Effects of memantine on mania-like phenotypes exhibited by Drosophila Shaker mutants.

INTRODUCTION: Increased glutamate levels and electrolytic fluctuations have been observed in acutely manic patients. Despite some efficacy of the non-competitive NMDA receptor antagonist memantine (Mem), such as antidepressant-like and mood-stabilizer drugs in clinical studies, its specific mechanisms of action are still uncertain. The present study aims to better characterize the Drosophila melanogaster fly Shaker mutants (SH), as a translational model of manic episodes within bipolar disorder in humans, and to investigate the potential anti-manic properties of Mem. METHODS AND RESULTS: Our findings showed typical behavioral abnormalities in SH, which mirrored with the overexpression of NMDAR-NR1 protein subunit, matched well to glutamate up-regulation. Such molecular features were associated to a significant reduction of SH brain volume in comparison to Wild Type strain flies (WT). Here we report on the ability of Mem treatment to ameliorate behavioral aberrations of SH (similar to that of Lithium), and its ability to reduce NMDAR-NR1 over-expression. CONCLUSIONS: Our results show the involvement of the glutamatergic system in the SH, given the interaction between the Shaker channel and the NMDA receptor, suggesting this model as a promising tool for studying the neurobiology of bipolar disorders. Moreover, our results show Mem as a potential disease-modifying therapy, providing insight on new mechanisms of action.

Healthy Women and Men Do Not Show Differences in Tongue Strength and Regular Effort Saliva Swallows as Assessed by Piezo-Resistive Sensors: Results from a Reproducibility Study.

The aim of this study was to establish the reproducibility of tongue strength measurements in healthy women and men during maximum anterior isometric pressure (MAIP) and regular effort saliva swallows (RESS). In this cross-sectional study, 30 healthy young adults were required to push with the tip of the tongue on a piezo-resistive sensor glued to the hard palate, immediately above the central incisor line. Tongue pressures exerted on the sensor during MAIP and spontaneous RESS were recorded. Participants underwent a retest procedure within the same session to verify the reproducibility of measurements, as determined by intraclass correlation coefficient (ICC), standard error of measurement (SEM), and minimum detectable change (MDC). Complete data were obtained from 30 subjects (15 women, 15 men; mean age 31.4 ± 7.8 years; mean weight 61.3 ± 9.4 kg). Compared to women, men showed a trend for generating larger MAIP (p = 0.06; d = 0.71) and RESS (p = 0.07; d = 0.69). After normalizing to body weight, height, and body mass index (BMI), such trends disappeared. At retest, MAIP and RESS proved stable and highly reliable (all ICCs ≥ 0.93) in men and women but associated to moderate variability as for SEM and MDC, with MAIP estimates associated to smaller SEM and MDC (SEM ranging 7.4-14.2%; MDC 18.6-20.9%) than RESS (SEM ranging 20.4-38.5%; MDC 52.5-55.6%). Piezo-resistive pressure sensors allow clinicians and researchers to perform reproducible measurements of tongue muscle performance. However, if therapeutic interventions are administered, measurement variability in tongue performance should be considered when appraising their clinical efficacy, especially for those populations who display impaired performance and may not be capable to generate high and stable forces. No gender-based differences emerged in the motor tasks tested.

Maternal Immune Activation Disrupts Dopamine System in the Offspring.

BACKGROUND: In utero exposure to maternal viral infections is associated with a higher incidence of psychiatric disorders with a supposed neurodevelopmental origin, including schizophrenia. Hence, immune response factors exert a negative impact on brain maturation that predisposes the offspring to the emergence of pathological phenotypes later in life. Although ventral tegmental area dopamine neurons and their target regions play essential roles in the pathophysiology of psychoses, it remains to be fully elucidated how dopamine activity and functionality are disrupted in maternal immune activation models of schizophrenia. METHODS: Here, we used an immune-mediated neurodevelopmental disruption model based on prenatal administration of the polyriboinosinic-polyribocytidilic acid in rats, which mimics a viral infection and recapitulates behavioral abnormalities relevant to psychiatric disorders in the offspring. Extracellular dopamine levels were measured by brain microdialysis in both the nucleus accumbens shell and the medial prefrontal cortex, whereas dopamine neurons in ventral tegmental area were studied by in vivo electrophysiology. RESULTS: Polyriboinosinic-polyribocytidilic acid-treated animals, at adulthood, displayed deficits in sensorimotor gating, memory, and social interaction and increased baseline extracellular dopamine levels in the nucleus accumbens, but not in the prefrontal cortex. In polyriboinosinic-polyribocytidilic acid rats, dopamine neurons showed reduced spontaneously firing rate and population activity. CONCLUSIONS: These results confirm that maternal immune activation severely impairs dopamine system and that the polyriboinosinic-polyribocytidilic acid model can be considered a proper animal model of a psychiatric condition that fulfills a multidimensional set of validity criteria predictive of a human pathology.

