Acute or chronic antidepressants do not modify [125I]cyanopindoiol binding to 5HT1B receptors in rat brain (original) (raw)
British Journal of Pharmacology, 1994
The aims of the present study were to determine whether long-term 5-hydroxytryptamine (5-HT) reuptake blockade and inhibition of type-A monoamine oxidase (MAO-A) lead to an enhancement of the electrically evoked release of tritium from guinea-pig brain slices preloaded with [3H]-5-HT, and to assess the sensitivity of the terminal 5-HTD autoreceptor, the M2-adrenoceptor also located on 5-HT terminals, and the 5-HT3 receptor that modulates 5-HT release following these two types of antidepressant treatments. 2 The electrically evoked release of tritium was significantly enhanced following a 21-day treatment with the 5-HT reuptake blocker, paroxetine and the reversible MAO-A inhibitor, befloxatone, in preloaded slices of the hypothalamus, hippocampus and frontal cortex 48 h after removal of the osmotic minipumps used to deliver the drugs. 3 The inhibitory effect of the terminal 5-HT autoreceptor agonist, 5-methoxytryptamine, on the evoked release of tritium was attenuated in slices of the hypothalamus, hippocampus, but not frontal cortex, following the paroxetine treatment. In the befloxatone group, the effectiveness of 5-methoxytryptamine was unaltered in the same brain structures. 4 The sensitivity of the 2-adrenoceptor on 5-HT terminals, assessed using UK 14.304, was attenuated in hypothalamus, hippocampus, but not frontal cortex slices prepared from befloxatone-treated guineapigs and preloaded with [H]-5-HT. The paroxetine treatment did not alter the sensitivity of this X2-adrenoceptor in the hypothalamus. 5 The sensitivity of the 2-adrenoceptor on noradrenaline terminals, also assessed using UK 14.304, was not altered in hippocampus and hypothalamus slices preloaded with [3H]-noradrenaline following the long-term befloxatone treatment. 6 In frontal cortex slices, [3H]-5-HT uptake was no longer significantly attenuated after a 21-day treatment with paroxetine, whereas it was still markedly inhibited in hypothalamus slices. The enhancing effect of paroxetine on the evoked release of [3H]-5-HT in the superfusion medium was no longer evident in frontal cortex slices of the paroxetine group. These data indicate that long-term 5-HT reuptake blockade desensitized the 5-HT transporter in the frontal cortex. 7 The capacity of the 5-HT3 receptor agonist, 2-methyl-5-HT, to enhance the electrically evoked release of tritium was not altered in hypothalamus, hippocampus, and frontal cortex slices prepared from befloxatone-treated guinea-pigs, but was significantly attenuated in the paroxetine group also treated for 21 days. Following a 2-day paroxetine treatment, the enhancing effect of 2-methyl-5-HT on tritium release was unaltered in frontal cortex slices.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2009
This study was undertaken to investigate the potential antidepressant-like properties of SL65.0155, a serotonin 5-HT 4 receptor partial agonist, in male rats of the Wistar strain tested in the forced swim test (FST), an experimental model widely used to assess antidepressant-like activity. The expression of hippocampal neurotrophic factors, such as the brain-derived neurotrophic factor (BDNF), the phosphorilated cAMP response element-binding protein (p-CREB), the B cell lymphoma-2 (Bcl-2), the Bax and the vascular endothelium growth factor (VEGF) were also evaluated by Western Blot analysis. Different groups of rats received intraperitoneally (i.p.) injections of SL65.0155 (0.1, 0.5 and 1 mg/kg), clomipramine (50 mg/kg), citalopram (15 mg/kg) or vehicle, respectively, 24, 5 and 1 h prior to the FST. Compared to the control group, SL65.0155 (0.5 and 1 mg/kg), clomipramine or citalopram injected animals showed an increased swimming and climbing behavior and reduced immobility time in the FST. Interestingly, this effect was not due to changes in the locomotor activity since all treated groups failed to show any change in motor ability as assessed in the open field test. Western blot analysis of hippocampal homogenates showed an enhancement of p-CREB, BDNF Bcl-2 and VEGF protein levels in SL65.0155 treated groups, but not in citalopram or clomipramine treated groups, used here as positive control. No change was found in Bax expression in any treated group. These findings give further support to the hypothesis that the stimulation of serotonin 5-HT 4 receptors may be a therapeutic target for depression.
