Effects Of 5-HT1A Receptor Antagonist Research Articles

Effects of 5-HT1A Receptor Antagonist and 5-HT2A Receptor Agonist on Morphine Withdrawal

Effects of 5-HT1A Receptor Antagonist and 5-HT2A Receptor Agonist on Morphine Withdrawal

Protective effects of 5-HT1A receptor antagonist and 5-HT2A receptor agonist on the biochemical and histological features in a rat model of Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disorder and neuropathologically characterized by the aggregation of amyloid-beta (Aβ) plaques, neurofibrillary tangles, enhanced oxidative stress and neurodegeneration. Involvement of serotonergic systems in AD has been supposed and it is suggested that serotonin receptors modulation may provide a novel therapeutic target for AD.This study aimed at investigating the protective effect of NAD-299 (the selective 5-HT1A receptor antagonist) and TCB-2 (the potent5-HT2A receptor agonist) on the hippocampal oxidative stress biomarkers and the number of intact neurons in streptozotocin (STZ)-induced Alzheimer's disease in rats.Fifty adult male Wistar rats weighing 250–300 g were divided into five groups: sham, STZ-treated, STZ + NAD-299 (5 μg/1 μl icv), STZ + TCB-2 (5 μg/1 μl icv) and STZ + NAD-299 (5 μg/0.5 μl icv) +TCB-2 (5 μg/0.5 μl icv). At the end of the study, the rats were weighed, then hippocampal oxidative stress markers [total antioxidant capacity (TAC), malondialdehyde (MDA), the total thiol group (TTG), and DNA damage] were measured. In addition, the number of intact neurons in the CA1 area of the hippocampus was determined using hematoxylin and eosin staining.The results showed that icv injection of STZ reduced hippocampal TAC, TTG levels and intact pyramidal cells and increased DNA damage and MDA levels in the hippocampus of STZ-treated rats. Icv administration of NAD-299, TCB-2, and NAD-299+TCB-2 increased TAC and TTG contents and hippocampal intact neurons and reduced hippocampal DNA damage, MDA levels in icv-STZ treated rats. Moreover, there was no significant difference in weight changes among the experimental groups.According to the obtained results, it is suggested that 5-HT1A receptor antagonist (NAD-299) and 5-HT2A receptor agonist (TCB-2) can reduce oxidative stress and neuronal loss in a rat model of AD and may prevent the AD progression.

Brain Serotonergic and Noradrenergic Deficiencies in Behavioral Variant Frontotemporal Dementia Compared to Early-Onset Alzheimer's Disease.

Routinely prescribed psychoactive drugs in behavioral variant frontotemporal dementia (FTD) for improvement of (non)cognitive symptoms are primarily based on monoamine replacement or augmentation strategies. These were, however, initially intended to symptomatically treat other degenerative, behavioral, or personality disorders, and thus lack disease specificity. Moreover, current knowledge on brain monoaminergic neurotransmitter deficiencies in this presenile disorder is scarce, particularly with reference to changes in Alzheimer's disease (AD). The latter hence favors neurochemical comparison studies in order to elucidate the monoaminergic underpinnings of FTD compared to early-onset AD, which may contribute to better pharmacotherapy. Therefore, frozen brain samples, i.e., Brodmann area (BA) 6/8/9/10/11/12/22/24/46, amygdala, and hippocampus, of 10 neuropathologically confirmed FTD, AD, and control subjects were analyzed by means of reversed-phase high-performance liquid chromatography. Levels of serotonergic, dopaminergic, and noradrenergic compounds were measured. In nine brain areas, serotonin (5-HT) concentrations were significantly increased in FTD compared to AD patients, while 5-hydroxyindoleacetic acid/5-HT ratios were decreased in eight regions, also compared to controls. Furthermore, in all regions, noradrenaline (NA) levels were significantly higher, and 3-methoxy-4-hydroxyphenylglycol/NA ratios were significantly lower in FTD than in AD and controls. Contrarily, significantly higher dopamine (DA) levels and reduced homovanillic acid/DA ratios were only found in BA12 and BA46. Results indicate that FTD is defined by distinct serotonergic and noradrenergic deficiencies. Additional research regarding the interactions between both monoaminergic networks is required. Similarly, clinical trials investigating the effects of 5-HT1A receptor antagonists or NA-modulating agents, such as α1/2/β1-blockers, seem to have a rationale and should be considered.

Effects of 5-HT1A receptor antagonists on fluoxetine-induced changes in extracellular serotonin concentrations in rat frontal cortex.

Clinical studies in which serotonin specific reuptake inhibitors have been co-administered with pindolol have demonstrated a shortened time to onset of antidepressant activity. This effect has been attributed to the antagonist effects of pindolol at the presynaptic 5-HT1A receptor which augments the action of the serotonin specific reuptake inhibitors. In the present study, we demonstrate that acute fluoxetine-induced increases in extracellular serotonin concentrations, as measured by microdialysis in the frontal cortex, can be potentiated by 5-HT1A receptor blockade using N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyridinyl)cyclohexa necarboxamide (WAY100635), the silent and selective 5-HT1A receptor antagonist. WAY100635 at doses as low as 0.03 mg/kg s.c. maintained this potentiation effect across a range of fluoxetine doses. In addition, using antagonists with different intrinsic agonist activities for the 5-HT1A receptor, we have determined that only compounds with very low intrinsic agonist activity can produce a potentiation of the acute fluoxetine-induced increases in extracellular serotonin.