PPARα regulates cholinergic-driven activity of midbrain dopamine neurons via a novel mechanism involving α7 nicotinic acetylcholine receptors.

Ventral tegmental area dopamine neurons control reward-driven learning, and their dysregulation can lead to psychiatric disorders. Tonic and phasic activity of these dopaminergic neurons depends on cholinergic tone and activation of nicotinic acetylcholine receptors (nAChRs), particularly those containing the ß2 subunit (ß2*-nAChRs). Nuclear peroxisome proliferator-activated receptors type-α (PPARα) tonically regulate ß2*-nAChRs and thereby control dopamine neuron firing activity. However, it is unknown how and when PPARα endogenous ligands are synthesized by dopamine cells. Using ex vivo and in vivo electrophysiological techniques combined with biochemical and behavioral analysis, we show that activation of α7-nAChRs increases in the rat VTA both the tyrosine phosphorylation of the ß2 subunit of nAChRs and the levels of two PPARα endogenous ligands in a Ca(2+)-dependent manner. Accordingly, in vivo production of endogenous PPARα ligands, triggered by α7-nAChR activation, blocks in rats nicotine-induced increased firing activity of dopamine neurons and displays antidepressant-like properties. These data demonstrate that endogenous PPARα ligands are effectors of α7-nAChRs and that their neuromodulatory properties depend on phosphorylation of ß2*-nAChRs on VTA dopamine cells. This reveals an autoinhibitory mechanism aimed at reducing dopamine cell overexcitation engaged during hypercholinergic drive. Our results unveil important physiological functions of nAChR/PPARα signaling in dopamine neurons and how behavioral output can change after modifications of this signaling pathway. Overall, the present study suggests PPARα as new therapeutic targets for disorders associated with unbalanced dopamine-acetylcholine systems.

Chronic cannabinoid exposure reduces phencyclidine-induced schizophrenia-like positive symptoms in adult rats.

RATIONALE: Chronic cannabis use can induce psychotic states that resemble schizophrenia. Yet, schizophrenic patients often smoke cannabis as a form of self-medication to counter the aversive symptoms of schizophrenia. We recently demonstrated an ameliorating effect of cannabinoid self-administration (SA) on negative and cognitive schizophrenia-like symptoms induced experimentally by the non-competitive N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). Whether cannabinoid SA alleviates or exacerbates schizophrenia-like positive symptoms is still unclear. OBJECTIVES: This follow-up study aimed to evaluate the effect of self-administered cannabinoid on PCP-induced schizotypic positive symptoms in adult rats. METHODS: Male rats were trained to self-administer either the cannabinoid CB1 receptor agonist WIN 55,212-2 (WIN; 12.5 µg/kg/infusion) or its vehicle (Veh) intravenously. The effects of acute and chronic intermittent intraperitoneal administration of PCP (2.5 mg/kg) on motor parameters were then tested in Veh-SA and WIN-SA. RESULTS: Cannabinoid SA significantly attenuated the psychotomimetic effects of PCP exposure observed in control rats. Following acute PCP administration, WIN-SA animals displayed more frequent rearing and lower anxiety-like profile than Veh-SA rats. WIN-SA rats also exhibited lower behavioural sensitisation to chronic PCP treatment as demonstrated by reduced hyperlocomotion in response to an acute PCP challenge. In addition, parallel experiments performed in experimenter-administered rats that received WIN at comparable SA doses confirmed the ameliorating effects of cannabinoid exposure on PCP-induced schizotypic behaviours, indicating that motivational effects were not responsible for the ameliorative effects of cannabinoids. CONCLUSIONS: Our results indicate that cannabis may exert protective effects on positive schizotypic symptoms in adult animals such as hypermotility and anxiety state.