1A Serotonin Receptor Research Articles

P.1.016 Control of the dendritic targeting of the 5-HT 1A serotonin receptor as an alternative antidepressant therapy

P.1.016 Control of the dendritic targeting of the 5-HT 1A serotonin receptor as an alternative antidepressant therapy

Antinociceptive activity of Annona diversifolia Saff. leaf extracts and palmitone as a bioactive compound

Annonas are consumed as fresh fruits, but are also widely used in folk medicine for treating pain and other ailments. Antinociceptive properties of the Annona diversifolia ethanol crude extract were tested using the pain-induced functional impairment model in rat (PIFIR) and the writhing test in mice. The ethanol extract caused a 25% recovery of limb function in rats; this response was significant and dose-dependent. Furthermore, this extract produced a similar antinociceptive response (ED 50 = 15.35 mg/kg) to that of the reference drug tramadol (ED 50 = 12.42 mg/kg) when evaluated in the writhing test in mice. Bio-guided fractionation yielded hexane and acetone active fractions from which the presence of palmitone and flavonoids was respectively detected. Palmitone produced an antinociceptive response with an ED 50 = 19.57 mg/kg in the writhing test. Antinociceptive responses from ethanol extract and tramadol were inhibited in the presence of either naloxone (1 mg/kg, s.c.)—an antagonist of endogenous opioids—or WAY100635 (0.8 mg/kg, s.c.)—a 5-HT 1A serotonin receptor antagonist. These results provide evidence that A. diversifolia possesses antinociceptive activity, giving support to their traditional use for treatment of spasmodic and arthritic pain. In addition, our results suggest the participation of endogenous opioids and 5-HT 1A receptors in this antinociceptive response.

Application of desirability-based multi(bi)-objective optimization in the design of selective arylpiperazine derivates for the 5-HT 1A serotonin receptor

The multiobjective optimization technique based on the desirability estimation of several interrelated responses (MOOP-DESIRE) has been recently applied to quantitative structure–activity relationship (QSAR) studies. However, the advantage of applying this new methodology to the study of selectivity and affinity to competitive targets has been little explored. We used the MOOP-DESIRE methodology and a variation of this, to study the arylpiperazine derivates that could interact with 5-HT 1A and 5-HT 2A, serotonin receptor subtypes with the objective of designing more selective molecules for the 5-HT 1A receptor. We did show that the model results are in agreement with the available pharmacophore descriptions, guaranteeing an appropriate structural correlation and proving the methodology, as a useful tool for the important problem of selective drug design.

Effect of 8-hydroxy-2-( N, N-di- n-propylamino)tetralin and MDMA on the discriminative stimulus effects of the classical hallucinogen DOM in rats

Co-administration of the 5-HT 1A serotonin receptor agonist (±)8-hydroxy-2-( N, N-di- n-propylamino)tetralin [(±)8-OH DPAT] enhances the discriminative stimulus effects of the classical hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) in rats. In the present investigation, using Sprague–Dawley rats trained to discriminate DOM (1.0 mg/kg) from saline vehicle under a VI-15 s schedule of reinforcement, it was shown that the stimulus-enhancing actions of 8-OH DPAT are related more to its R(+)-isomer than to its S(−)-enantiomer, and that the (±)- and R(+)8-OH DPAT-induced effects are antagonized by the 5-HT 1A receptor antagonist NAN-190. (±)8-OH DPAT and its isomers substitute in rats trained to discriminate the designer drug N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA; methylenedioxymethamphetamine) from vehicle indicating some similarity of effect. On this basis, it was hypothesized that MDMA might be capable of enhancing the DOM stimulus. Co-administration of MDMA with low (i.e., 0.1 and 0.3 mg/kg) doses of DOM resulted in greater DOM-appropriate responding than engendered by administration of DOM alone. As such, the present findings are the first to demonstrate an MDMA-induced enhancing effect on the discriminative stimulus actions of a classical hallucinogen. The results also suggest that a 5-HT 1A serotonin receptor mechanism might contribute to this phenomenon.

