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Sleep disorders affect millions of people around the world and have a high comorbidity with psychiatric disorders. While current hypnotics mostly increase non-rapid eye movement sleep (NREMS), drugs acting selectively on enhancing rapid eye movement sleep (REMS) are lacking. This polysomnographic study in male rats showed that the first-in-class selective melatonin MT1 receptor partial agonist UCM871 increases the duration of REMS without affecting that of NREMS. The REMS-promoting effects of UCM871 occurred by inhibiting, in a dose–response manner, the firing activity of the locus ceruleus (LC) norepinephrine (NE) neurons, which express MT1 receptors. The increase of REMS duration and the inhibition of LC-NE neuronal activity by UCM871 were abolished by MT1 pharmacological antagonism and by an adeno-associated viral (AAV) vector, which selectively knocked down MT1 receptors in the LC-NE neurons. In conclusion, MT1 receptor agonism inhibits LC-NE neurons and triggers REMS, thus representing a novel mechanism and target for REMS disorders and/or psychiatric disorders associated with REMS impairments. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome of both acute and chronic liver disease. As a metabolic disorder, HE is considered to be reversible and therefore is expected to resolve following the replacement of the diseased liver with a healthy liver. However, persisting neurological complications are observed in up to 47% of transplanted patients. Several retrospective studies have shown that patients with a history of HE, particularly overt-HE, had persistent neurological complications even after liver transplantation (LT). These enduring neurological conditions significantly affect patient's quality of life and continue to add to the economic burden of chronic liver disease on health care systems. This review discusses the journey of the brain through the progression of liver disease, entering the invasive surgical procedure of LT and the conditions associated with the post-transplant period. In particular, it will discuss the vulnerability of the HE brain to peri-operative factors and post-LT conditions which may explain non-resolved neurological impairment following LT. In addition, the review will provide evidence; (i) supporting overt-HE impacts on neurological complications post-LT; (ii) that overt-HE leads to permanent neuronal injury and (iii) the pathophysiological role of ammonia toxicity on astrocyte and neuronal injury/damage. Together, these findings will provide new insights on the underlying mechanisms leading to neurological complications post-LT. [ABSTRACT FROM AUTHOR]

Hyperammonemia associated with chronic liver disease (CLD) is implicated in the pathogenesis of hepatic encephalopathy (HE). The gut is a major source of ammonia production that contributes to hyperammonemia in CLD and HE and remains the primary therapeutic target for lowering hyperammonemia. As an ammonia‐lowering strategy, Escherichia coli Nissle 1917 bacterium was genetically modified to consume and convert ammonia to arginine (S‐ARG). S‐ARG was further modified to additionally synthesize butyrate (S‐ARG + BUT). Both strains were evaluated in bile‐duct ligated (BDL) rats; experimental model of CLD and HE. Methods: One‐week post‐surgery, BDLs received non‐modified EcN (EcN), S‐ARG, S‐ARG + BUT (3x1011 CFU/day) or vehicle until sacrifice at 3 or 5 weeks. Plasma (ammonia/pro‐inflammatory/liver function), liver fibrosis (hydroxyproline), liver mRNA (pro‐inflammatory/fibrogenic/anti‐apoptotic) and colon mRNA (pro‐inflammatory) biomarkers were measured post‐sacrifice. Memory, motor‐coordination, muscle‐strength and locomotion were assessed at 5 weeks. Results: In BDL‐Veh rats, hyperammonemia developed at 3 and further increased at 5 weeks. This rise was prevented by S‐ARG and S‐ARG + BUT, whereas EcN was ineffective. Memory impairment was prevented only in S‐ARG + BUT vs BDL‐Veh. Systemic inflammation (IL‐10/MCP‐1/endotoxin) increased at 3 and 5 weeks in BDL‐Veh. S‐ARG + BUT attenuated inflammation at both timepoints (except 5‐week endotoxin) vs BDL‐Veh, whereas S‐ARG only attenuated IP‐10 and MCP‐1 at 3 weeks. Circulating ALT/AST/ALP/GGT/albumin/bilirubin and gene expression of liver function markers (IL‐10/IL‐6/IL‐1β/TGF‐β/α‐SMA/collagen‐1α1/Bcl‐2) were not normalized by either strain. Colonic mRNA (TNF‐α/IL‐1β/occludin) markers were attenuated by synthetic strains at both timepoints vs BDL‐Veh. Conclusion: S‐ARG and S‐ARG + BUT attenuated hyperammonemia, with S‐ARG + BUT additional memory protection likely due to greater anti‐inflammatory effect. These innovative strategies, particularly S‐ARG + BUT, have potential to prevent HE. [ABSTRACT FROM AUTHOR]

