Early reduced dopaminergic tone mediated by D3 receptor and dopamine transporter in absence epileptogenesis

Abstract Objective In Genetic Absence Epilepsy Rats From Strasbourg ( GAERS s), epileptogenesis takes place during brain maturation and correlates with increased mRNA expression of D3 dopamine receptors (D3R). Whether these alterations are the consequence of seizure repetition or contribute to the development of epilepsy remains to be clarified. Here, we addressed the involvement of the dopaminergic system in epilepsy onset in GAERS s. Methods Experiments were performed using rats at different stages of brain maturation from three strains according to their increasing propensity to develop absence seizures: nonepileptic control rats ( NEC s), Wistar Hannover rats, and GAERS s. Changes in dopaminergic neurotransmission were investigated using different behavioral and neurochemical approaches: autoradiography of D3R and dopamine transporter, single photon emission computed tomographic imaging, acute and chronic drug effects on seizure recordings (dopaminergic agonists and antagonists), quinpirole-induced yawns and dopamine synaptosomal uptake, microdialysis, brain tissue monoamines, and brain-derived neurotrophic factor quantification. Results Autoradiography revealed an increased expression of D3R in 14-day-old GAERS s, before absence seizure onset, that persists in adulthood, as compared to age-matched NEC s. This was confirmed by increased yawns, a marker of D3R activity, and increased seizures when animals were injected with quinpirole at low doses to activate D3R. We also observed a concomitant increase in the expression and activity of the dopamine transporter in GAERS s before seizure onset, consistent with both lowered dopamine basal level and increased phasic responses. Significance Our data show that the dopaminergic system is persistently altered in GAERS s, which may contribute not only to behavioral comorbidities but also as an etiopathogenic factor in the development of epilepsy. The data suggest that an imbalanced dopaminergic tone may contribute to absence epilepsy development and seizure onset, as its reversion by a chronic treatment with a dopamine stabilizer significantly suppressed epileptogenesis. Our data suggest a potential new target for antiepileptic therapies and/or improvement of quality of life of epileptic patients.