Solvent-Free Microwave Synthesis of 3-(4-Benzo[b]thiophene-2-carbonyl)-1-piperazinyl-1-benzo[b]thiophen-2-yl-1-propanones. New Hetero Bis-Ligands with Potential 5-HT1A Serotonergic Activity

- A novel series of2-benzothiophenealkylpiperazine derivatives 11(a-d) with potential affinity at 5-HT 1A serotonin receptors have been synthesized via solvent-free, microwave-promoted Michael addition of benzo[b]thiophene piperazine derivatives 6(a-c) to substituted benzo[b]thiophen-2-yl propenones 10(b,c).

MPPF et imagerie des récepteurs 5-HT 1A de la sérotonine

[ 18F]MPPF is a 5-HT 1A antagonist of serotonin receptors, with interesting pharmacological properties. Its labelling is obtained with fluorine 18 and PET studies achieve molecular and functional neuroimaging of 5-HT 1A serotonin receptors.

A comparison of recent parametric neuroreceptor mapping approaches based on measurements with the high affinity PET radioligands [ 11C]FLB 457 and [ 11C]WAY 100635

In positron emission tomography (PET) studies, the detailed mapping of neuroreceptor binding is a trade-off between parametric accuracy and spatial precision. Logan's graphical approach is a straightforward way to quickly obtain binding potential values at the voxel level but it has been shown to have a noise-dependent negative bias. More recently suggested approaches claim to improve parametric accuracy with retained spatial resolution. In the present study, we used PET measurements on regional D 2 dopamine and 5-HT 1A serotonin receptor binding in man to compare binding potential (BP) estimates of six different parametric imaging approaches to the traditional Logan ROI-based approach which was used as a “gold standard”. The parametric imaging approaches included Logan's reference tissue graphical analysis (PILogan), its version recently modified by Varga and Szabo (PIVarga), two versions of the wavelet-based approach, Gunn's basis function method (BFM) and Gunn et al.'s recent compartmental theory-based approach employing basis pursuit strategy for kinetic modeling (called DEPICT). Applicability for practical purposes in basic and clinical research was also considered. The results indicate that the PILogan and PIVarga approaches fail to recover the correct values, the wavelet-based approaches overcome the noise susceptibility of the Logan fit with generally good recovery of BP values, and BFM and DEPICT seem to produce values with a bias dependent on receptor density. Further investigations on this bias and other phenomena revealed fundamental issues regarding the use of BFM and DEPICT on noisy voxel-wise data. In conclusion, the wavelet-based approaches seem to provide the most valid and reliable estimates across regions with a wide range of receptor densities. Furthermore, the results support the use of receptor parametric imaging in applied studies in basic or clinical research.

Modulation of a (+)amphetamine discriminative stimulus in rats by 8-hydroxy-2-( N, N-di- n-propylamino)tetralin (8-OH DPAT)

It is well established that the discriminative stimulus (DS) effect of amphetamine involves a dopaminergic and/or noradrenergic mechanism. These catecholamines can be modulated by the 5-HT 1A serotonin receptor agonist 8-hydroxy-2-( N, N-di- n-propylamino)tetralin (8-OH DPAT). The present study was conducted to determine whether 8-OH DPAT could influence the DS effects of (+)amphetamine. Administration of 8-OH DPAT doses to Sprague–Dawley rats trained to discriminate 1 mg/kg of (+)amphetamine (ED 50 = 0.33 mg/kg) using a two-lever operant paradigm (VI-15 s schedule of reinforcement for appetitive reward) failed to result in stimulus generalization when administered alone, and failed to antagonize the stimulus effect when administered in combination with the training dose of (+)amphetamine. However, administration of 8-OH DPAT doses that produced saline-like responding (i.e., 0.01–0.1 mg/kg; < 20% amphetamine-appropriate responding) in combination with the ED 50 dose of (+)amphetamine resulted in the animals' making a progressively greater number of responses on the drug-appropriate lever such that a combination of 0.1 mg/kg of 8-OH DPAT plus (+)amphetamine (0.33 mg/kg) elicited 91% (+)amphetamine-appropriate responding. In a separate study, administration of (+)amphetamine doses in combination with fixed doses of 8-OH DPAT (either 0.01 or 0.1 mg/kg) resulted in an apparent leftward shift of the dose–response curve. The results indicate that (+)amphetamine can be more effective as a discriminative stimulus in the presence of 8-OH DPAT than in its absence.

