Acute or chronic antidepressants do not modify [125I]cyanopindoiol binding to 5HT1B receptors in rat brain (original) (raw)
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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.
European Journal of Pharmacology, 1993
A variety of antidepressants of different chemical classes were tested for their in vivo and in vitro activity at 5-HTlc receptors in the brain. Conventional tricyclic antidepressants (imipramine, desipramine, maprotiline, clomipramine, trimipramine, amitriptyline, nortriptyline, doxepin, amoxapine) as well as mianserin and trazodone were found to display high to low nanomolar affinity for 5-HTlc receptors. Antidepressants of other chemical classes and with other mechanisms of action (affecting amine uptake systems: fluoxetine, citalopram, sertraline, fluvoxamine, nomifensine, amineptine; or monoamine oxidase inhibitors: moclobemide, iproniazid) had negligible affinities (micromolar range) for 5-HTlc receptors, except fluoxetine. When tested in an in vivo rat model thought to reveal functional agonistic or antagonistic properties at 5-HTlc receptors, all antidepressants displaying high affinity for this receptor type (except clomipramine and trimipramine)
British Journal of Pharmacology, 1995
A combined study of receptor binding in central neuronal cell membranes and functional responses in isolated segments of guinea‐pig small intestine allowed characterization of the interaction of four antidepressant drugs with central and peripheral 5‐HT3 and 5‐HT4 receptors. Clomipramine, paroxetine and fluoxetine inhibited [3H]‐DAU 6215 binding to 5‐HT3 recognition sites in NG 108‐15 cells with IC50 values in the range 1.3–4 μm. Litoxetine had an IC50 of 0.3 μm. The specific binding of [3H]‐GR 113808 to 5‐HT4 recognition sites in pig striatal membranes was inhibited by all four antidepressants with negligible potency (IC50 values ≥ 20 μm). In whole ileal segments, concentration‐response curves to 5‐HT were biphasic, with the high‐ and low‐potency phases involving 5‐HT4 and 5‐HT3 receptors, respectively. Curves to 2‐methyl‐5‐hydroxytryptamine (2‐methyl‐5‐HT: a 5‐HT3 receptor agonist) and 5‐methoxytryptamine (5‐MeOT: a 5‐HT4 receptor agonist) were monophasic. All antidepressants were...
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.
Psychopharmacology, 2005
Rationale: The selective serotonin reuptake inhibitors (SSRIs) and the serotonin and noradrenaline reuptake inhibitors (SNRIs) increase synaptic levels of serotonin, leading to an increased activation of a multitude of specific postsynaptic 5-HT receptors. However, it is not yet known which 5-HT receptor subtypes mediate the therapeutic effects of antidepressants. Methods: The effects of the SSRI, paroxetine and the SNRI, venlafaxine were evaluated in the mouse four plates test (FPT). Results: Paroxetine administered intraperitoneally (IP) (0.5, 2-8 mg/kg) potently augmented the number of punished passages accepted by mice in this paradigm. The effects of paroxetine (8 mg/kg) were not reversed by the selective 5-HT 2C receptor antagonist, RS 10-2221 (0.1 mg/kg and 1 mg/kg) or the selective 5-HT 2B/2C receptor antagonist SB 206553 (0.1 mg/kg and 1 mg/kg), at doses which lack an effect when administered alone. In contrast, the selective 5-HT 2A receptor antagonist, SR 46349B (0.1 mg/kg and 1 mg/kg) completely abolished the paroxetine-induced increase in punished passages. The acute administration of venlafaxine induced an anxiolyticlike effect in the FPT at the doses of 2-16 mg/kg. This effect was reversed by the 5-HT 2B/2C receptor antagonist as did SR 46349B, for both doses administered. Our results strongly suggest that activation of 5-HT 2A receptors is critically involved in the anxiolytic activity of paroxetine, whereas the 5-HT 2A and 5-HT 2B receptors are involved in the antipunishment action of venlafaxine in the FPT. The co-administration of selective 5-HT 2A, 2B, 2C receptor agonists (DOI, 0.06 mg/kg and 0.25 mg/kg; BW 723C86, 0.5 mg/kg and 2 mg/kg and RO 60-0175, 0.06 mg/kg and 0.25 mg/kg), respectively, was subsequently investigated. The effects of sub-active doses of paroxetine (0.25 mg/kg and 1 mg/kg) were augmented by BW 723C86 and RO 60-0175 receptor agonist challenge. The anti-punishment effects of venlafaxine (0.25 mg/kg and 1 mg/kg) were potentialised only by DOI co-administration. Conclusion: These results indicate that the co-administration of 5-HT 2 receptor agonists with paroxetine and venlafaxine may provide a powerful tool for enhancing the clinical efficacy of these antidepressants.
