Hive General Discourse

	Main Index Search Register Login Who's Online FAQ Links
	Main Index Search Register Login Who's Online FAQ Links

	2 Online, 0 Active		You are not logged in

This is a historical archiveThe forum is read-only. Private information has been removed. It is not possible to login.

	General Discourse

All 2 posts Subject: Recent Psychedelic Pharmacology Research Please login to post Down

Rhodium
(Chief Bee)
12-03-03 23:57
No 474567
User Picture       Recent Psychedelic Pharmacology Research
(Rated as: excellent)

Behavioral evidence for mu-opioid and 5-HT2A receptor interactions
Gerard J. Marek
European Journal of Pharmacology 474(1), 77-83 (2003) (https://www.rhodium.ws/pdf/mu-opioid.5ht2a.receptor.interaction.pdf)
DOI:10.1016/S0014-2999(03)01971-X

Abstract
Electrophysiological studies have demonstrated a physiological interaction between 5-HT2A and -opioid receptors in the medial prefrontal cortex. Furthermore, behavioral studies have found that phenethylamine hallucinogens induce head shakes when directly administered into the medial prefrontal cortex. The receptor(s) by which morphine suppresses head shakes induced by serotonin agonists have not been characterized. We administered mu-opioid receptor agonists and antagonists to adult male Sprague–Dawley rats prior to treatment with the phenethylamine hallucinogen 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), which is known to induce head shakes via 5-HT2A receptors. The suppressant action of the moderately selective mu-opioid receptor agonist, buprenorphine (ID50~0.005 mg/kg, i.p.; a mu-opioid receptor partial agonist and mu-opioid receptor antagonist) was blocked by naloxone and pretreatment with the irreversible mu-opioid receptor antagonist clocinnamox. Another mu-opioid receptor agonist fentanyl also suppressed DOI-induced head shakes. In contrast, a mu-opioid receptor agonist was without effect on DOI-induced head shakes. Thus, activation of mu-opioid receptors can suppress head shakes induced by hallucinogenic drugs.
____ ___ __ _

Nefazodone in the rat: mimicry and antagonism of (-)-DOM-induced stimulus control
J. R. Eckler, , R. A. Rabin and J. C. Winter
Pharmacology Biochemistry and Behavior 75(2), 405-410 (2003) (https://www.rhodium.ws/pdf/nefazodone.dom.pdf)
DOI:10.1016/S0091-3057(03)00132-1

Abstract
Nefazodone is presently marketed as an antidepressant that inhibits both serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake while antagonizing pirenpirone (5-HT2) receptors. This 5-HT receptor type is believed to play a prominent role in the underlying mechanism of action of serotonergic hallucinogens. Antidepressant medications now represent the most commonly prescribed psychoactive medications in the world and are likely to be ingested in the presence of hallucinogens with increased frequency; the consequences are largely unknown. The present investigation examined the interaction between the serotonergic phenethylamine hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine [(-)-DOM], and nefazodone, in rats trained with (-)-DOM [0.6 mg/kg; 75 min pretreatment time] as a discriminative stimulus. The data indicate that maximal substitution of nefazodone for the (-)-DOM stimulus was present using a 45-min pretreatment time before testing. Using this pretreatment time, a dose of nefazodone of 12.0 mg/kg administered alone resulted in 76% DOM-appropriate responding. When a range of doses of nefazodone was combined with the training dose of (-)-DOM, a pattern of responding compatible with partial agonism was observed. The intermediate degree of (-)-DOM generalization to nefazodone was significantly antagonized by the 5-HT antagonists, 5-HT2, SR 46349B (5HT2A/2C), and M100907 (5-HT2A). Taken together, the present data suggest that (a) nefazodone acts as a partial agonist and (b) these effects are mediated by the 5-HT2A receptor.
____ ___ __ _