Pharmacological Reports, 2012
This paper summarizes a series of electrophysiological studies aimed at finding the effects of the activation of 5-HT 7 receptors on neuronal excitability as well as on excitatory and inhibitory synaptic transmission in the hippocampus and in the frontal cortex of the rat. These studies demonstrated that 5-HT 7 receptors play an important role in the modulation of the activity of the hippocampal network by regulating the excitability of pyramidal cells of the CA1 area, as well as via their effect on GABA and glutamatergic transmission. The reactivity of 5-HT 7 receptors in the hippocampus is decreased by repeated administration of antidepressant drugs and increased by a prolonged high level of corticosterone. More importantly, administration of antidepressant drug, imipramine, prevents the occurrence of corticosterone-induced changes in the function of hippocampal 5-HT 7 receptors. It has also been found that the blockade of 5-HT 7 receptors by the selective antagonist SB 269970, lasting for a few days, causes similar changes to those observed after long-term administration of antidepressants. Thus, it seems that the pharmacological blockade of 5-HT 7 receptors produces faster effects compared to classic antidepressant drugs. A similarity between the changes in the glutamatergic transmission induced by the blockade of 5 HT 7 receptors and those caused by repeated administration of the antidepressant drug, imipramine, has also been found in the frontal cortex. It has also been shown that the changes in glutamatergic transmission and the impairment of long-term synaptic plasticity in the frontal cortex of animals subjected to repeated restraint stress are reversed by the blockade of 5-HT 7 receptors. Overall, these studies, together with the data provided by other investigators, support the hypothesis that 5-HT 7 receptor antagonists may become a prototype of a new class of antidepressant drugs. Such compounds will not function by blocking 5-HT reuptake, as many of the currently used drugs, but through a direct interaction with the 5-HT 7 receptor. This type of action is highly selective and usually does not require the occurrence of adaptive changes in neuronal functions, thus allowing for a much quicker therapeutic effect.
Journal of Neural Transmission, 2003
Using in vivo microdialysis in the freely moving rat we have examined the effects of 5-HT 6 receptor antagonism on the neurochemical outcome of antidepressant treatment. Acute administration of both desipramine (10 mg/kg s.c.) and venlafaxine (10 mg/kg s.c.) produced a 2 fold increase in extracellular noradrenaline (NA) but no change in frontal cortex dopamine (DA), 5-HT or glutamate. Fluoxetine (20 mg/kg s.c.) produced no change in extracellular levels of any of the neurotransmitters examined. SB-271046 produced a 3 fold increase in extracellular glutamate. Combination treatment of SB-271046 with each antidepressant produced no change in the antidepressant-induced changes in NA, DA or 5-HT. In contrast, both fluoxetine and venlafaxine attenuated the SB-271046-induced increase in extracellular glutamate, suggesting that 5-HT and possibly NA may be having an inhibitory action on the excitatory pathways enhanced by 5-HT 6 receptor blockade. Furthermore, these data indicate that the neurochemical effects induced by NA and/or 5-HT reuptake inhibitors are not enhanced by 5-HT 6 receptor blockade indicating that 5-HT 6 receptor antagonists are unlikely to augment the therapeutic efficacy of these types of antidepressants.
