Differential Regulation of the Excitability of Prefrontal Cortical Fast-Spiking Interneurons and Pyramidal Neurons by Serotonin and Fluoxetine

Serotonin exerts a powerful influence on neuronal excitability. In this study, we investigated the effects of serotonin on different neuronal populations in prefrontal cortex (PFC), a major area controlling emotion and cognition. Using whole-cell recordings in PFC slices, we found that bath application of 5-HT dose-dependently increased the firing of FS (fast spiking) interneurons, and decreased the firing of pyramidal neurons. The enhancing effect of 5-HT in FS interneurons was mediated by 5-HT2 receptors, while the reducing effect of 5-HT in pyramidal neurons was mediated by 5-HT1 receptors. Fluoxetine, the selective serotonin reuptake inhibitor, also induced a concentration-dependent increase in the excitability of FS interneurons, but had little effect on pyramidal neurons. In rats with chronic fluoxetine treatment, the excitability of FS interneurons was significantly increased, while pyramidal neurons remained unchanged. Fluoxetine injection largely occluded the enhancing effect of 5-HT in FS interneurons, but did not alter the reducing effect of 5-HT in pyramidal neurons. These data suggest that the excitability of PFC interneurons and pyramidal neurons is regulated by exogenous 5-HT in an opposing manner, and FS interneurons are the major target of Fluoxetine. It provides a framework for understanding the action of 5-HT and antidepressants in altering PFC network activity

Psychostimulants and atomoxetine alter the electrophysiological activity of prefrontal cortex neurons, interaction with catecholamine and glutamate NMDA receptors.

RATIONALE Attention-deficit hyperactivity disorder (ADHD) is the most frequently diagnosed neuropsychiatric disorder in childhood. Currently available ADHD drugs include the psychostimulants methylphenidate (MPH) and D-amphetamine (D-AMP), acting on norepinephrine and dopamine transporters/release, and atomoxetine (ATX), a selective norepinephrine uptake inhibitor. Recent evidence suggests an involvement of glutamate neurotransmission in the pathology and treatment of ADHD, via mechanisms to be clarified. OBJECTIVE We have investigated how ADHD drugs could modulate, through interaction with catecholamine receptors, basal and glutamate-induced excitability of pyramidal neurons in the prefrontal cortex (PFC), a region which plays a major role in control of attention and impulsivity. METHODS We have used the technique of extracellular single-unit recording in anaesthetised rats coupled with microiontophoresis. RESULTS Both MPH (1-3 mg/kg) and D-AMP (1-9 mg/kg) increased the firing activity of PFC neurons in a dopamine D1 receptor-dependent manner. ATX administration (1-6 mg/kg) also increased the firing of neurons, but this effect is not significantly reversed by D1 (SCH 23390) or alpha1 (prazosin) receptor antagonists but potentiated by alpha2 antagonist (yohimbine). All drugs induced a clear potentiation of the excitatory response of PFC neurons to the microiontophoretic application of the glutamate agonist N-methyl-D-aspartate (NMDA), but not to the glutamate agonist α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). The potentiating effect of D-AMP on NMDA-induced activation of PFC neurons was partially reversed or prevented by dopamine D1 receptor blockade. CONCLUSION Our data shows that increase in excitability of PFC neurons in basal conditions and via NMDA receptor activation may be involved in the therapeutic response to ADHD drugs

Pharmacology, Systematic Review and Recent Clinical Trials of Metadoxine

BACKGROUND Metadoxine is composed of pyroglutamic acid and vitamin B6. Administrations of metadoxine are indicated in cases of acute alcohol intoxication or in chronic alcoholism. OBJECTIVES To reference all available clinical trials investigating the effects of metadoxine on humans. A focus was put on alcohol intoxication and chronic alcoholism, alcohol abstinence and survival rates. Adverse events were also taken into consideration. Finally, potential roles of metadoxine in treating disorders of the central nervous system will be assessed. METHODS PRISMA guidelines were followed. Computerised literature searches were performed in July 2017 to retrieve all clinical trials investigating metadoxine from the MEDLINE®, the European Union Clinical Trials Register and the ClinicalTrials.gov databases, using the following equation: "metadoxine". Inclusion criteria were all published clinical trials investigating metadoxine in humans, regardless of outcome measures. Exclusion criteria were articles not abstracted, studies, studies in rodents, retrospective studies and reviews. RESULTS Sixteen studies were included. Evidence suggests that metadoxine appears safe to use, as it rarely induced adverse events (reported in 7 out of the 7 studies measuring safety/tolerability). Moreover, metadoxine seems efficient in treating acute alcohol intoxication (2/2 studies) as well as improving liver functions following chronic alcoholism (4/5 studies). Finally, currently on-going clinical trials will reveal if metadoxine could be indicated in attention deficit and hyperactivity disorders as well as fragile X syndrome. CONCLUSION Metadoxine appears safe to use and seems efficient to improve liver functions following alcohol-related diseases. Further clinical trials will be necessary to determine if metadoxine can be promising for treating brain disorders. PROSPERO registration number: CRD42017072964