Multiple Dopamine Receptor Subtypes in the Medial Prefrontal Cortex of the Rat Regulate Set-Shifting

119

Personal success often requires the choice to expend greater effort for larger rewards, and deficits in such effortful decision making accompany a number of illnesses including depression, schizophrenia, and attention-deficit/hyperactivity disorder. Animal models have implicated brain regions such as the basolateral amygdala (BLA) and anterior cingulate cortex (ACC) in physical effort-based choice, but disentangling the unique contributions of these two regions has proven difficult, and effort demands in industrialized society are predominantly cognitive in nature. Here we utilize the rodent cognitive effort task (rCET), a modification of the five-choice serial reactiontime task, wherein animals can choose to expend greater visuospatial attention to obtain larger sucrose rewards. Temporary inactivation (via baclofen-muscimol) of BLA and ACC showed dissociable effects: BLA inactivation caused hard-working rats to 'slack off' and 'slacker' rats to work harder, whereas ACC inactivation caused all animals to reduce willingness to expend mental effort. Furthermore, BLA inactivation increased the time needed to make choices, whereas ACC inactivation increased motor impulsivity. These data illuminate unique contributions of BLA and ACC to effort-based decision making, and imply overlapping yet distinct circuitry for cognitive vs physical effort. Our understanding of effortful decision making may therefore require expanding our models beyond purely physical costs.

Section: Discussionmentioning

confidence: 99%

Dissociable Contributions of Anterior Cingulate Cortex and Basolateral Amygdala on a Rodent Cost/Benefit Decision-Making Task of Cognitive Effort

Hosking

Cocker

Winstanley

2014

119

“…In order to reconcile our results with the biochemical and the electrophysiological findings, we postulate that cooperation between the two receptor subtypes, in the same or on different neuronal population, would be required for accurate task-relevant information processing. It is worth noting that recently Floresco et al (2006) suggested that D1 and D2 dopamine receptors might cooperate within the PFC to favor setshifting. However, even if it is difficult to exclude that the effects observed in the present study could be partially due to alteration in set-shifting, if the effect observed was solely due to impairment in behavioral flexibility a reduction in the exploration of the novel object in S6 should have also been observed, in both experiments and this was not the case.…”

Section: Prefrontal Cortex Dopamine In Spatial Learningmentioning

confidence: 99%

D1 and D2 Receptor Antagonist Injections in the Prefrontal Cortex Selectively Impair Spatial Learning in Mice

Rinaldi

Mandillo

Oliverio

et al. 2006

The prefrontal cortex (PFC) is a cortical area involved in selecting and retaining information to produce complex behaviors. Within the PFC, the dopaminergic system plays an important role in information processing. Thus, the objective of this study was to test whether bilateral administration of the D1 and D2 receptor antagonists in the prelimbic region of the PFC influenced the performance of mice in a non-associative spatial learning task. CD1 mice were bilaterally microinjected in the PFC with either the D1 receptor antagonist, SCH23390 (SCH 6.25; 12.5; 50 ng), or the D2 receptor antagonist, sulpiride (SULP 12.5; 50; 100 ng) and placed into an open field containing five different objects. After three sessions of habituation two objects were repositioned (spatial change) and in the subsequent session one of the objects was substituted (non-spatial change). No significant alteration was observed in the habituation pattern of the animals after D1 or D2 receptor blockade. When two of the objects were displaced, control mice explored the displaced objects far more than the non-displaced ones, while mice treated with SCH or SULP spent a comparable amount of time re-exploring the two object categories. Conversely, DA antagonists had no effects on the discrimination of the new object. Thus, the administration of both SCH and SULP selectively impaired the ability of mice to discriminate a spatial change, without affecting any other behavioral parameter. These findings could provide a model to study the role of the PFC dopaminergic system in spatial learning and to study the neural mechanisms underlying cognitive and attention deficits often observed in psychiatric disorders.

“…The results of Ridley et al (1981) support a strong involvement of the D 2 -like receptors, as haloperidol has higher affinity for this subtype than the others. In addition, Floresco et al (2006) demonstrated that administration of the D 2 /D 3 subtype selective antagonist, eticlopride, potently impaired the ability of rats to change their behavior in response to a conditional change of rule in a set-shifting task. More direct evidence in support of these results derives from a recent study of D 2 receptor gene knockout mice.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, the role of the D 1 -like receptors in behavioral flexibility is less clear. Although blockade of D 1 -like receptors in the prefrontal cortex (PFC) impaired performance of a set-shifting task, stimulation of the D 1 -like receptors in the PFC did not (Ragozzino, 2002;Floresco et al, 2006). However, it is simply unknown whether the D 1 -like receptors play a role in reversal learning, although the D 1 -like receptors are critically involved in other cognitive functions, such as working memory (Sawaguchi and Goldman-Rakic, 1991;Williams and Goldman-Rakic, 1995) and visual attention (Granon et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Dopamine D2/D3 Receptors Play a Specific Role in the Reversal of a Learned Visual Discrimination in Monkeys

Lee

Groman

London

et al. 2007

140

123

Converging evidence supports a role for mesocorticolimbic dopaminergic systems in a subject's ability to shift behavior in response to changing stimulus-reward contingencies. To characterize the dopaminergic mechanisms involved in this function, we quantified the effects of subtype-specific dopamine (DA) receptor antagonists on acquisition, retention, and reversal of a visual discrimination task in nonhuman primates (Chlorocebus aethiops sabaeus). We used a modified Wisconsin General Test Apparatus that was equipped with three food boxes, each fitted with a lid bearing a unique visual cue; one of the cues concealed a food reward, whereas the other two concealed an empty box. The monkeys were trained first to acquire a novel discrimination (eg A + , B À , C À ) in a single session, before experiencing either a reversal of the discrimination (eg A À , B + , C À ) or the acquisition of a completely new discrimination (eg D + , E À , F À ), on the following day. Systemic administration of the D 2 /D 3 receptor antagonist raclopride (0.001-0.03 mg/kg) failed to significantly affect the performance of reversal learning when reversal sessions were run without a retention session. But, raclopride (0.03 mg/kg) significantly impaired performance under the reversal condition when reversal sessions were run right after a retention session; however, it did not affect acquisition of a novel visual discrimination. Specifically, raclopride significantly increased the number of reversal errors made before reaching the performance criterion in the reversal, but not in new learning sessions. In contrast, the D 1 /D 5 receptor antagonist SCH 23390 did not significantly modulate acquisition of a novel discrimination or reversal learning at doses (0.001-0.03 mg/kg, i.m.) that did not suppress behavior generally. In addition, none of the drug treatments affected retention of a previously learned discrimination. The results strongly suggest that D 2 /D 3 receptors, but not D 1 /D 5 receptors, selectively mediate reversal learning, without affecting the capacity to learn a new stimulus-reward association. These data support the hypothesis that phasic DA release, acting through D 2 -like receptors, mediates behavioral flexibility.