Brain Research Bulletin, 2012
Flinders Sensitive Line (FSL) rat is as an animal model of depression with altered parameters of the serotonergic (5-HT) system function (5-HT synthesis rates, tissue concentrations, release, receptor density and affinity), as well as an altered sensitivity of these parameters to different 5-HT based antidepressants. The effects of acute and chronic treatments with the 5-HT 1B agonist, CP-94253 on 5-HT synthesis, in the FSL rats and the Flinders Resistant Line (FRL) controls were measured using ␣-[ 14 C]methyl-l-tryptophan (␣-MTrp) autoradiography. CP-94253 (5 mg/kg), or an adequate volume of saline, was injected i.p. as a single dose in the acute experiment or delivered via the subcutaneously implanted osmotic minipump (5 mg/kg/day for 14 days) in the chronic experiment. The acute treatment with CP-94253 significantly decreased the 5-HT synthesis in both the FRL and FSL rats, with a more widespread effect in the FRL rats. Chronic treatment with CP-94253 significantly decreased 5-HT synthesis in the FRL rats, while 5-HT synthesis in the FSL rats was significantly increased throughout the brain. In both the acute and chronic experiment, the FRL rats had higher brain 5-HT synthesis rates, relative to the FSL rats.
Antidepressants are functional antagonists at the serotonin type 3 (5-HT3) receptor
Molecular Psychiatry, 2003
Antidepressants are commonly supposed to enhance serotonergic and/or noradrenergic neurotransmission by inhibition of neurotransmitter reuptake through binding to the respective neurotransmitter transporters or through inhibition of the monoamine oxidase. Using the concentration-clamp technique and measurements of intracellular Ca 2 þ , we demonstrate that different classes of antidepressants act as functional antagonists at the human 5-HT 3A receptor stably expressed in HEK 293 cells and at endogenous 5-HT 3 receptors of rat hippocampal neurons and N1E-115 neuroblastoma cells. The tricyclic antidepressants desipramine, imipramine, and trimipramine, the serotonin reuptake inhibitor fluoxetine, the norepinephrine reuptake inhibitor reboxetine, and the noradrenergic and specific serotonergic antidepressant mirtazapine effectively reduced the serotonin-induced Na þ -and Ca 2 þ -currents in a dose-dependent fashion. This effect was voltage-independent and, with the exception of mirtazapine, noncompetitive. Desipramine, imipramine, trimipramine, and fluoxetine also accelerated receptor desensitization. Moclobemide and carbamazepine had no effect on the serotonin-induced cation current. By analyzing analogues of desipramine and carbamazepine, we found that a basic propylamine side chain increases the antagonistic potency of tricyclic compounds, whereas it is abolished by an uncharged carboxamide group. The antagonistic effects of antidepressants at the 5-HT 3 receptor did not correlate with their effects on membrane fluidity. In conclusion, structurally different types of antidepressants modulate the function of this ligand-gated ion channel. This may represent a yet unrecognized pharmacological principle of antidepressants.
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.
Controversies on the role of 5-HT2C receptors in the mechanisms of action of antidepressant drugs
Neuroscience & Biobehavioral Reviews, 2014
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.