piperidines and Anhedonia

Several psychiatric conditions are affected by neuroinflammation and neuroimmune activation. The transcription factor nuclear factor kappa light-chain-enhancer of activated B cells (NFkB) plays a major role in inflammation and innate immunity. The neurokinin-1 receptor (NK1R) is the primary endogenous target of the neuroactive peptide substance P, and some data suggests that NK1R stimulation may influence NFkB activity. Both NK1R and NFkB have been shown to play a functional role in complex behaviors including stress responsivity, depression, and addiction. In this study, we test whether NFkB activity in the brain (stimulated by lipopolysaccharide administration) is dependent upon the NK1R.. Adult male Wistar rats were treated systemically with the NK1R antagonist L822429 followed by administration of systemic lipopolysaccharide (LPS, a strong activator of NFkB). Hippocampal extracts were used to assess expression of proinflammatory cytokines and NFkB-DNA-binding potential. For behavioral studies, rats were trained to consume 1% (w/v) sucrose solution in a continuous access two-bottle choice model. After establishment of baseline, animals were treated with L822429 and LPS and sucrose preference was measured 12 h post-treatment.. Systemic LPS treatment causes a significant increase in proinflammatory cytokine expression and NFkB-DNA-binding activity within the hippocampus. These increases are attenuated by systemic pretreatment with the NK1R antagonist L822429. Systemic LPS treatment also led to the development of anhedonic-like behavior, evidenced by decreased sucrose intake in the sucrose preference test. This behavior was significantly attenuated by systemic pretreatment with the NK1R antagonist L822429.. Systemic LPS treatment induced significant increases in NFkB activity, evidenced by increased NFkB-DNA binding and by increased proinflammatory cytokine expression in the hippocampus. LPS also induced anhedonic-like behavior. Both the molecular and behavioral effects of LPS treatment were significantly attenuated by systemic NK1R antagonism, suggesting that NK1R stimulation lies upstream of NFkB activation following systemic LPS administration and is at least in part responsible for NFkB activation.

Topics: Anhedonia; Animals; Hippocampus; Lipopolysaccharides; Male; Neurokinin-1 Receptor Antagonists; NF-kappa B; Piperidines; Rats; Rats, Wistar; Receptors, Neurokinin-1

The treatment of depression in old age is complicated by frequent co-morbidity with cognitive impairment. Anti-dementia drugs have some efficacy to improve cognitive performance and there is an inconsistent literature regarding the effect of such drugs on depressive symptoms. Here, we have investigated whether anti-dementia drugs would have antidepressant-like and pro-cognitive effects in a well-validated animal model of depression and cognitive impairment, chronic mild stress (CMS).. Rats were subjected to CMS for a total of 8 weeks. After 2 weeks, subgroups of stressed and non-stressed animals were treated daily, for 5 weeks followed by 1 week of drug withdrawal, with vehicle, imipramine (10 mg/kg), rivastigmine (2 mg/kg), donepezil (0.3 mg/kg) or memantine (5 mg/kg). Sucrose intake was tested weekly, and animals were also tested in the elevated plus maze (at week 7) and in an object recognition task (at weeks 7 and 8).. CMS decreased sucrose intake, had an anxiogenic effect in the elevated plus maze, and impaired performance in the object recognition test. Imipramine, rivastigmine and donepezil normalized performance in all three tests. Memantine had anxiolytic and pro-cognitive effects, but did not reverse CMS-induced anhedonia.. The fact that all three anti-dementia drugs reversed CMS-induced cognitive impairment and that cholinesterase inhibitors, but not memantine, have antidepressant-like effects in this model suggest that different mechanisms may underlie CMS-induced anhedonia and cognitive impairment. We discuss the clinical implications of these findings.

