the attentional shift, which was improved by the α1-adrenoreceptor antagonist benoxathian
• the α1-adrenoreceptor antagonist benoxathian alone did not influence the shift in attention¹⁰
• CRF fusion into the locus coeruleus improved extradimensional set-shifting at low doses, while higher doses impaired reversal learning.188
• Noradrenaline reuptake inhibitors improving behavioral flexibility¹¹
• Atomoxetine improved set-shifting in rats with noradrenergic lesions, while it worsened performance in intact rats¹²
• Atomoxetine improved set-shifting at low doses¹³, while high doses worsened it 189

The α1/2-adrenoreceptor agonist clonidine dramatically impaired extradimensional set-shifting in healthy human volunteers in a task similar to the Wisconsin Card Sort Test. The α2-adrenoreceptor antagonist idazoxan showed the same effect, which was potentiated by additional clonidine administration.¹⁴
In contrast, the α2-adrenoreceptor agonist guanfacine did not affect cognitive performance in young healthy male adults¹⁵

3. Beta blockers facilitate cognitive flexibility¶

β-Adrenoreceptor blockade by beta-blockers such as propranolol and atenolol shows an improvement in cognitive flexibility¹⁶, while also reducing stress and anxiety levels, which could influence the outcome.⁶