Melatonin (MLT) levels fluctuate according to the external light/dark cycle in both diurnal and nocturnal mammals. We previously demonstrated that melatonin MT2 receptor knockout (MT2−/−) mice show a decreased nonrapid eye movement sleep over 24 hours and increased wakefulness during the inactive (light) phase. Here, we investigated the role of MT2 receptors in physiological light/dark cycle fluctuations in the activity of dorsal raphe nucleus (DRN) serotonin (5‐HT) neurons and anxiety‐ and depression‐like behavior. We found that the 5‐HT burst‐firing activity was tonically reduced across the whole 24 hours in MT2−/− mice compared with MT2+/+ mice. Importantly, the physiological changes in the spontaneous firing activity of DRN 5‐HT neurons during the light/dark cycle were nullified in MT2−/− mice, with a higher DRN 5‐HT neural firing activity during the light phase in MT2−/− than in MT2+/+ mice. The role of MT2 receptors over DRN 5‐HT neurons was confirmed by acute pharmacological studies in which the selective MT2 receptors agonist UCM1014 dose dependently inhibited DRN 5‐HT activity, mostly during the dark phase. Compared with MT2+/+, MT2−/− mice displayed an anxiety‐like phenotype in the novelty‐suppressed feeding and in the light/dark box tests; while anxiety levels in the light/dark box test were lower during the dark than during the light phase in MT2+/+ mice, the opposite was seen in MT2−/− mice. No differences between MT2+/+ and MT2−/− mice were observed for depression‐like behavior in the forced swim and in the sucrose preference tests. These results suggest that MT2 receptor genetic inactivation impacts 5‐HT neurotransmission and interferes with anxiety levels by perturbing the physiologic light/dark pattern. [ABSTRACT FROM AUTHOR]

Background: Loss of muscle mass and strength is common in cirrhosis and increases the risk of hyperammonaemia and hepatic encephalopathy. Resistance training optimizes muscle mass and strength in several chronic diseases. However, the beneficial effects of resistance training in cirrhosis remain to be investigated. Bile duct‐ligated (BDL) rats develop chronic liver disease, hyperammonaemia, reduced muscle mass and strength. Our aim was to test the effects of resistance training on muscle mass, function and ammonia metabolism in BDL‐rats. Methods: A group of BDL‐rats underwent a progressive resistance training programme and a group of non‐exercise BDL‐rats served as controls. Resistance training comprised of ladder climbing with a progressive increase in carrying weights attached to the tail. Training was performed 5 days a week during 4 weeks. Muscle strength and body composition were assessed using grip strength and EchoMRI. Weight and circumference of the gastrocnemius muscle (normalized to bodyweight), plasma ammonia and glutamine synthetase protein expression and activity were assessed. Results: BDL + exercise rats had significantly larger gastrocnemius circumference compared to non‐exercise BDL‐rats: ratio 0.082 vs 0.075 (P < 0.05). Gastrocnemius muscle weight was higher in exercisers than controls: 0.006 vs 0.005 (P < 0.05). A tendency towards a lower plasma ammonia in the exercise group compared to controls was observed (P = 0.10). There were no differences in lean body mass, GS protein expression and activity between the groups. Conclusion: Resistance training in rats with chronic liver disease beneficially effects muscle mass and strength. The effects were followed by non‐significant reduction in blood ammonia; however, a tendency was observed. See Editorial on Page 625 [ABSTRACT FROM AUTHOR]

Muscle mass loss and hepatic encephalopathy (complex neuropsychiatric disorder) are serious complications of chronic liver disease (cirrhosis) which impact negatively on clinical outcome and quality of life and increase mortality. Liver disease leads to hyperammonemia and ammonia toxicity is believed to play a major role in the pathogenesis of hepatic encephalopathy. However, the effects of ammonia are not brain-specific and therefore may also affect other organs and tissues including muscle. The precise pathophysiological mechanisms underlying muscle wasting in chronic liver disease remains to be elucidated. In the present study, we characterized body composition as well as muscle protein synthesis in cirrhotic rats with hepatic encephalopathy using the 6-week bile duct ligation (BDL) model which recapitulates the main features of cirrhosis. Compared to sham-operated control animals, BDL rats display significant decreased gain in body weight, altered body composition, decreased gastrocnemius muscle mass and circumference as well as altered muscle morphology. Muscle protein synthesis was also significantly reduced in BDL rats compared to control animals. These findings demonstrate that the 6-week BDL experimental rat is a relevant model to study liver disease-induced muscle mass loss. [ABSTRACT FROM AUTHOR]