The 5-HT 1A serotonin receptor is located on calbindin- and parvalbumin-containing neurons in the rat brain

The 5-HT 1A receptor is a well-characterized serotonin receptor playing a role in many central nervous functions and known to be involved in depression and other mental disorders. In situ hybridization, immunocytochemical, and binding studies have shown that the 5-HT 1A receptor is widely distributed in the rat brain, with a particularly high density in the limbic system. The receptor’s localization in the different neuronal subtypes, which may be of importance for understanding its role in neuronal circuitries, is, however, unknown. In this study we show by immunocytochemical double-labeling techniques, that the 5-HT 1A receptor is present on both pyramidal and principal cells, and calbindin- and parvalbumin-containing neurons, which generally define two different subtypes of interneurons. Moreover, semiquantitative analysis showed that the receptor’s distribution in the different neuronal types varies between brain areas. In cortex, hippocampus, hypothalamus, and amygdala the receptor was located on both principal cells and calbindin- and parvalbumin-containing neurons. In septum and thalamus, the receptor was mostly present on calbindin- and parvalbumin-containing cells. Especially in the medial septum and thalamic reticular nucleus, the receptor highly colocalized with parvalbumin-positive neurons. These results suggest a diverse function of the 5-HT 1A receptor in modulating neuronal circuitry in different brain areas, that may depend on the type of neuron the receptor is predominantly located on.

Relationship between chromatographic behavior and affinity to 5-hT1A serotonin receptors of new buspirone analogues

It has been assumed that systematic information on the behavior of a series of analytes in a number of chromatographic systems can be exploited to evaluate their biological activity. Computerized methods of multivariate data processing, such as principal component analysis (PCA), allow the extraction of systematic information from large sets of diverse and mutually interrelated retention parameters. High-performance liquid chromatography (HPLC) is a unique method that can readily produce a great amount of retention data on large sets of drug analytes. A group of 65 new buspirone analogues were chromatographed in 9 carefully designed HPLC systems. A matrix of 65 x 9 HPLC data was subjected to statistical analysis by PCA. A grouping of analytes was obtained which was exclusively due to a systematic similarity of their behavior in the HPLC systems studied. That grouping was related to the affinity of the agents to 5-HT 1A serotonin receptors. It has been demonstrated that chemometrically processed HPLC parameters may help to segregate drugs and drug candidates according to differences in their pharmacological properties. That, in turn, may help to guide the biotesting strategy and limit the number of biological assays in the search for new drugs.

1,2,4]Triazole derivatives as 5-HT 1A serotonin receptor ligands

A series of new 4-amino-3-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl] propyl]thio]-5-(substitutedphenyl)[1,2,4]triazoles 11a– t was synthesized in order to obtain compounds with high affinity and selectivity for 5-HT 1A receptor over the α 1-adrenoceptor. A series of isomeric 4-amino-2-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl]propyl]-5-(substitutedphenyl)-2,4-dihydro-3H[1,2,4]triazole-3-thiones 12a– r was also isolated and characterized. New compounds were tested to evaluate their affinity for 5-HT 1A receptor and α 1-adrenoceptor in radioligand binding experiments. As a general trend, triazoles 11a– t showed a preferential affinity for the 5-HT 1A receptor whereas isomeric 2,4-dihydro-3H[1,2,4]triazole-3-thiones 12a– r preferentially bind to the α 1-adrenoceptor site. Several molecules showed affinities in the nanomolar range and 4-amino-3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5-(4-propyloxy-phenyl)[1,2,4]triazole ( 11o) was the most selective derivative for the 5-HT 1A receptor ( K i α 1/ K i 5-HT 1A=55). The decrease in 5-HT 1A receptor selectivity in 3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5-(substitutedphenyl)[1,2,4] triazole 14a– b, lacking in the amino group in 4-position of the triazole ring, in comparison with their analogues in the series 11a– t, suggest that the amino function represents a critical structural feature in determining 5-HT 1A receptor selectivity in this class of compounds.