Neurochemistry International, 2009
Deficiencies in brain serotonergic neurotransmission, which is in part associated with the alteration of brain serotonin (5-HT) receptors, have been proposed as part of a neurochemical imbalance in affective disorders, including depression. The drugs used for the treatment of these disorders generally act through and/or on the serotonergic system. Different animal models of depression have provided researchers with tools to obtain a better understanding of drug actions and possibilities to obtain insight into the neurochemical bases of these disorders. The measurements of the 5-HT 1A and 5-HT 1B receptor densities in a rat model of depression, Flinders sensitive line (FSL) rats, and comparisons with Sprague-Dawley (SPD) and Flinders resistant line (FRL) rats, are reported here. The receptor sites were quantified by autoradiography in more than 25 distinct brain regions known to have relatively large densities of respective sites. Some brain regions (e.g., dental gyrus, septal nucleus) were divided into several parts, according to previously known subdivisions, because of a substantial heterogeneity of these receptors. The densities in the FSL rats (''depressed'' rats) were compared statistically to those in the SPD rats. In addition, comparisons were made to the densities in the FRL rats (rats not showing depressive symptoms). Comparisons were performed with the SPD and FRL rats because both of these strains have been used as control animals in studies of FSL rats. The results show that the densities of 5-HT 1A receptors are not significantly different between the FSL and SPD rats, but they are significantly different from the FRL rats. 5-HT 1A receptor density is significantly higher in the FRL rats than the SPD rats. The 5-HT 1B receptors were significantly greater in the FSL rats than in either the SPD or FRL rats. In addition, the FRL rats have 5-HT 1B receptor densities significantly lower in many brain regions than the SPD rats. The data presented here, in addition to previously reported differences in regional synthesis between these strains and the effect of acute citalopram on synthesis, suggest that SPD rats are likely a more appropriate control than FRL rats, when studies of FSL rats are performed with drugs acting directly or indirectly on, or through, the brain serotonergic system. However, comparisons, particularly of neurochemical and/or biological parameters in FRL rats, may reveal new insight into the alterations of 5-HT neurotransmission in this animal model of depression and possibly human depression, as well as the elevation of symptoms with treatments. The data also suggest that there could be a different fraction of 5-HT 1A receptors in high and low affinity states in these strains, as well as the possibility of different intracellular signalling. ß
The Role of 5-HT2C Receptors in the Antidepressant Response: A Critical Review
Modern Trends in Pharmacopsychiatry, 2010
Evidence from the various sources indicates alterations in 5-HT 2C receptor functions in anxiety, depression and suicide, and other stress-related disorders treated with antidepressant drugs. Although the notion of a 5-HT 2C receptor desensitization following antidepressant treatments is rather well anchored in the literature, this concept is mainly based on in vitro assays and/or behavioral assays (hypolocomotion, hyperthermia) that have poor relevance to anxio-depressive disorders. Our objective herein is to provide a comprehensive overview of the studies that have assessed the effects of antidepressant drugs on 5-HT 2C receptors. Relevant molecular (second messengers, editing), neurochemical (receptor binding and mRNA levels), physiological (5-HT 2C receptor-induced hyperthermia and hormone release), behavioral (5-HT 2C receptor-induced changes in feeding, anxiety, defense and motor activity) data are summarized and discussed. Setting the record straight about drug-induced changes in 5-HT 2C receptor function in specific brain regions should help to determine which pharmacotherapeutic strategy is best for affective and anxiety disorders.
In vitro profile of the antidepressant candidate OPC14523 at rat and human 5HT 1A receptors
European Journal of Pharmacology, 2005
This study determined the in vitro functional profile of 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2quinolinone monomethanesulfonate (OPC-14523) at rat and human serotonin (5-HT) 5-HT 1A receptors and binding affinity of OPC-14523 at human frontocortical 5-HT 1A receptors. OPC-14523 (1 AM) increased guanosine-5V-O-(3-[ 35 S]thio)-triphosphate ([ 35 S]GTPgS) binding to 5-HT 1A receptor-containing regions of rat brain tissue sections (¨53% of the effect of 1 AM (+)8-hydroxy-2-(di-n-propylamino)tetralin ((+)8-OH-DPAT) that were blocked by the selective 5-HT 1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2pyridinylcyclohexanecarboxamide (WAY-100635). OPC-14523 also behaved as a partial agonist in its stimulation of [ 35 S]GTPgS binding to membranes from rat hippocampus (pEC 50 = 7.60 T 0.23, E max = 41.1% of the effect of 10 AM (+)8-OH-DPAT), human frontal cortex (pEC 50 = 7.89 T 0.08; E max = 64% of the effect of 10 AM (+)8-OH-DPAT), and Chinese Hamster Ovary cells expressing cloned human 5-HT 1A receptors (pEC 50 = 8.0 T 0.11; E max = 85.5% of the effect of 10 AM 5-HT), and all of these effects of OPC-14523 were blocked by WAY-100635.
