Investigating serotonergic contributions to cognitive effort allocation, attention, and impulsive action in female rats

Abstract

Background: Individuals must frequently evaluate whether it is worth allocating cognitive effort for desired outcomes. Motivational deficits are a common feature of psychiatric illness such as major depression. Selective serotonin reuptake inhibitors are commonly used to treat this disorder, yet some data suggest these compounds are ineffective at treating amotivation, and may even exacerbate it. Aims: Here we used the rodent Cognitive Effort Task (rCET) to assess serotonergic (5-hydroxytryptamine, 5-HT) contributions to decision-making with cognitive effort costs. Methods: The rCET is a modified version of the 5-choice serial reaction time task, a well-validated test of visuospatial attention and impulse control. At the start of each rCET trial, rats chose one of two levers, which set the difficulty of an attentional challenge, namely the localization of a visual stimulus illuminated for 0.2 or 1 s on hard versus easy trials. Successful completion of hard trials was rewarded with double the sugar pellets. Twenty-four female Long–Evans rats were trained on the rCET and systemically administered the 5-HT1A agonist 8-OH-DPAT, the 5-HT2A antagonist M100907, the 5-HT2C agonist Ro-60-0175, as well as the 5-HT2C antagonist SB 242, 084. Results: 5-HT2A antagonism dose-dependently reduced premature responding, while 5-HT2C antagonism had the opposite effect. 8-OH-DPAT impaired accuracy of target detection at higher doses, while Ro-60-0175 dose-dependently improved accuracy on difficult trials. However, none of the drugs affected the rats’ choice of the harder option. Conclusion: When considered with existing work evaluating decision-making with physical effort costs, it appears that serotonergic signalling plays a minor role in guiding effort allocation.

5-HT2C receptor perturbation has bidirectional influence over instrumental vigour and restraint

“…In parallel to the improvements in Go trial performance, we also observed an increase in inappropriate, premature responses on No-Go trials following systemic SB242084, which once again was specific to small reward trials. There is much evidence from both manipulation [29,30] and physiological [31,32] approaches that central serotonin is a key modulator of the ability to wait for reward, with 5-HT 2C receptors playing a central role in mediating this [6,11,12,15,17,20]. However, the effect we observed here did not manifest as an overall increase in impulsivity nor a gross timing deficit.…”

“…Notably, however, this occurred in the context of a task with no equivalent effort requirements (note that while this task was arguably cognitively demanding, a recent study found no effect of 5-HT 2C receptor agents on cognitive effort allocation [11]). Moreover, this enhanced response speed did not come at any cost to instrumental precision; after having received the 5HT 2C receptor ligand, rats were no less likely to choose the correct lever or make more lever presses than required.…”

“…Several lines of research have shown that 5-HT, and its 5-HT 2C receptor in particular, plays an important role in regulating instrumental vigour. For instance, depletion of central 5-HT or antagonism of the 5-HT 2C receptor both speed responding and increase willingness to work for reward [5][6][7][8][9][10][11]. This has resulted in 5-HT 2C receptors being considered a possible target for the treatment of disorders of motivation such as apathy [7][8][9][10]12,13].…”

Evaluation of cognitive effort in rats is not critically dependent on ventrolateral orbitofrontal cortex

“…Transgene status was not utilized for the current study but was included as a between‐subjects variable for all analyses. Under baseline conditions, this strain behaves similar to regular Long‐Evans cohorts on the rCET, and transgene status does not generally interact with pharmacological interventions (Silveira, Wittekindt, Mortazavi, Hathaway, & Winstanley, 2020). We opted to use females given enough rats of the same age were readily available, and they display similar rCET behaviour to males (Silveira et al., 2020).…”

“…Under baseline conditions, this strain behaves similar to regular Long‐Evans cohorts on the rCET, and transgene status does not generally interact with pharmacological interventions (Silveira, Wittekindt, Mortazavi, Hathaway, & Winstanley, 2020). We opted to use females given enough rats of the same age were readily available, and they display similar rCET behaviour to males (Silveira et al., 2020). While we did not track oestrous cycle, this does not affect baseline choice patterns in other rodent decision‐making tasks (Orsini, Willis, Gilbert, Bizon, & Setlow, 2015; Uban, Rummel, Floresco, & Galea, 2012).…”