New 3-[4-(aryl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propane derivatives with dual action at 5-HT 1A serotonin receptors and serotonin transporter as a new class of antidepressants

A series of new 3-[4-(aryl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propane derivatives were synthesized in an attempt to find a new class of antidepressant drugs with dual activity at 5-HT 1A serotonin receptors and serotonin transporter. Title compounds were evaluated for in vitro activity on 5-HT 1A receptor and 5-HT transporter. They show high nanomolar affinity for both activities, and in particular, compounds 1-(5-chlorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-ol ( 7) and 1-(5-fluorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-ol ( 8) show values (nM) of K i =30 and 2.3 for 5-HT 1A receptors and K i =30 and 12 for serotonin transporters, respectively. In GTPγS binding assays, compound 8 revealed antagonist properties to 5-HT 1A receptors. Such a pharmacological profile could lead to potent antidepressant agents with new dual mechanism of action.

Effect of enterosorbent noolith on behavior and serotonin (1A) receptors in mouse brain.

Protective properties of a new enterosorbent noolith (lithium ions immobilized on mineral matrix) were studied in C57Bl/6J mice predisposed to depression caused by intermale confrontations. The drug was administered daily for 15 days after the 5th confrontation and then the animals were tested in the forced swimming test. The number of specific(3)H-8-OH-DPAT binding sites in 3 brain regions was determined. It is shown that noolith produced an antidepressive effect manifested in decreased immobility time in the Porsolt test. Moreover, noolith reduced the number of 1A-serotonin receptors in the frontal cortex and hypothalamus. It is concluded that noolith possesses protective properties.

Behavioral effect of 1A-serotonin receptor agonist ipsapirone in mice previously defeated in male-male encounters.

The effect of 1A-serotonin receptor agonist ipsapirone (3 mg/kg) on mouse behavior was studied in the "wall" and Porsolt tests. The effects of the test drug were compared in intact animals and mice previously defeated in 20 intermale encounters (victims). Ipsapirone was ineffective in victims and effective in intact mice in the wall test. In the Porsolt test the drug prolonged stupor in victims.

Binding of β-carbolines and related agents at serotonin (5-HT 2 and 5-HT 1A), dopamine (D 2) and benzodiazepine receptors

A large series of β-carbolines was examined for their ability to bind at [ 3H]agonist-labeled 5-HT 2A serotonin receptors. Selected β-carbolines were also examined at 5-HT 2C serotonin receptors, 5-HT 1A serotonin receptors, dopamine D 2 receptors, and benzodiazepine receptors. Indolealkylamines and phenylisopropylamines were also evaluated in some of these binding assays. The β-carbolines were found to bind with modest affinity at 5-HT 2A receptors, and affinity was highly dependent upon the presence of ring substituents and ring saturation. The β-carbolines displayed little to no affinity for 5-HT 1A serotonin receptors, dopamine D 2 receptors and, with the exception of β-CCM, for benzodiazepine receptors. Examples of β-carbolines, indolealkylamines (i.e. N, N-dimethyltryptamine analogs), and phenylisopropylamines have been previously shown to produce common stimulus effects in animals trained to discriminate the phenylisopropylamine hallucinogen DOM (i.e. 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane) from vehicle. Although the only common receptor population that might account for this action is 5-HT 2A, on the basis of a lack of enhanced affinity for agonist-labeled 5-HT 2A receptors, as well as on their lack of agonist action in the PI hydrolysis assay, it is difficult to conclude that the β-carbolines behave in a manner consistent with that of other classical hallucinogens.

Serotonergic modulation of the P13 midlatency auditory evoked potential in the rat

The vertex-recorded, sleep state-dependent P13 midlatency auditory evoked potential in the rat may be generated, in part, by pedunculopontine nucleus (PPN) projections. Injections into the PPN of the 5-HT 1A serotonin receptor agonist, 8-hydroxy-2-di-n-propylaminotetralin hydrobromide (DPAT), were found to reduce the amplitude of the P13 potential in a dose- and time-dependent manner. The suppressive effect of DPAT was blocked or reduced by pretreatment with the 5-HT 1A serotonin receptor antagonist, Pindobind. These results show that the P13 potential can be modulated by known inhibitory serotonergic inputs to the PPN.