Characterization of a novel effect of serotonin 5-HT1A and 5-HT2A receptors: increasing cGMP levels in rat frontal cortex
Meredith J. Regina, Jerrold C. Winter and Richard A. Rabin
Neuropharmacology 45(8), 1041-1049 (2003) (https://www.rhodium.ws/pdf/5ht1a.5ht2a.cgmp.frontal.cortex.pdf)
DOI:10.1016/S0028-3908(03)00287-9

Abstract
Elucidating the mechanisms of action of hallucinogens has become an increasingly important area of research as their abuse has grown in recent years. Although serotonin receptors appear to play a role in the behavioral effects of the phenethylamine and indoleamine hallucinogens, the signaling pathways activated by these agents are unclear. Here it is shown that administration of serotonin (5-hydroxytryptamine, 5-HT) increased cyclic guanosine monophosphate (cGMP) production in frontal cortical slices of rat brain. The effect of 5-HT was greater than that of N-methyl-D-aspartate (NMDA), a stimulant of cGMP formation in the central nervous system. The 5-HT2A/2C receptor phenethylamine agonist, 2,5-dimethoxy-4-methylamphetamine (DOM), increased cGMP content in the slices. Additionally 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT), a 5-HT1A/7 receptor agonist also increased cGMP production. Stimulation of cGMP formation by DOM was prevented by a 5-HT2A/2C receptor antagonist, pirenperone, as well as by a 5-HT2A receptor selective antagonist, MDL100907. A 5-HT2C receptor antagonist, SB242084, did not block the effect of DOM. Stimulation of cGMP production by DPAT was blocked by the 5-HT1A receptor antagonist, WAY100635. Stimulation of cGMP formation by serotonin could be prevented by pirenperone orWAY100635. In summary, activation of serotonin 5-HT1A and 5-HT2A receptors increase brain cGMP levels.
____ ___ __ _

Behavioral characterization of 2-O-desmethyl and 5-O-desmethyl metabolites of the phenylethylamine hallucinogen DOM
J. R. Eckler, J. Chang-Fong, R. A. Rabin, C. Smith, M. Teitler, R. A. Glennon and J. C. Winter
Pharmacology Biochemistry and Behavior 75(4), 845-852 (2003) (https://www.rhodium.ws/pdf/o-desmethyl-dom.behavioral.characterization.pdf)
DOI:10.1016/S0091-3057(03)00159-X

Abstract
The present investigation was undertaken to test the hypothesis that known metabolites of the phenylethylamine hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) are pharmacologically active. This hypothesis was tested by evaluating the ability of racemic DOM metabolites 2-O-desmethyl DOM (2-DM-DOM) and 5-O-desmethyl DOM (5-DM-DOM) to substitute for the stimulus properties of (+)lysergic acid diethylamide (LSD). The data indicate that both metabolites are active in LSD-trained subjects and are significantly inhibited by the selective 5-HT2A receptor antagonist M100907. Full generalization of LSD to both 2-DM-DOM and 5-DM-DOM occurred, and 5-DM-DOM was slightly more potent than 2-DM-DOM. Similarly, 5-DM-DOM had a slightly higher affinity than 2-DM-DOM for both 5-HT2A and 5-HT2C receptors. Additionally, it was of interest to determine if the formation of active metabolite(s) resulted in a temporal delay associated with maximal stimulus effects of DOM. We postulated that if metabolite formation resulted in the aforementioned delay, direct administration of the metabolites might result in maximally stable stimulus effects at an earlier pretreatment time. This hypothesis was tested by evaluating (1) the time point at which DOM produces the greatest degree of LSD-appropriate responding, (2) the involvement of 5-HT2A receptor in the stimulus effects of DOM at various pretreatment times by administration of M100907 and (3) the ability of 2-DM-DOM and 5-DM-DOM to substitute for the stimulus properties of LSD using either 15- or 75-min pretreatment time. The data indicate that (a) the DOM stimulus produces the greatest degree of LSD-appropriate responding at the 75-min time point in comparison with earlier pretreatment times and (b) the stimulus effects of DOM are differentially antagonized by M100907 and this effect is a function of DOM pretreatment time prior to testing. Both 2-DM-DOM and 5-DM-DOM were found to be most active, at all doses tested, using a 75-min versus a 15-min pretreatment time. The present data do not permit unequivocal acceptance or rejection of the hypothesis that active metabolites of (-)-DOM provide a full explanation of the observed discrepancy between brain levels of (-)-DOM and maximal stimulus effects.
____ ___ __ _