Topics: Anhedonia; Animals; Antidepressive Agents; Cholinesterase Inhibitors; Cognitive Dysfunction; Depressive Disorder; Disease Models, Animal; Donepezil; Indans; Male; Nootropic Agents; Piperidines; Rats; Rats, Wistar; Recognition, Psychology; Rivastigmine; Stress, Psychological

Binge eating (BE) disrupts feeding and subverts reward mechanism. Since cocaine- and amphetamine-regulated transcript peptide (CART) mediates satiety as well as reward, its role in BE justifies investigation. To induce BE, rats were provided restricted access to high fat sweet palatable diet (HFSPD) for a period of 4 weeks. Immunoreactivity profile of the CART elements, and accompanying neuroplastic changes were studied in satiety- and reward-regulating brain nuclei. Further, we investigated the effects of CART, CART-antibody or rimonabant on the intake of normal chow or HFSPD. Rats fed on HFSPD showed development of BE-like phenotype as reflected by significant consumption of HFSPD in short time frame, suggestive of dysregulated satiety mechanisms. At the mid-point during BE, CART-immunoreactivity was significantly increased in hypothalamic arcuate (ARC), lateral (LH), nucleus accumbens shell (AcbSh) and paraventricular nucleus of thalamus (PVT). However, for next 22-h post-binge time-period, the animals showed no interest in food, and low CART expression. Pre-binge treatment with rimonabant, a drug recommended for the treatment of BE, produced anorexia, increased CART expression in ARC and LH, but not in AcbSh and PVT. Higher dose of CART was required to produce anorexia in binged rats. While neuronal tracing studies confirmed CART fiber connectivity from ARC and LH to AcbSh, increase in CART and synaptophysin immunostaining in this pathway in BE rats suggested strengthening of the CART connectivity. We conclude that CART bearing ARC-LH-PVT-AcbSh reward circuit may override the satiety signaling in ARC-PVN pathway in BE rats.

Topics: Anhedonia; Animals; Binge-Eating Disorder; Brain; Cannabinoid Receptor Antagonists; Disease Models, Animal; Eating; Male; Nerve Tissue Proteins; Neural Pathways; Piperidines; Pyrazoles; Random Allocation; Rats, Wistar; Reward; Rimonabant; Satiation; Synaptophysin

In patients with epilepsy, a common comorbidity diagnosed is depression. Temporal lobe epilepsy or post status epilepticus (SE) animal model establish and validate the co morbidity and common pathogenesis of depression and epilepsy. Elevation in serotonin concentration gives an inhibitory response to epileptic discharge and stabilizes the depressed mood disorder. Piperine is a potent monoaminooxidase inhibitor and stimulates the synthesis of serotonin. So the present work is undertaken to investigate the effect of piperine on depression associated with by status epilepticus induced by pilocarpine in rats.. Status epilepticus was induced in the rats by administration of pilocarpine 350 mg/kg i.p.. Behaviour tests like forced swimming test (FST), saccharin consumption test, actophotometer test and rotarod test were conducted. Antidepressant effect and neuroprotective effect of piperine (25 mg/kg, p.o. for 10 days) in post status epilepticus animal model was evaluated. Brain serotonin concentration was also estimated. Fluoxetine (20 mg/kg p.o.) was used as standard.. Only piperine but not fluoxetine significantly increased the decrease in number of rotations of wheel in FST, and decrease volume of saccharine consumption caused by pilocarpine. Both fluoxetine and piperine significantly increase the pilocarpine induced decrease in activity score in actophotometer, time taken to fall in rotarod and concentration of serotonin in brain.. The underlying mechanism behind depression in epilepsy may be alteration in monoaminergic pathways and GABAergic pathways. The antidepressant activity of piperine in post-SE rats may be attributed to its MAO inhibitor activity and neuroprotective activity.

Topics: Alkaloids; Anhedonia; Animals; Anticonvulsants; Behavior, Animal; Benzodioxoles; Biogenic Monoamines; Brain Chemistry; Chromatography, Thin Layer; Convulsants; Depression; Epilepsy; Female; Fluoxetine; Male; Motor Activity; Pilocarpine; Piperidines; Polyunsaturated Alkamides; Postural Balance; Rats; Serotonin; Spectrophotometry, Infrared; Status Epilepticus; Swimming