Mesocortical dopamine hypofunction and prefrontal plasticity deficits in the cuprizone model

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system frequently associated with cognitive impairment, which critically depends on the integrity of the prefrontal cortex (PFC) and its mesocortical dopaminergic inputs. However, direct experimental evidence linking prefrontal dopamine dysfunction to MS-related cognitive deficits is limited. Here, we investigated the contribution of mesocortical dopaminergic transmission to cognitive and behavioral alterations using the cuprizone model of demyelination in male Wistar rats. After six weeks of 1% cuprizone administration, we combined ex vivo electrophysiology in the rostral ventral tegmental area (rVTA) and medial PFC (mPFC), in vivo microdialysis of extracellular dopamine in the mPFC, behavioral assessment of cognition and anxiety-like behavior, gait analysis, and plasma corticosterone measurements. Cuprizone reduced the spontaneous firing rate of rVTA dopaminergic neurons and decreased glutamatergic miniature excitatory postsynaptic current frequency. In the mPFC, cuprizone increased pyramidal neuron excitability and presynaptic glutamatergic transmission, while impairing long-term potentiation and reducing NMDA receptor-mediated currents. Microdialysis showed reduced basal extracellular dopamine levels in the mPFC which, together with the results on the EPM and the marked decrease observed in plasma corticosterone, indicate blunted mesocortical and hypothalamic–pituitary–adrenal axis responsiveness. Cuprizone-treated rats exhibited working memory deficits with preserved performance in a task not strictly PFC-dependent, reduced anxiety-like behavior, and subtle gait changes. These findings suggest that cuprizone-induced intoxication disrupts VTA–mPFC circuitry, leading to mesocortical dopamine hypofunction, altered cortical plasticity, and executive dysfunction, and support targeting mesocortical dopamine transmission as a potential strategy for MS-related cognitive symptoms.