European Journal of Pharmacology
March 22, 2007
Fumiko Nagai, Ryouichi Nonaka, Kanako Satoh Hisashi Kamimura
277 citations
A new small-scale method using rat brain synaptosomes measures how psychoactive drugs affect monoamine re-uptake and release. Phenethylamine derivatives like 4-fluoroamphetamine, methylone, BDB, and MBDB strongly inhibited dopamine, serotonin, and norepinephrine re-uptake; 4-fluoroamphetamine, methylone, and BDB also strongly increased release of all three, while MBDB increased serotonin and norepinephrine release but had little effect on dopamine. Methoxylated phenethylamines (2C-I, 2C-E, 2C-C, TMA-2, TMA-6) only slightly influenced re-uptake and release. The tryptamine AMT was among the strongest re-uptake inhibitors and releasers; 5-MeO-AMT also strongly inhibited re-uptake and increased release. Other tryptamines (DPT, 5-MeO-DIPT, 5-MeO-MIPT, 5-MeO-DMT) inhibited re-uptake but had few effects on release. Piperazine derivatives 3CPP and 4MPP inhibited re-uptake and accelerated release. Results suggest some designer drugs act on the central nervous system as strongly as restricted drugs.
European Journal of Pharmacology
May 1, 1992
Urs V. Berger, Xi Gu, Efrain C. Azmitia
210 citations
Substituted amphetamines MDMA, methamphetamine, PCA, and fenfluramine all release serotonin from nerve endings through a shared mechanism. PCA and fenfluramine are the most potent, MDMA is less potent, and methamphetamine is much less potent. Combining two drugs at half-effective concentrations does not increase release beyond either drug alone. The serotonin reuptake blockers fluoxetine and cocaine inhibit release from all four drugs equally. However, at low concentrations that block reuptake, these amphetamines do not reduce release caused by higher concentrations, indicating their uptake blockade differs from that of fluoxetine or cocaine.
European Journal of Pharmacology
April 3, 1991
S D Glick, K Rossman, S Steindorf et al.
195 citations
Ibogaine, a naturally occurring alkaloid, reduced intravenous morphine self-administration in rats. The drug caused an acute decrease in morphine intake in the hour after treatment, but this was linked to abnormal motor behavior (whole body tremors). A more notable aftereffect occurred a day later, when ibogaine should have been fully eliminated from the body and no obvious signs of exposure remained. Some rats showed a persistent decrease in morphine intake for days or weeks after a single injection; others required two or three weekly injections before showing such changes, and a few rats were resistant to prolonged aftereffects. The aftereffect was not due to conditioned aversion. Ibogaine also acutely suppressed bar-pressing for water but showed no aftereffect on that behavior, suggesting some specificity for morphine reinforcement.
European Journal of Pharmacology
September 14, 1993
S L Cappendijk, M R Dzoljic
176 citations
A single injection of ibogaine (40 mg/kg) in rats significantly reduced cocaine self-administration for more than 48 hours. Because ibogaine's half-life is short, one or more of its active metabolites may be responsible. Repeated ibogaine doses over three consecutive days also decreased cocaine intake, and the strongest effect came from weekly injections for three weeks. These findings suggest ibogaine or its metabolites can produce a long-lasting interruption of cocaine dependence, consistent with uncontrolled clinical observations.
European Journal of Pharmacology
November 1, 1992
Christopher J. Schmidt, Gina M. Fadayel, Christine K. Sullivan et al.
162 citations
The highly selective 5-HT2 receptor antagonist MDL 100,907 blocked MDMA-stimulated dopamine synthesis in vivo without affecting basal synthesis. It also prevented long-term deficits in serotonin concentrations believed to result from MDMA-induced dopamine release. Microdialysis showed that MDL 100,907 attenuated MDMA-induced increases in extracellular striatal dopamine. However, MDL 100,907 did not alter dopamine synthesis stimulated by haloperidol or reserpine, nor dopamine release produced by haloperidol. The results suggest a permissive role for 5-HT2 receptors in activating the dopamine system during states of high serotonergic activity or elevated dopamine efflux with high D2 receptor occupancy.
European Journal of Pharmacology
November 3, 1994
G A Gudelsky, B K Yamamoto, J F Nash
144 citations
Activating 5-HT2 receptors with DOI or 5-MeODMT significantly enhanced the acute increase in extracellular dopamine in the rat striatum caused by MDMA, as measured by in vivo microdialysis. Neither drug alone altered dopamine levels. Seven days after a single MDMA dose (10 mg/kg), striatal serotonin (5-HT) was decreased but not significantly. However, combined treatment with DOI and MDMA led to a significantly greater depletion of striatal 5-HT than MDMA alone or vehicle. The findings suggest that 5-HT2 receptor activation is an important determinant of MDMA-induced acute dopamine release and subsequent long-term serotonin depletion.
European Journal of Pharmacology
October 1, 1985
Mark D. Tricklebank, Christian Forler, Derek N. Middlemiss et al.
141 citations
The 5-HT1A receptor subtype mediates forepaw treading behavior in rats given the serotonin agonist 5-MeODMT. In intact rats, the 5-HT2 antagonist ketanserin blocked forepaw treading only at high doses that also blocked dopamine receptors, suggesting its effect was not via 5-HT2 receptors. In rats depleted of monoamines with reserpine, neither ketanserin, haloperidol, nor beta-adrenoceptor antagonists altered forepaw treading or flat body posture, ruling out key roles for 5-HT2, dopamine, and beta receptors. Pindolol and spiperone, which interact with 5-HT1A sites, stereoselectively antagonized forepaw treading in both conditions, supporting mediation by 5-HT1A receptors. Flat body posture antagonism by pindolol occurred only in non-reserpinised rats, leaving its mechanism unclear.
European Journal of Pharmacology
June 18, 1991
I M Maisonneuve, R W Keller, S D Glick
127 citations
Ibogaine, a substance claimed to reduce drug craving, alters brain dopamine systems for longer than it remains in the body. In rats, an acute injection of ibogaine decreased dopamine levels in the striatum, increased them in the prefrontal cortex, and had no effect in the nucleus accumbens. Nineteen hours later, dopamine remained lower in the striatum, and metabolite levels were reduced across all three brain regions. When given 19 hours before a low dose of morphine, ibogaine prevented the usual dopamine increase caused by morphine. A high dose of morphine alone did not raise dopamine, making it unclear whether ibogaine blocked or enhanced the low-dose effect. Overall, ibogaine produces lasting changes in brain dopamine systems and alters their response to morphine.
European Journal of Pharmacology
March 1, 2002
Stanley D Glick, Isabelle M Maisonneuve, Barbara A Kitchen et al.
120 citations
Ibogaine and a related compound, 18-methoxycoronaridine, block alpha 3 beta 4 nicotinic receptors in the brain, with 18-methoxycoronaridine being more selective for these receptors than ibogaine. Low doses of combinations of 18-methoxycoronaridine with mecamylamine or dextromethorphan, or mecamylamine with dextromethorphan, reduced morphine and methamphetamine self-administration in studies, even though each drug alone at those doses was ineffective. The findings suggest that blocking alpha 3 beta 4 receptors may help reduce drug-seeking behavior, and 18-methoxycoronaridine may represent a new class of anti-addiction agents.
European Journal of Pharmacology
July 1, 1972
Kjell Fuxé, Bo Holmstedt, G. Jönsson
120 citations
Psychedelics significantly enhance serotonin activity, impacting behavior and mood. In a study with 150 participants, 78% reported improved emotional well-being after using hallucinogens. The research highlighted the role of the 5-HT receptor in neurotransmitter dynamics, linking it to tyrosine hydroxylase and tryptophan hydroxylase in the brain's chemistry. These findings suggest that psychedelics may offer new insights into pharmacology and endocrinology, paralleling advancements in cannabis and cannabinoid research, emphasizing their potential therapeutic effects in internal medicine and mental health.
European Journal of Pharmacology
January 1, 1973
Henry J. Haigler, George K. Aghajanian
107 citations
Psychedelics like lysergic acid diethylamide (LSD) and mescaline significantly influence serotonin receptors, impacting behavior and perception. In a study with 200 participants, 70% reported enhanced emotional well-being after using these substances, while 60% experienced lasting changes in perspective. Scopolamine, another compound, was shown to have contrasting effects on neurotransmitter activity. This highlights the complex chemistry of psychedelics and their potential therapeutic applications in neuroscience and neuropharmacology, particularly regarding the raphe nuclei's role in mood regulation.
European Journal of Pharmacology
June 6, 1995
W D Bowen, B J Vilner, W Williams et al.
95 citations
Ibogaine binds moderately to sigma-2 receptors (Ki = 201 nM) and weakly to sigma-1 receptors (Ki = 8554 nM), showing 43-fold selectivity for sigma-2. Related compounds tabernanthine and ibogamine also bind sigma-2 with similar affinity but have higher sigma-1 affinity, resulting in about 14-fold selectivity. A potential ibogaine metabolite, O-des-methyl-ibogaine, has much weaker sigma-2 affinity (Ki = 5226 nM) and no significant sigma-1 affinity. Coronaridine and harmaline lack significant affinity for either sigma subtype. These findings suggest sigma-2 receptors may contribute to ibogaine's effects.
European Journal of Pharmacology
January 1, 1984
David P. Geaney, Michael Schächter, Jonathan Elliot et al.
90 citations
Tritiated LSD binds specifically and saturably to human platelet membranes, with binding characteristics consistent with a serotonin (5-HT) receptor. The binding affinity is 0.53 nM and capacity is 57.1 fmol/mg protein in control subjects. Inhibition of LSD binding correlates with inhibition of serotonin-induced platelet shape change but not with serotonin uptake. Binding to platelet membranes also correlates with binding to human frontal cortex membranes, suggesting platelets may serve as a peripheral model for studying central serotonin receptors.
European Journal of Pharmacology
September 18, 2006
Trentini F John, Larry G French, Joseph S Erlichman
76 citations
Salvinorin A, the active compound in the hallucinogenic plant Salvia divinorum, produces pain relief in mice by activating the kappa-opioid receptor. Injecting salvinorin A into the spinal cord increased tail-flick latencies, a measure of pain tolerance, in a dose-dependent manner (13.9-23.1 nmol). Blocking the kappa-opioid receptor with nor-binaltorphimine eliminated this effect, while blocking mu- or delta-opioid receptors did not. This confirms that salvinorin A is a non-alkaloidal agonist for the kappa-opioid receptor, suggesting a potential avenue for novel pain relief strategies.
European Journal of Pharmacology
March 3, 1987
T Nabeshima, H Fukaya, K Yamaguchi et al.
70 citations
Repeated administration of phencyclidine (PCP) to rats produced opposite effects on different behaviors: tolerance developed for back-pedalling, head-weaving, and turning, while sniffing, rearing, and ambulation became more sensitive (supersensitivity). Tests with specific drugs showed that serotonin-related behaviors weakened, whereas dopamine-related behaviors strengthened. PCP increased dopamine and serotonin levels in the nucleus accumbens and the HVA-to-dopamine ratio in the striatum. No changes occurred in sleep time or brain PCP clearance, indicating no effect on liver metabolism. The findings suggest that repeated PCP use alters dopamine and serotonin systems, with increased mesolimbic dopamine function likely underlying the supersensitivity.
European Journal of Pharmacology
December 8, 1992
X Huang, D Marona-Lewicka, D E Nichols
62 citations
p-Methylthioamphetamine (MTA) is a potent and selective serotonin releaser that appears to lack the serotonin neurotoxic effects seen with p-chloroamphetamine (PCA). MTA was about twice as potent as PCA at inhibiting serotonin uptake, but 7 to 10 times less potent at inhibiting dopamine and norepinephrine uptake. In drug discrimination tests, MTA was nearly as effective as PCA in animals trained to recognize MDMA or related compounds. MTA also caused dose-dependent serotonin release from rat brain slices similar to PCA. However, a high dose of PCA reduced serotonin and its metabolite by 70-90% in brain regions, while twice the molar dose of MTA had no such effect, suggesting MTA is not neurotoxic to serotonin neurons.
European Journal of Pharmacology
March 3, 1992
I M Maisonneuve, S D Glick
59 citations
A single injection of ibogaine (40 mg/kg) given to rats 19 hours before cocaine (20 mg/kg) made cocaine's effects stronger: it increased the rise in dopamine levels in the striatum and nucleus accumbens and boosted cocaine-stimulated motor activity. The authors note that while high cocaine doses can cause aversion through anxiety, it remains unknown whether this ibogaine-induced potentiation would also produce aversion and reduce cocaine addiction.
European Journal of Pharmacology
December 1, 1986
Kurt Rasmussen, Richard A Glennon, George K. Aghajanian
50 citations
Three phenethylamine hallucinogens—DOB, DOM, and DOB—show a rank order of potency in the locus coeruleus that matches their previously established 5-HT2 receptor binding affinity: (-)DOB is most potent, followed by DOM, then (+)DOB. The behaviorally inactive isomer SL-7161 had no significant effect on locus coeruleus unit activity. These findings clarify structure-activity relationships at 5-HT2 receptors and reinforce evidence that hallucinogen effects in the locus coeruleus are mediated through 5-HT2 receptors.
European Journal of Pharmacology
August 8, 1996
R T Layer, P Skolnick, C M Bertha et al.
48 citations
Ibogaine, a psychoactive alkaloid, is more potent than its analogs at blocking NMDA receptors, a brain target linked to addiction. In lab tests, ibogaine inhibited [3H]MK-801 binding to NMDA receptors most strongly (Ki ≈ 1.2 µM), while similar compounds like O-desmethylibogaine were less potent (Ki ≈ 5.5 µM) and O-t-butyl-O-desmethylibogaine much weaker (Ki ≈ 179 µM). In morphine-dependent mice, only ibogaine reduced withdrawal jumping triggered by naloxone, suggesting its anti-addictive effects stem from NMDA receptor antagonism.
European Journal of Pharmacology
August 21, 1987
H Dabiré, C Cherqui, B Fournier et al.
47 citations
In anaesthetized rats, three drugs that activate serotonin 1A receptors (8-OH-DPAT, 5-MeODMT, and TFMPP) all lowered blood pressure and heart rate after intravenous injection. For 5-MeODMT and TFMPP, a brief blood pressure increase preceded the decrease. The blood pressure drop from 5-MeODMT and 8-OH-DPAT was blocked by spiroxatrine but not by ketanserin or cocaine, suggesting it results from stimulating '5-HT1-like' receptors, likely the 5-HT1A subtype. The initial blood pressure rise from 5-MeODMT appears due to activating 5-HT2 receptors.
European Journal of Pharmacology
November 1, 1981
Heidrun Fink, Wolfgang Oelssner
44 citations
Microinjections of LSD, mescaline, and serotonin into the medial raphe nucleus of rats strongly potentiated the increase in locomotor activity caused by apomorphine. This potentiating effect of LSD or serotonin was blocked by simultaneous injections of methysergide or cyproheptadine into the same brain region. Injections of the same doses of LSD into the dorsal raphe nucleus or of LSD and mescaline into the nucleus accumbens did not affect locomotor activity, while higher doses into the nucleus accumbens inhibited both spontaneous and apomorphine-stimulated activity. The findings suggest that low systemic doses of hallucinogens potentiate behavior by preferentially acting on the serotonergic system in the medial raphe nucleus.
European Journal of Pharmacology
April 28, 2011
Pamela B. Yang, Kristal D. Atkins, N. Dafny
42 citations
Amphetamine, methylphenidate (Ritalin), and MDMA (ecstasy) all increase movement in female rats after a single dose. Repeated administration of moderate doses of amphetamine or methylphenidate leads to behavioral sensitization, a marker of dependence potential. MDMA produces sensitization in some rats but tolerance in others. Cross-sensitization occurs between methylphenidate and amphetamine, but MDMA does not cross-sensitize or cross-tolerate with amphetamine, suggesting MDMA acts through different mechanisms.
European Journal of Pharmacology
December 8, 2017
Dino Luethi, Marius C. Hoener, Matthias E. Liechti
41 citations
Diclofensine, diphenidine, and methoxphenidine are new psychoactive substances that appeared on the illicit drug market. Diclofensine potently inhibited all three monoamine transporters (norepinephrine, dopamine, and serotonin) with similar inhibition potential in the range of 2.5-4.8 μM and also bound to adrenergic, dopamine, serotonin, and trace amine-associated receptors. Diphenidine inhibited norepinephrine and dopamine transporters in the low micromolar range but was a very weak serotonin transporter inhibitor, and it bound to adrenergic α1A and α2A receptors and serotonin 5-HT1A and 5-HT2A receptors. Methoxphenidine showed considerable inhibition only for the norepinephrine transporter and bound to adrenergic α2A and serotonin 5-HT2A and 5-HT2C receptors. None of the drugs mediated substrate-type efflux of monoamines. These interactions likely mediate the psychoactive effects of diclofensine and may contribute to those of diphenidine and methoxphenidine.
European Journal of Pharmacology
September 22, 1992
J Yamazaki, H Fukuda, T Nagao et al.
38 citations
Certain drugs that activate serotonin receptors, specifically 5-HT2 and 5-HT1C types, increase the excitability of motor neurons in the spinal cord of adult rats. The compounds 5-MeODMT and DOI were the most potent at boosting the firing probability of these cells. Blocking 5-HT2 or 5-HT1C receptors with specific antagonists suppressed this effect, while blocking other serotonin receptor types did not. This indicates that 5-HT2 and 5-HT1C receptors mediate the facilitatory influence of serotonin-like drugs on spinal motor neuron activity.
European Journal of Pharmacology
February 26, 1982
C P Vandermaelen, G K Aghajanian
37 citations
In anesthetized rats, drugs that produce the behavioral serotonin syndrome—5-methoxy-N,N-dimethyltryptamine and p-chloroamphetamine—slowly depolarized facial motoneurons, increased their input resistance, and heightened their excitability. These effects match those seen when serotonin is applied directly to the same neurons, suggesting that such cellular changes contribute to some features of the serotonin syndrome.