Biochemical and Behavioral Evidence for Antidepressant-Like Effects of 5-HT6 Receptor Stimulation
Journal of Neuroscience, 2007
The primary action of several antidepressant treatments used in the clinic raises extracellular concentrations of serotonin (5-HT), which subsequently act on multiple 5-HT receptors. The present study examined whether 5-HT 6 receptors might be involved in the antidepressant-like effects mediated by enhanced neurotransmission at 5-HT synapses. A selective 5-HT 6 receptor antagonist, SB271046, was evaluated for its ability to counteract fluoxetine-induced biochemical and behavioral responses in mice. In addition, biochemical and behavioral effects of the 5-HT 6 receptor agonist, 2-ethyl-5-methoxy-N,N-dimethyltryptamine (EMDT), were assessed in mice to ascertain whether enhancement of 5-HT 6 receptor-mediated neurotransmission engenders antidepressant-like effects. SB271046 significantly counteracted the stimulatory actions of fluoxetine on cortical c-fos mRNA, phospho-Ser845-GluR1, and in the tail suspension antidepressant assay, whereas it had no effect on these parameters by itself. EMDT increased the phosphorylation states of Thr 34 -DARPP-32 and Ser 845 -GluR1, both in brain slices and in the intact brain, which were effects also seen with the antidepressant fluoxetine; as with fluoxetine, these effects were demonstrated to be independent of D 1 receptor stimulation. Systemic administration of EMDT increased c-fos mRNA expression in the striatum and cerebral cortex and reduced immobility in the tail suspension test. The antidepressant-like effects of EMDT in the tail suspension test were prevented by SB271046. Our results indicate that 5-HT 6 receptor stimulation may be a mechanism initiating some of the biochemical and behavioral outcomes of 5-HT reuptake inhibitors, such as fluoxetine. These findings also indicate that selective 5-HT 6 receptor agonists may represent a novel antidepressant drug class.
Neuropharmacology, 1999
The effects of selective serotonin re-uptake inhibitor (SSRI), paroxetine, and 5-HT 1A , 5-HT 1B and 5-HT 1B/1D receptor antagonists on in vivo extracellular 5-HT levels in the guinea-pig frontal cortex and dorsal hippocampus were investigated using the technique of microdialysis. The aim of the study was to further investigate the autoreceptor roles of the 5-HT 1A , 5-HT 1B and 5-HT 1D receptors in the median 6s dorsal raphe nuclei. In the frontal cortex, 5-HT 1A (WAY 100635, 1 mg/kg i.p.) or 5-HT 1B (SB-224289, 4 mg/kg i.p.) receptor antagonists had no effect on extracellular levels of 5-HT, whilst the mixed 5-HT 1B/1D receptor antagonist (GR 127935, 0.3 mg/kg i.p) produced a significant decrease in extracellular 5-HT levels. Paroxetine (10 mM) significantly increased extracellular 5-HT levels when perfused locally into the cortex. Administration of SB-224289, followed 120 min later by WAY 100635, had no effect on extracellular 5-HT levels. In contrast, sequential administration of either WAY 100635 and GR 127935, or SB-224289 and paroxetine significantly increased extracellular 5-HT levels. In the dorsal hippocampus, whilst 5-HT 1A receptor antagonism elicited by administration of WAY 100635 had no effect, both 5-HT 1B and mixed 5-HT 1B/1D receptor blockade significantly increased extracellular 5-HT levels. Administration of SB-224289 followed 120 min later with WAY 100635, or WAY 100635 followed 30 min later with GR 127935, potentiated the effect of the three compounds alone, significantly increasing extracellular 5-HT levels. These data demonstrate that to simultaneously increase extracellular 5-HT in both frontal cortex and dorsal hippocampus of the guinea-pig brain concurrent 5-HT 1A , 5-HT 1B and 5-HT 1D receptor blockade is required. Whereas in the dorsal hippocampus, 5-HT 1B receptor blockade is sufficient to elicit an increase in extracellular 5-HT levels.
Pharmacology Biochemistry and Behavior, 2015
More effective treatments for major depression are needed. We studied if the selective 5-HT 3 receptor antagonist ondansetron can potentiate the antidepressant potential of the selective serotonin (5-HT) reuptake inhibitor (SSRI) paroxetine using behavioral, neurochemical and electrophysiological methods. Flinders Sensitive Line (FSL) rats, treated with ondansetron, and/or a sub-effective dose of paroxetine, were assessed in the forced swim test. The effects of an acute intravenous administration of each compound alone and in combination were evaluated with respect to 5-HT neuronal firing rate in the dorsal raphe nucleus (DRN). Effects of s.c. administration of the compounds alone and in combination on extracellular levels of 5-HT were assessed in the ventral hippocampus of freely moving rats by microdialysis. The results showed that ondansetron enhanced the antidepressant activity of paroxetine in the forced swim test. It partially prevented the suppressant effect of paroxetine on DRN 5-HT neuronal firing and enhanced the paroxetine-induced increase of hippocampal extracellular 5-HT release. These findings indicate that 5-HT 3 receptor blockade potentiates the antidepressant effects of SSRIs. Since both paroxetine and ondansetron are used clinically, it might be possible to validate this augmentation strategy in depressed patients.