Dopaminergic Reactivity In Idiopathic Generalized Epilepsy: A "Proof Of Concept" Clinical, Pharmacological And Neurophysiological Study

Clinical data regarding the effects of dopaminergic drugs in idiopathic generalized epilepsies are scarce. The general observation that antipsychotic agents (dopaminergic antagonists) worsen seizures, has suggested that dopaminergic agonists would have antiepileptic effects. However, this has never been clearly demonstrated, besides in few limited studies (Mervaala, 1990 ; Quesney, 1980, 1981). More recently, Positron Emission Tomography (PET) investigations using dopaminergic markers (Fluoro-Dopa, SCH23390, DAT) have shown dopaminergic deficits in several epileptic syndromes: ring chromosome 20 syndrome (Biraben 2004), juvenile myoclonic epilepsy (Ciumas 2008), temporal lobe epilepsy (Bouilleret 2008), frontal lobe epilepsy (Fedi 2008). These data give rise to a renewal of interest for the involvement of the dopaminergic neurotransmission in epilepsies. Based on our experimental data from animal studies (see Deransart and Depaulis, 2002), the investigators propose an original study investigating the involvement of the dopaminergic system in idiopathic generalized epilepsies using behavioural as well as neurophysiological markers of the dopaminergic response, in conditions where seizing activities in patients are facilitated (EEG follow-up after sleep deprivation). This approach is based on the concept developed in our laboratory concerning the involvement of the basal ganglia, and more precisely the dopaminergic pathways, in the control of spike-wave discharges in idiopathic generalized epilepsies.

The primary objective is to assess dopaminergic reactivity using a behavioural marker (i.e. yawning) in patients with idiopathic generalized epilepsy compared to matched healthy controls after injection of either low dose of apomorphine or placebo. Other parameters will be recorded as secondary outcomes: behavioural (blinking), biochemical (prolactin, GH) and neurophysiological (Spike-Waves Discharge: SWD rating) markers. Safety parameters will be recorded to assess tolerance.

Experimental data: hyperdopaminergic response in a model of absence-epilepsy in the rat. Since the late 80's, our laboratory has demonstrated the existence of an endogenous neural mechanism that controls the occurrence of epileptic seizures in different animal models, a system based on the hypothesis that the basal ganglia modulate the synchronisation of epileptic rhythmic activities (Depaulis 1994). The studies performed in GAERS (Genetic Absence Epilepsy Rats from Strasbourg, a validated model of absence-epilepsy in rat) have shown that inhibition of the main output structure of basal ganglia (i.e., the substantia nigra pars reticulata) had antiepileptic effects (Depaulis 1994; Deransart 1996). Similarly, deep brain stimulation of the substantia nigra pars reticulata as well as of the subthalamic nucleus interrupts seizures (Vercueil 1998; Feddersen 2007). Systemic and intrastriatal dopamimetics injections in GAERS also suppress seizures, whereas antagonists worsen them (Warter et al, 1988; Deransart et al., 2000). Electrophysiological data showed respectively decreased and increased activity of DA neurons during and at the end of absence-seizures (Lücking et al. 2002). An increase in D3 receptor transcripts was also observed in adult GAERS as compared to inbred non epileptic control rats (NEC), within the ventral striatum (Deransart et al. 2001). These data suggest changes in the DA tone in GAERS with fully developed epileptic phenotype. According to the key role of DA D3 neurotransmission in the foetal cortical development (Levant B, 1995) and modulation of DA tone (Nissbrandt et al., 1995; Gilbert et al., 1995; Kreiss et al., 1995), the researchers investigated whether the putative impaired DA tone in GAERS correlates with functional changes in spontaneous and quinpirole-induced yawning behaviour (Kurashima et al. 1995; Collins et al.2005). The hypothesis of an increased dopaminergic tone in GAERS was thus addressed using pharmacology and microdialysis. In GAERS and NEC (i) spontaneous and quinpirole-induced yawning behaviour and (ii) changes in intra-accumbens dopamine contents induced by amphetamine and K+ and measured by microdialysis were investigated. Spontaneous yawning was significantly decreased in GAERS (0.3±0.2 yawn/hr, n=9) as compared to NEC (5.4±1.2, n=8) and Wistar Harlan rats (9.7±2.3, n=7). Quinpirole-induced yawning was significantly increased in GAERS (29.4±4.9) as compared to NEC (10.5±2.7) and Wistar-Harlan rats (22.6±3.5). Quinpirole also increased the number of absence-seizures in GAERS (+47.4±8.6%). When compared to NEC, basal levels of DA were 40% lower in GAERS whereas amphetamine and K+ produced a higher increase in extracellular dopamine in GAERS. The increased quinpirole-induced yawning in GAERS may account for an overexpression in D3 transcripts. The increased responsiveness of dopamine transmission observed in GAERS after pharmacological manipulations, as compared to NEC, suggests a " hyperdopaminergic " phenotype of GAERS. Altogether, these data support that GAERS have an impaired DA tone that may be associated with the development of mechanisms controlling absences seizures (Deransart et al, in preparation).

Altogether, these data suggest that a phasic involvement (" on request ") of the basal ganglia - notably under the influence of the dopaminergic neurotransmission - may underlie the rapid changes in extracellular activity recorded in output structures of the basal ganglia at the end of seizures in this model (Deransart 2003). Such a phasic functioning of the dopaminergic system in the control of seizures could also reconcile with the apparent discrepancy regarding the fact that seizures appear to escape chronic high-frequency stimulations of the substantia nigra (Feddersen 2007). These data strengthen the need for a re-appraisal of clinical approaches, especially based from a dynamic point of view regarding the involvement of the dopaminergic system in epilepsy.

Clinical data: