Dorsal and ventral striatal dopamine D1 and D2 receptors differentially modulate distinct phases of serial visual reversal learning.

Impaired cognitive flexibility in visual reversal-learning tasks has been observed in a wide range of neurological and neuropsychiatric disorders. Although both human and animal studies have implicated striatal D2-like and D1-like receptors (D2R; D1R) in this form of flexibility, less is known about the contribution they make within distinct sub-regions of the striatum and the different phases of visual reversal learning. The present study investigated the involvement of D2R and D1R during the early (perseverative) phase of reversal learning as well as in the intermediate and late stages (new learning) after microinfusions of D2R and D1R antagonists into the nucleus accumbens core and shell (NAcC; NAcS), the anterior and posterior dorsomedial striatum (DMS) and the dorsolateral striatum (DLS) on a touchscreen visual serial reversal-learning task. Reversal learning was improved after dopamine receptor blockade in the nucleus accumbens; the D1R antagonist, SCH23390, in the NAcS and the D2R antagonist, raclopride, in the NAcC selectively reduced early, perseverative errors. In contrast, reversal learning was impaired by D2R antagonism, but not D1R antagonism, in the dorsal striatum: raclopride increased errors in the intermediate phase after DMS infusions, and increased errors across phases after DLS infusions. These findings indicate that D1R and D2R modulate different stages of reversal learning through effects localised to different sub-regions of the striatum. Thus, deficits in behavioral flexibility observed in disorders linked to dopamine perturbations may be attributable to specific D1R and D2R dysfunction in distinct striatal sub-regions.

Glutamatergic and Serotonergic Modulation of Rat Medial and Lateral Orbitofrontal Cortex in Visual Serial Reversal Learning.

Adapting behavior to a dynamic environment requires both steadiness when the environment is stable and behavioral flexibility in response to changes. Much evidence suggests that cognitive flexibility, which can be operationalized in reversal learning tasks, is mediated by cortico-striatal circuitries, with the orbitofrontal cortex (OFC) playing a prominent role. The OFC is a functionally heterogeneous region, and we have previously reported differential roles of lateral (lOFC) and medial (mOFC) regions in a touchscreen serial visual reversal learning task for rats using pharmacological inactivation. Here, we investigated the effects of pharmacological overactivation of these regions using a glutamate transporter 1 (GLT-1) inhibitor, dihydrokainate (DHK), which increases extracellular glutamate by blocking its reuptake. We also tested the impact of antagonism of the serotonin 2A receptor (5-HT2AR), which modulates glutamate action, in the mOFC and lOFC on the same task. Overactivation induced by DHK produced dissociable effects in the mOFC and lOFC, with more prominent effects in the mOFC, specifically improving performance in the early, perseveration phase. Intra-lOFC DHK increased the number of omitted responses without affecting errors. In contrast, blocking the 5-HT2AR in the lOFC impaired reversal learning overall, while mOFC 5-HT2AR blockade had no effect. These results further support dissociable roles of the rodent mOFC and lOFC in deterministic visual reversal learning and indicate that modulating glutamate transmission through blocking the GLT-1 and the 5-HT2AR have different roles in these two structures.

Acute phencyclidine administration induces c-Fos-immunoreactivity in interneurons in cortical and subcortical regions.

Dysfunction of N-Methyl-d-aspartate receptors (NMDARs) is believed to underlie some of the symptoms in schizophrenia, and non-competitive NMDAR antagonists (including phencyclidine (PCP)) are widely used as pharmacological schizophrenia models. Furthermore, mounting evidence suggests that impaired γ-aminobutyric acid (GABA) neurotransmission contributes to the cognitive deficits in schizophrenia. Thus alterations in GABAergic interneurons have been observed in schizophrenia patients and animal models. Acute systemic administration of PCP increases levels of c-Fos in several cortical and subcortical areas, but whether such induction occurs in specific populations of GABAergic interneuron subtypes still remains to be established. We performed an immunohistochemical analysis of the PCP-induced c-Fos-immunoreactivity (IR) in parvalbumin (PV) and calbindin (CB) interneuron subtypes in the cortex and thalamus of rats. A single dose of PCP (10mg/kg, s.c.) significantly increased total number of c-Fos-IR in: (1) the prelimbic, infralimbic, anterior cingulate, ventrolateral orbital, motor, somatosensory and retrosplenial cortices as well as the nucleus accumbens (NAc), field CA1 of the hippocampus (CA1) field of hippocampus and mediodorsal thalamus (MD); (2) PV-IR cells in the ventrolateral orbitofrontal and retrosplenial cortices and CA1 field of hippocampus; and (3) CB-IR cells in the motor cortex. Overall, our data indicate that PCP activates a wide range of cortical and subcortical brain regions and that a substantial part of this activation is present in GABAergic interneurons in certain regions. This suggests that the psychotomimetic effect of PCP may be mediated via GABAergic interneurons.