Single doses of MK-801, a non-competitive antagonist of NMDA receptors, increase the number of 5-HT 1A serotonin receptors in the rat brain

In the present study, we investigated the impact of MK-801, a non-competitive NMDA receptor antagonist, on the density of serotonergic receptors of the 5-HT 1A subtype and on the metabolism of serotonin in various regions of the rat brain containing terminals and cell bodies of serotonergic neurons. The binding of [ 3H]8-OH-DPAT to 5-HT 1A serotonin receptors was increased after MK-801 (0.4 mg/kg) as was shown by autoradiographic studies in the frontal, cingulate and part of enthorinal cortex, subregions of the hippocampus and raphe nuclei. The above receptor changes were observed at 2 h and, in some brain regions, at 24 h after MK-801. In saturation binding studies, an increase in the B max value in the rat hippocampus was found after MK-801 (0.4 mg/kg) while no changes being noted in the K d value. MK-801 (0.4 mg/kg) increased the concentration of the serotonin metabolite 5-HIAA in the prefrontal cortex and hippocampus, respectively, at 2 and 3 or 3 h after administration, being without effect on the level of serotonin. In the dorsal raphe nucleus, MK-801 (0.4 mg/kg) decreased the level of serotonin without affecting the level 5-HIAA (0.5 h after administration) or increased the level of 5-HIAA without altering the concentration of serotonin (3 h after administration). It is concluded that single administration of MK-801 may alter the density of serotonergic 5-HT 1A receptors and in consequence influence the function of the central nervous system associated with activation of 5-HT 1A receptors.

3H]5-Methyl-urapidil labels 5-HT 1A receptors and α 1-adrenoceptors in the rat CNS. In vitro binding and autoradiographic studies

The tritiated derivative of the potent antihypertensive agent, 5-methyl-urapidil, was used as a radioligand in binding studies with rat brain membranes and tissue sections. Serotonin and prazosin inhibited [ 3H]5-methyl-urapidil binding to membranes from the rat hippocampus, cerebral cortex and brainstem biphasically, leading to the definition of serotomn high-affinity and prazosin high-affinity [ 3H]5-niethyl-urapidil binding sites. Comparison of these serotonin-sensitive [ 3H]5-methyl-urapidil binding sites with the 5-HT 1A sites labelled by [ 3H]8-hydroxy-2-(di-n-propylamino)tetralin [ 3H]8-oh-dpat) revealed striking similarities regarding pharmacological properties, respective densities and regional distribution. On the other hand, the prazosin-sensitive [ 3H]5-methylurapidil binding sites should correspond to the oiiA-subtype of adrenoceptors which has recently been defined. Detailed autoradiographic investigations allowed the detection of 5-HT.A sites labelled by both [ 3H]5-methyl-urapidil and [ 3H]8-OH-DPAT in the posterior raphe nuclei (pallidus and obscurus) which are possibly involved in the hypotensive action of 5-methyl-urapidil. These data demonstrate that [ 3H]5-methyl-urapidil is a useful radioligand for the visualization and quantification of both 5-HT 1A serotonin receptors and α-adrenoceptors in the central nervous system.

A Sac I RFLP is detected with the 5-HT 1a serotonin receptor probe G21

A Sac I RFLP is detected with the 5-HT 1a serotonin receptor probe G21

Regional changes in brain 5-HT 1A serotonin receptors in the rat model of persistent spasmodic dyskinesias induced by iminodipropionitrile

Chronic injection of iminodipropionitrile (IDPN) to rats causes persistent motor abnormalities such as hyperactivity, lateral and vertical dyskinesia of the neck, and random circling. These behavioral changes are very similar to those observed after the acute administration of serotonin (5-HT) agonists in rodents. Moreover, some aspects of this syndrome are reproduced by stimulation of 5-HT 1A receptors. The present quantitative autoradiographic study revealed a number of changes in 8-hydroxy-2-[di- n-propylamino- 3H]tetralin(8-OH[ 3H]DPAT)-labeled 5-HT 1A receptors in the brains of IDPN-treated rats. There were significant increases of 8-OH[ 3H]DPAT binding in the frontal cortex and in the caudate-putamen. In contrast, there were significant decreases in the interpeduncular nucleus, the pyramidal layer of the CA3 field of hippocampus, the superior colliculus and the pars reticulata of the substantia nigra. These provide further evidence for the involvement of the 5-HT system in the development of the IDPN-induced dyskinetic syndrome.