Depletion of cholinergic interneurons in the ventral striatum (nucleus accumbens or N.Acc.) in adult rats increases the locomotor activating effects of amphetamine. It also impairs sensorimotor gating processes, an effect reversed by the antipsychotic haloperidol. These behavioral effects are suggestive of pronounced hyper-responsiveness of the mesolimbic dopamine (DA) projection to the N.Acc. However, it is unclear whether local cholinergic depletion results predominantly in exaggerated presynaptic DA release or a postsynaptic upregulation of DAergic function. The purpose of the present study is to test the former possibility by employing in vivo voltammetry to examine changes in the levels of extracellular DA within the N.Acc. in response to either mild tail pinch stress or amphetamine administration. While both cholinergic-lesioned and control rats showed reliable stress-induced increases in extracellular DA on two consecutive test days, those in the lesioned rats were significantly less pronounced. In response to amphetamine, a separate cohort of lesioned rats also exhibited smaller increases in extracellular DA release than controls, despite showing greater locomotor activity. Moreover, the increased behavioral response to amphetamine in lesioned rats coincided temporally with decreasing levels of DA in the N.Acc. The results confirm that cholinergic depletion within the N.Acc. suppresses presynaptic DA release and suggest that lesion-induced behavioral effects are more likely due to postsynaptic DA receptor upregulation. The results are also discussed in the context of schizophrenia, where post mortem studies have revealed a selective loss of cholinergic interneurons within the ventral striatum. Synapse, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Despite the growing non-medical consumption of amphetamine (Amph) during adolescence, its long-term neurobiological and behavioural effects have remained largely unexplored. The present research sought to characterize the behavioural profile and electrophysiological properties of midbrain monoaminergic neurons in adult rodents after Amph exposure during adolescence. Adolescent rats were administered vehicle, 0.5, 1.5, or 5.0 mg/kg.d Amph from postnatal day (PND) 30–50. At adulthood (PND 70), rats were tested in an open-field test (OFT) and elevated plus maze (EPM), paralleled by in-vivo extracellular recordings of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) neurons from the dorsal raphe nucleus, ventral tegmental area, and locus coeruleus, respectively. 5-HT firing in adulthood was increased in rats that had received Amph (1.5 mg/kg.d) during adolescence. At this regimen, DA firing activity was increased, but not NE firing. Conversely, the highest Amph dose regimen (5.0 mg/kg.d) enhanced NE firing, but not DA or 5-HT firing rates. In the OFT, Amph (1.5 mg/kg.d) significantly increased the total distance travelled, while the other doses were ineffective. In the EPM, all three Amph doses increased time spent in the open arms and central platform, as well as the number of stretch-attend postures made. Repeated adolescent exposure to Amph differentially augments monoaminergic neuronal firing in a dose-specific fashion in adulthood, with corresponding alterations in locomotion, risk assessment (stretch-attend postures and central platform occupancy) and risk-taking behaviours (open-arm exploration). Thus, adolescent Amph exposure induces long-lasting neurophysiological alterations that may have implications for drug-seeking behaviour in the future. [ABSTRACT FROM PUBLISHER]

Melatonin activates two brain G-protein coupled receptors, MT1 and MT2 , whose differential roles in the sleep-wake cycle remain to be defined. The novel MT2 receptor partial agonist, N-{2-[(3-methoxyphenyl) phenylamino] ethyl} acetamide (UCM765), is here shown to selectively promote non-rapid eye movement sleep (NREMS) in rats and mice. The enhancement ofNREMSby UCM765 is nullified by the pharmacological blockade or genetic deletion of MT2 receptors.MT2 , but not MT1 , knock-out mice show a decrease in NREMS compared to the wild strain. Immunohistochemical labeling reveals that MT2 receptors are localized in sleep-related brain regions, and notably the reticular thalamic nucleus (Rt). Microinfusion of UCM765 in the Rt promotes NREMS, and its systemic administration induces an increase in firing and rhythmic burst activity of Rt neurons, which is blocked by the MT2 antagonist 4-phenyl-2-propionamidotetralin. Since developing hypnotics that increase NREMS without altering sleep architecture remains a medical challenge, MT2 receptors may represent a novel target for the treatment of sleep disorders. [ABSTRACT FROM AUTHOR]

Background: Melancholic depression, described also as endogenous depression, is a mood disorder with distinctive specific psychopathological features and biological homogeneity, including anhedonia, circadian variation of mood, psychomotor activation, weight loss, diurnal cortisol changes, and sleep disturbances. Although several hypotheses have been proposed, the etiology of this disorder is still unknown. Methods: Behavioral, electrophysiological and biochemical approaches were used to characterize the emotional phenotype, serotonergic and noradrenergic electrical activity, and corticosterone in melatonin MT1 receptor knockout mice and their wild type counterparts, during both light and dark phases. Results: Melatonin MT1 receptor knockout mice have decreased mobility in the forced swim and tail suspension tests as well as decreased sucrose consumption, mostly during the dark/inactive phase. These mood variations are reversed by chronic treatment with the tricyclic antidepressant desipramine. In addition, MT1 receptor knockout mice exhibit psychomotor disturbances, higher serum levels of corticosterone the dark phase, and a blunted circadian variation of corticosterone levels. In vivo electrophysiological recordings show a decreased burst-firing activity of locus coeruleus norepinephrine neurons during the dark phase. The circadian physiological variation in the spontaneous firing activity of high-firing neuronal subpopulations of both norepinephrine neurons and dorsal raphe serotonin neurons are abolished in MT1 knockout mice. Conclusions: These data demonstrate that melatonin MT1 receptor knockout mice recapitulate several behavioral and neurobiological circadian changes of human melancholic depression and, for the first time, suggest that the MT1 receptor may be implicated in the pathogenesis of melancholic depression and is a potential pharmacological target for this mental condition. [ABSTRACT FROM AUTHOR]