Benjamin Gronier

In vivo electrophysiological effects of methylphenidate in the prefrontal cortex: Involvement of dopamine D1 and alpha 2 adrenergic receptors

Attention deficit hyperactivity disorder (ADHD) is the most commonly diagnosed psychiatric disorder in children. Psychostimulants such as methylphenidate (MPH) are used as first line treatment. The prefrontal cortex (PFC) has a proven role in the expression of ADHD. Previous studies from our laboratory have demonstrated that MPH activates the firing activity of medial PFC neurones in anaesthetised rats. The aim of the present study was to determine the respective contribution and location of the different types of catecholamine receptors in mediating these excitatory effects and to compare these effects with those induced by other selective dopamine or noradrenaline uptake blockers. Single unit activity of presumed pyramidal PFC neurones was recorded in rats anaesthetised with urethane. The activation of firing elicited by an iv administration of MPH (1 or 3mg/kg) was partially reduced or prevented by the selective D1 receptor antagonist SCH 23390 administered systemically (0.5mg/kg, iv), or locally by passive diffusion through the recording electrode. On the other hand, administration of the alpha 2 receptor antagonist yohimbine (1mg/kg, iv) significantly potentiated the excitatory effect of MPH and activated PFC neurones previously treated with a low inactive dose of MPH (0.3mg/kg, iv). Local administration of MPH (1mM through the recording electrode) significantly increased the firing of PFC neurones in a D1 receptor-dependent manner. In addition, the response of PFC neurones to MPH, administered at a low dose (0.3mg/kg, iv), is greatly potentiated by dopamine (1mM), but not by noradrenaline (1mM), diffusing passively through the recording electrode, and this effect is reversed by D1 receptor blockade. Finally, the selective dopamine uptake inhibitor GBR 12909 (6 mg/kg, iv) and desipramine (6 mg/kg, iv) only activate a subset of PFC neurones. These results demonstrate the involvement of cortical dopamine D1 and noradrenergic alpha 2 receptors in the in vivo electrophysiological effects of MPH on PFC neurones.

Increased cortical neuronal responses to NMDA and improved attentional set-shifting performance in rats following prebiotic (B-GOS®) ingestion.

We have previously shown that prebiotics (dietary fibres that augment the growth of indigenous beneficial gut bacteria) such as Bimuno™ galacto-oligosaccharides (B-GOS®), increased N-methyl-D-aspartate (NMDA) receptor levels in the rat brain. The current investigation examined the functional correlates of these changes in B-GOS®-fed rats by measuring cortical neuronal responses to NMDA using in vivo NMDA micro-iontophoresis electrophysiology, and performance in the attentional set-shifting task. Adult male rats were supplemented with B-GOS® in the drinking water 3 weeks prior to in vivo iontophoresis or behavioural testing. Cortical neuronal responses to NMDA iontophoresis, were greater (+30%) in B-GOS® administered rats compared to non-supplemented controls. The intake of B-GOS® also partially hindered the reduction of NMDA responses by the glycine site antagonist, HA-966. In the attentional set-shifting task, B-GOS® -fed rats shifted from an intra-dimensional to an extra-dimensional set in fewer trials than controls, thereby indicating greater cognitive flexibility. An initial exploration into the mechanisms revealed that rats ingesting B-GOS® had increased levels of plasma acetate, and cortical GluN2B subunits and Acetyl Co-A Carboxylase mRNA. These changes were also observed in rats fed daily for 3 weeks with glyceryl triacetate, though unlike B-GOS®, cortical histone deacetylase (HDAC1, HDAC2) mRNAs were also increased which suggested an additional epigenetic action of direct acetate supplementation. Our data demonstrate that a pro-cognitive effect of B-GOS® intake in rats is associated with an increase in cortical NMDA receptor function, but the role of circulating acetate derived from gut bacterial fermentation of this prebiotic requires further investigation.

Chronic methylphenidate treatment during adolescence has long-term effects on monoaminergic function.

Background: Psychostimulants like methylphenidate or D-amphetamine are often prescribed for attention deficit and hyperactivity disorders in children. Whether such drugs can be administered into a developing brain without consequences in adulthood is still an open question. Methods: Here, using in vivo extracellular electrophysiology in anesthetised preparations, combined with behavioural assays, we have examined the long-term consequences in adulthood of a chronic methylphenidate oral administration (5 mg/kg/day, 15 days) in early adolescent (post-natal day 28) and late adolescent (post-natal day 42) rats, by evaluating body weight change, sucrose preference (indicator of anhedonia), locomotor sensitivity to D-amphetamine and electrical activities of ventral tegmental area dopamine and dorsal raphe nucleus serotonin neurons. Results: Chronic methylphenidate treatment during early or late adolescence did not induce weight deficiencies and anhedonia-like behaviours at adulthood. However, it increased bursting activities of dorsal raphe nucleus serotonin neurons. Furthermore, chronic methylphenidate treatment during early but not during late adolescence enhanced D-amphetamine-induced rearing activity, as well as ventral tegmental area dopamine cell excitability (firing, burst and population activity), associated with a partial desensitisation of dopamine D2 auto-receptors. Conclusions: We have demonstrated here that early, but not late, adolescent exposure to oral methylphenidate may induce long-lasting effects on monoamine neurotransmission. The possible clinical implication of these data will be discussed.