Rafal Rygula

The effects of acute pharmacological stimulation of the 5-HT, NA and DA systems on the cognitive judgement bias of rats in the ambiguous-cue interpretation paradigm.

In the present study, we investigated the effects of acute pharmacological stimulation of the serotonergic (5-HT), noradrenergic (NA) and dopaminergic (DA) systems on the valence of cognitive judgement bias of rats in the ambiguous-cue interpretation (ACI) paradigm. To accomplish this goal, after initial behavioural training, different groups of rats received single injections of citalopram, desipramine or d-amphetamine and were subsequently tested with the ACI paradigm. Each drug was administered in 3 doses using a fully randomised Latin square design. Citalopram at the dose of 1mg/kg significantly biased animals towards positive interpretation of the ambiguous cue, while at higher doses (5 and 10mg/kg), the animals interpreted the ambiguous cue more negatively. Desipramine at all 3 tested doses (1, 2 and 5mg/kg) significantly biased animals towards negative interpretation of the ambiguous cue, while d-amphetamine at the dose of 1mg/kg induced positive bias, having no effects at lower doses (0.1 and 0.5mg/kg). Our results indicate that cognitive bias in rats can be influenced by acute pharmacological intervention.

Effects of optimism on motivation in rats

In humans, optimism is a cognitive construct related to motivation; optimists exert effort, whereas pessimists disengage from effort. In this study, using a recently developed ambiguous-cue interpretation (ACI) paradigm we took the unique opportunity to investigate whether “optimism” as a trait is correlated with motivation in rodents. In a series of ACI tests (cognitive bias screening, CBS), we identified rats displaying “pessimistic” and “optimistic” traits. Subsequently, we investigated the trait differences in the motivation of these rats to gain reward and to avoid punishment using a progressive ratio (PR) schedule of reinforcement paradigm. Although “optimistic” and “pessimistic” animals did not differ in their motivation to avoid punishment, the “optimistic” rats were significantly more motivated to gain reward than their “pessimistic” conspecifics. For the first time, we showed an association between cognitive judgment bias and motivation in an animal model. Because both investigated processes are closely related to mental health and wellbeing, our results may be valuable for preclinical modeling of many psychiatric disorders.

The effects of cocaine and mazindol on the cognitive judgement bias of rats in the ambiguous-cue interpretation paradigm

Recent research has shown that pharmacological enhancement of dopaminergic function increases an optimism bias in humans. The present study investigated whether acute dopaminergic system stimulation through the administration of two dopamine-mimetic drugs, cocaine and mazindol, have similar effects in rats. To accomplish this goal, after initial behavioural training, two groups of rats received single injections of either cocaine or mazindol and were subsequently tested with the ambiguous-cue interpretation (ACI) paradigm. Both drugs were administered in three doses using the fully randomised Latin square designs. Cocaine (1, 2 and 5mg/kg) had no significant effect on the interpretation of the ambiguous cue. Mazindol at all three doses (0.5, 1 and 2mg/kg) significantly biased animals towards negative interpretation of the ambiguous cue. The results are discussed in relation to pharmacological and behaviourally evoked actions of tested compounds.

Trait “pessimism” is associated with increased sensitivity to negative feedback in rats

Several cognitive theories of depression have proposed that cognitive judgment bias determines individual vulnerability to this disorder. Indeed, we have recently demonstrated a relationship between pessimistic judgment bias and vulnerability of rats to the stress-induced anhedonia, and a negative correlation between the level of pessimism and motivation. To further characterize the effects of trait pessimism on cognitive processes associated with depression, in the present study we compared the sensitivity of rats displaying optimistic and pessimistic traits to positive and negative feedback. The animals were initially trained and tested in the rat version of the probabilistic reversal-learning (PRL) task, which allowed for the assessment of feedback sensitivity in individual animals. Subsequently, the rats were re-trained and tested in a series of ambiguous-cue interpretation (ACI) tests, which allowed for the classification of animals displaying “optimistic” and “pessimistic” traits. The “pessimistic” rats were significantly more sensitive to negative feedback than their “optimistic” conspecifics, as indicated by an increased proportion of lose-shift behaviors. The results of our study demonstrate the interrelation and co-existence of two cognitive biases that may predict vulnerability to depressive disorder.

Anandamide mediates cognitive judgement bias in rats.

In the present study, we investigated the effects of acute pharmacological manipulation of the endocannabinoid (EC) system on the valence of cognitive judgement bias of rats in the ambiguous-cue interpretation (ACI) paradigm. To accomplish this goal, after initial behavioural training, different groups of rats received single, systemic injections of the irreversible anandamide (AEA) hydrolysis inhibitor URB597, the cannabinoid receptor type 1 (CB1) inverse agonist AM251, the cannabinoid receptor type 2 (CB2) inverse agonist AM630, the combination of URB597 and AM251, and a combination of URB597 and AM630 and were subsequently tested with the ACI paradigm. We report that URB597 at a dose of 1 mg/kg significantly biased animals towards positive interpretation of the ambiguous cue and that this effect was abolished by pre-treatment with AM251 (1 mg/kg) or AM630 (1 mg/kg). The CB1 and CB2 inverse agonists administered alone (1 mg/kg) had no statistically significant effects on the interpretation of the ambiguous cue by rats. Our findings suggest involvement of the endocannabinoid system in the mediation of optimistic judgement bias.

Cognitive Judgment Bias Interacts with Risk Based Decision Making and Sensitivity to Dopaminergic Challenge in Male Rats

Although the cognitive theory has implicated judgment bias in various psychopathologies, its role in decision making under risk remains relatively unexplored. In the present study, we assessed the effects of cognitive judgment bias on risky choices in rats. First, we trained and tested the animals on the rat version of the probability-discounting (PD) task. During discrete trials, the rats chose between two levers; a press on the “small/certain” lever always resulted in the delivery of one reward pellet, whereas a press on the “large/risky” lever resulted in the delivery of four pellets. However, the probability of receiving a reward from the “large/risky” lever gradually decreased over the four trial blocks. Subsequently, the rats were re-trained and evaluated on a series of ambiguous-cue interpretation (ACI) tests, which permitted their classification according to the display of “optimistic” or “pessimistic” traits. Because dopamine (DA) has been implicated in both: risky choices and optimism, in the last experiment, we compared the reactivity of the dopaminergic system in the “optimistic” and “pessimistic” animals using the apomorphine (APO; 2 mg/kg s.c.) sensitivity test. We demonstrated that as risk increased, the proportion of risky lever choices decreased significantly slower in “optimists” compared with “pessimists” and that these differences between the two groups of rats were associated with different levels of dopaminergic system reactivity. Our findings suggest that cognitive judgment bias, risky decision-making and DA are linked, and they provide a foundation for further investigation of the behavioral traits and cognitive processes that influence risky choices in animal models.

Lesions of the Orbitofrontal but Not Medial Prefrontal Cortex Affect Cognitive Judgment Bias in Rats

Neuroimaging studies in humans have recently shown that the prefrontal cortex (PFC) and orbitofrontal cortex (OFC) mediate bias in the judgment of forthcoming events. In the present study, we sought to determine whether cognitive judgment bias (CJB) is also dependent on these prefrontal regions in non-human animals. For this, we trained a cohort of rats in the ambiguous-cue interpretation (ACI) paradigm, subjected them to excitotoxic lesions in the medial PFC (mPFC) and OFC, and tested the effects of neuronal loss within these regions on CJB. Comparison of the lesions’ behavioral effects in the ACI paradigm revealed that neuronal loss within the OFC but not within the mPFC influences the interpretation of ambiguous cues by animals. Our findings demonstrate the specific involvement of the OFC in CJB in rats.

Effects of acute dopaminergic and serotonergic manipulations in the ACI paradigm depend on the basal valence of cognitive judgement bias in rats

Abstract Recent findings have revealed that pharmacological enhancement of dopaminergic (DA) function by the administration of a DA precursor (dihydroxy‐l‐phenylalanine; L‐DOPA), but not the selective serotonin reuptake inhibitor (SSRI) citalopram, increases an optimism bias in humans. To test whether dopamine might play a similar role in non‐human animals, in the present study, we evaluated the effects of acute injections of L‐DOPA, the D2 receptor antagonist haloperidol, and the SSRI escitalopram on cognitive judgement bias of rats in the ambiguous‐cue interpretation (ACI) paradigm. Three different doses of each drug were administered in a fully randomised Latin‐square design, along with saline treatment as a control, 30 min before the ACI tests. Initial analysis revealed that only animals treated with L‐DOPA were more ‘pessimistic’ than the saline‐treated controls. Neither haloperidol nor escitalopram significantly affected the cognitive judgement bias of rats. However, further analysis revealed that the effects of the tested compounds might depend on the basal cognitive judgement bias of the tested animals. When we divided the rats into ‘optimistic’ and ‘pessimistic’ groups based on their cognitive judgement bias in the drug‐free state, it turned out that acute administration of L‐DOPA caused a ‘pessimistic’ shift in ‘optimistic’ animals while showing no significant effects on ‘pessimists’. Acute administration of haloperidol caused a ‘pessimistic’ shift in ‘optimistic’ animals and an ‘optimistic’ shift in ‘pessimists’. Acute administration of escitalopram caused a ‘pessimistic’ shift in ‘optimistic’ animals and had no significant effects on ‘pessimists’, except that the middle tested dose rendered the rats more ‘optimistic’.