Electron-conformational study for the structure–hallucinogenic activity relationships of phenylalkylamines
Ahmet Altun, Kurtulus Golcuk, Mustafa Kumru and Abraham F. Jalbout
Bioorganic & Medicinal Chemistry 11(18), 3861-3868 (2003) (https://www.rhodium.ws/pdf/sar.pea.electron-conformational.pdf)
DOI:10.1016/S0968-0896(03)00437-1

Abstract
The structure–hallucinogenic activity relationships of a series of phenylethylamine and phenylisopropylamine derivatives have been investigated in the frameworks of electron-conformational method. The calculated geometry and electronic structure parameters accompanying to each atom and bond of each molecule in view were arranged as a matrix called electron-conformational matrix of contiguity (ECMC). The features that are responsible for strong and weak activity demonstrations have been found as submatrices of ECMCs belonging to some template compounds. Two electron-conformational features present in nonhallucinogenic compounds have been revealed. A quantitative model has been improved for predicting hallucinogenic activity numerically. A test series was used to verify the results obtained.

Lego
(Hive Bee)
10-13-04 20:55
No 535708
User Picture       Pharmacol. characterisation of 5-HT2 binding site
(Rated as: good read)

Pharmacological characterisation of the agonist radioligand binding site of 5-HT_2A, 5-HT_2B and 5-HT_2C receptors
Antony R. Knight , Anil Misra, Kathleen Quirk, Karen Benwell, Dean Revell, Guy Kennett1 and Mike Bickerdike
Naunyn-Schmiedeberg's Archives of Pharmacology, 2004, 370(2), 114-123
DOI:10.1007/s00210-004-0951-4

Abstract: In the present study we compared the affinity of various drugs for the high affinity agonist-preferring binding site of human recombinant 5-HT_2A, 5-HT_2B and 5-HT_2C receptors stably expressed in monoclonal mammalian cell lines. To ensure that the agonist-preferring conformation of the receptor was preferentially labelled in competition binding experiments, saturation analysis was conducted using antagonist and agonist radiolabels at each receptor. Antagonist radiolabels ([³H]-ketanserin for 5-HT_2A receptor and [³H]-mesulergine for 5-HT_2B and 5-HT_2C receptor) bound to a larger population of receptors in each preparation than the corresponding agonist radiolabel ([¹²⁵I]-DOI for 5-HT_2A receptor binding and [3^H]-5-HT for 5-HT_2B and 5-HT_2C receptor binding). Competition experiments were subsequently conducted against appropriate concentrations of the agonist radiolabels bound to the agonist-preferring subset of receptors in each preparation. These studies confirmed that there are a number of highly selective antagonists available to investigate 5-HT₂ receptor subtype function (for example, MDL 100907, RS-127445 and RS-102221 for 5-HT_2A, 5-HT_2B and 5-HT_2C receptors respectively). There remains, however, a lack of highly selective agonists. (–)DOI is potent and moderately selective for 5-HT_2A receptors, BW723C86 has poor selectivity for human 5-HT_2B receptors, while Org 37684 and VER-3323 display some selectivity for the 5-HT_2C receptor. We report for the first time in a single study, the selectivity of numerous serotonergic drugs for 5-HT₂ receptors from the same species, in mammalian cell lines and using, exclusively, agonist radiolabels. The results indicate the importance of defining the selectivity of pharmacological tools, which may have been over-estimated in the past, and highlights the need to find more selective agonists to investigate 5-HT₂ receptor pharmacology.

The tendency is to push it as far as you can

	https://the-hive.archive.erowid.org	the-hive@erowid.org



Powdered by Syndicalism Release 0.13.0 Premium, (C) 2015 - 2019, SomaSoft Incorporated
Links Erowid Rhodium

	All 2 posts		Subject: Recent Psychedelic Pharmacology Research		Please login to post		Down


		Rhodium (Chief Bee) 12-03-03 23:57 No 474567				Recent Psychedelic Pharmacology Research (Rated as: excellent)
						Behavioral evidence for mu-opioid and 5-HT2A receptor interactions Gerard J. Marek European Journal of Pharmacology 474(1), 77-83 (2003) (https://www.rhodium.ws/pdf/mu-opioid.5ht2a.receptor.interaction.pdf) DOI:10.1016/S0014-2999(03)01971-X Abstract Electrophysiological studies have demonstrated a physiological interaction between 5-HT2A and -opioid receptors in the medial prefrontal cortex. Furthermore, behavioral studies have found that phenethylamine hallucinogens induce head shakes when directly administered into the medial prefrontal cortex. The receptor(s) by which morphine suppresses head shakes induced by serotonin agonists have not been characterized. We administered mu-opioid receptor agonists and antagonists to adult male Sprague–Dawley rats prior to treatment with the phenethylamine hallucinogen 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), which is known to induce head shakes via 5-HT2A receptors. The suppressant action of the moderately selective mu-opioid receptor agonist, buprenorphine (ID50~0.005 mg/kg, i.p.; a mu-opioid receptor partial agonist and mu-opioid receptor antagonist) was blocked by naloxone and pretreatment with the irreversible mu-opioid receptor antagonist clocinnamox. Another mu-opioid receptor agonist fentanyl also suppressed DOI-induced head shakes. In contrast, a mu-opioid receptor agonist was without effect on DOI-induced head shakes. Thus, activation of mu-opioid receptors can suppress head shakes induced by hallucinogenic drugs. ____ ___ __ _ Nefazodone in the rat: mimicry and antagonism of (-)-DOM-induced stimulus control J. R. Eckler, , R. A. Rabin and J. C. Winter Pharmacology Biochemistry and Behavior 75(2), 405-410 (2003) (https://www.rhodium.ws/pdf/nefazodone.dom.pdf) DOI:10.1016/S0091-3057(03)00132-1 Abstract Nefazodone is presently marketed as an antidepressant that inhibits both serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake while antagonizing pirenpirone (5-HT2) receptors. This 5-HT receptor type is believed to play a prominent role in the underlying mechanism of action of serotonergic hallucinogens. Antidepressant medications now represent the most commonly prescribed psychoactive medications in the world and are likely to be ingested in the presence of hallucinogens with increased frequency; the consequences are largely unknown. The present investigation examined the interaction between the serotonergic phenethylamine hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine [(-)-DOM], and nefazodone, in rats trained with (-)-DOM [0.6 mg/kg; 75 min pretreatment time] as a discriminative stimulus. The data indicate that maximal substitution of nefazodone for the (-)-DOM stimulus was present using a 45-min pretreatment time before testing. Using this pretreatment time, a dose of nefazodone of 12.0 mg/kg administered alone resulted in 76% DOM-appropriate responding. When a range of doses of nefazodone was combined with the training dose of (-)-DOM, a pattern of responding compatible with partial agonism was observed. The intermediate degree of (-)-DOM generalization to nefazodone was significantly antagonized by the 5-HT antagonists, 5-HT2, SR 46349B (5HT2A/2C), and M100907 (5-HT2A). Taken together, the present data suggest that (a) nefazodone acts as a partial agonist and (b) these effects are mediated by the 5-HT2A receptor. ____ ___ __ _ Characterization of a novel effect of serotonin 5-HT1A and 5-HT2A receptors: increasing cGMP levels in rat frontal cortex Meredith J. Regina, Jerrold C. Winter and Richard A. Rabin Neuropharmacology 45(8), 1041-1049 (2003) (https://www.rhodium.ws/pdf/5ht1a.5ht2a.cgmp.frontal.cortex.pdf) DOI:10.1016/S0028-3908(03)00287-9 Abstract Elucidating the mechanisms of action of hallucinogens has become an increasingly important area of research as their abuse has grown in recent years. Although serotonin receptors appear to play a role in the behavioral effects of the phenethylamine and indoleamine hallucinogens, the signaling pathways activated by these agents are unclear. Here it is shown that administration of serotonin (5-hydroxytryptamine, 5-HT) increased cyclic guanosine monophosphate (cGMP) production in frontal cortical slices of rat brain. The effect of 5-HT was greater than that of N-methyl-D-aspartate (NMDA), a stimulant of cGMP formation in the central nervous system. The 5-HT2A/2C receptor phenethylamine agonist, 2,5-dimethoxy-4-methylamphetamine (DOM), increased cGMP content in the slices. Additionally 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT), a 5-HT1A/7 receptor agonist also increased cGMP production. Stimulation of cGMP formation by DOM was prevented by a 5-HT2A/2C receptor antagonist, pirenperone, as well as by a 5-HT2A receptor selective antagonist, MDL100907. A 5-HT2C receptor antagonist, SB242084, did not block the effect of DOM. Stimulation of cGMP production by DPAT was blocked by the 5-HT1A receptor antagonist, WAY100635. Stimulation of cGMP formation by serotonin could be prevented by pirenperone orWAY100635. In summary, activation of serotonin 5-HT1A and 5-HT2A receptors increase brain cGMP levels. ____ ___ __ _ Behavioral characterization of 2-O-desmethyl and 5-O-desmethyl metabolites of the phenylethylamine hallucinogen DOM J. R. Eckler, J. Chang-Fong, R. A. Rabin, C. Smith, M. Teitler, R. A. Glennon and J. C. Winter Pharmacology Biochemistry and Behavior 75(4), 845-852 (2003) (https://www.rhodium.ws/pdf/o-desmethyl-dom.behavioral.characterization.pdf) DOI:10.1016/S0091-3057(03)00159-X Abstract The present investigation was undertaken to test the hypothesis that known metabolites of the phenylethylamine hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) are pharmacologically active. This hypothesis was tested by evaluating the ability of racemic DOM metabolites 2-O-desmethyl DOM (2-DM-DOM) and 5-O-desmethyl DOM (5-DM-DOM) to substitute for the stimulus properties of (+)lysergic acid diethylamide (LSD). The data indicate that both metabolites are active in LSD-trained subjects and are significantly inhibited by the selective 5-HT2A receptor antagonist M100907. Full generalization of LSD to both 2-DM-DOM and 5-DM-DOM occurred, and 5-DM-DOM was slightly more potent than 2-DM-DOM. Similarly, 5-DM-DOM had a slightly higher affinity than 2-DM-DOM for both 5-HT2A and 5-HT2C receptors. Additionally, it was of interest to determine if the formation of active metabolite(s) resulted in a temporal delay associated with maximal stimulus effects of DOM. We postulated that if metabolite formation resulted in the aforementioned delay, direct administration of the metabolites might result in maximally stable stimulus effects at an earlier pretreatment time. This hypothesis was tested by evaluating (1) the time point at which DOM produces the greatest degree of LSD-appropriate responding, (2) the involvement of 5-HT2A receptor in the stimulus effects of DOM at various pretreatment times by administration of M100907 and (3) the ability of 2-DM-DOM and 5-DM-DOM to substitute for the stimulus properties of LSD using either 15- or 75-min pretreatment time. The data indicate that (a) the DOM stimulus produces the greatest degree of LSD-appropriate responding at the 75-min time point in comparison with earlier pretreatment times and (b) the stimulus effects of DOM are differentially antagonized by M100907 and this effect is a function of DOM pretreatment time prior to testing. Both 2-DM-DOM and 5-DM-DOM were found to be most active, at all doses tested, using a 75-min versus a 15-min pretreatment time. The present data do not permit unequivocal acceptance or rejection of the hypothesis that active metabolites of (-)-DOM provide a full explanation of the observed discrepancy between brain levels of (-)-DOM and maximal stimulus effects. ____ ___ __ _ Electron-conformational study for the structure–hallucinogenic activity relationships of phenylalkylamines Ahmet Altun, Kurtulus Golcuk, Mustafa Kumru and Abraham F. Jalbout Bioorganic & Medicinal Chemistry 11(18), 3861-3868 (2003) (https://www.rhodium.ws/pdf/sar.pea.electron-conformational.pdf) DOI:10.1016/S0968-0896(03)00437-1 Abstract The structure–hallucinogenic activity relationships of a series of phenylethylamine and phenylisopropylamine derivatives have been investigated in the frameworks of electron-conformational method. The calculated geometry and electronic structure parameters accompanying to each atom and bond of each molecule in view were arranged as a matrix called electron-conformational matrix of contiguity (ECMC). The features that are responsible for strong and weak activity demonstrations have been found as submatrices of ECMCs belonging to some template compounds. Two electron-conformational features present in nonhallucinogenic compounds have been revealed. A quantitative model has been improved for predicting hallucinogenic activity numerically. A test series was used to verify the results obtained.



		Lego (Hive Bee) 10-13-04 20:55 No 535708				Pharmacol. characterisation of 5-HT2 binding site (Rated as: good read)
						Pharmacological characterisation of the agonist radioligand binding site of 5-HT_2A, 5-HT_2B and 5-HT_2C receptors Antony R. Knight , Anil Misra, Kathleen Quirk, Karen Benwell, Dean Revell, Guy Kennett1 and Mike Bickerdike Naunyn-Schmiedeberg's Archives of Pharmacology, 2004, 370(2), 114-123 DOI:10.1007/s00210-004-0951-4 Abstract: In the present study we compared the affinity of various drugs for the high affinity agonist-preferring binding site of human recombinant 5-HT_2A, 5-HT_2B and 5-HT_2C receptors stably expressed in monoclonal mammalian cell lines. To ensure that the agonist-preferring conformation of the receptor was preferentially labelled in competition binding experiments, saturation analysis was conducted using antagonist and agonist radiolabels at each receptor. Antagonist radiolabels ([³H]-ketanserin for 5-HT_2A receptor and [³H]-mesulergine for 5-HT_2B and 5-HT_2C receptor) bound to a larger population of receptors in each preparation than the corresponding agonist radiolabel ([¹²⁵I]-DOI for 5-HT_2A receptor binding and [3^H]-5-HT for 5-HT_2B and 5-HT_2C receptor binding). Competition experiments were subsequently conducted against appropriate concentrations of the agonist radiolabels bound to the agonist-preferring subset of receptors in each preparation. These studies confirmed that there are a number of highly selective antagonists available to investigate 5-HT₂ receptor subtype function (for example, MDL 100907, RS-127445 and RS-102221 for 5-HT_2A, 5-HT_2B and 5-HT_2C receptors respectively). There remains, however, a lack of highly selective agonists. (–)DOI is potent and moderately selective for 5-HT_2A receptors, BW723C86 has poor selectivity for human 5-HT_2B receptors, while Org 37684 and VER-3323 display some selectivity for the 5-HT_2C receptor. We report for the first time in a single study, the selectivity of numerous serotonergic drugs for 5-HT₂ receptors from the same species, in mammalian cell lines and using, exclusively, agonist radiolabels. The results indicate the importance of defining the selectivity of pharmacological tools, which may have been over-estimated in the past, and highlights the need to find more selective agonists to investigate 5-HT₂ receptor pharmacology. The tendency is to push it as far as you can

All 2 posts	End of thread	Top