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
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 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
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
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
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
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
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.
European journal of pharmacology
April 7, 1992
C W Callaway, M A Geyer
35 citations
Injecting S-MDMA (a form of MDMA, or ecstasy) directly into a brain region called the nucleus accumbens made rats more active, similar to the effect of amphetamine. Blocking serotonin with fluoxetine did not prevent this hyperactivity, even though it blocks the effects of systemically given S-MDMA. A drug that only releases serotonin, MBDB, did not increase activity when injected into the nucleus accumbens, though it does when given systemically. These results suggest that S-MDMA's effects in the nucleus accumbens are due to its ability to release catecholamines like dopamine, not serotonin, and differ from its systemic actions.
European journal of pharmacology
November 2, 1993
M D Schechter, T L Gordon
33 citations
Rats were trained to distinguish the effects of ibogaine, a hallucinogenic alkaloid used in West Central Africa and studied for treating chemical dependency, from a placebo. Ibogaine from three different suppliers (Sigma Chemical Co., the National Institute on Drug Abuse, and NDA International Inc.'s Endabuse) produced similar discrimination in the rats, with effective doses ranging from 2.5 to 3.4 mg/kg. Other drugs tested, including those affecting dopamine and serotonin systems, did not produce ibogaine-like effects. The findings suggest that ibogaine from these sources is comparable for preclinical research.
European journal of pharmacology
June 2, 1994
D Marona-Lewicka, D E Nichols
32 citations
MMAI (5-methoxy-6-methyl-2-aminoindan) appears to be a selective serotonin releaser without psychostimulant or hallucinogenic effects. In rats trained to discriminate MMAI from saline, only other serotonin-releasing drugs fully mimicked MMAI's effects. MMAI did not produce amphetamine-like or LSD-like stimulus effects. Depleting serotonin with p-chlorophenylalanine blocked MMAI's discriminative cue for about a week, and selective serotonin reuptake inhibitors reduced its discriminability. Behavioral observations showed MMAI induced a syndrome similar to that caused by serotonin precursors or receptor agonists, including hypolocomotion, catalepsy-like posture, and flat body posture. The findings suggest MMAI acts primarily by releasing serotonin rather than directly activating or blocking neurotransmitter receptors.
European journal of pharmacology
February 13, 1990
L Cancela, M Volosin, V A Molina
31 citations
Rats immobilized for 2 hours daily over 7 days developed a heightened behavioral response to a serotonin receptor agonist, 5-MeODMT, measured by forepaw treading and hind-limb abduction. Giving naloxone before each stress session fully blocked this increased reactivity. Conversely, pairing morphine or beta-endorphin with immobilization for 3 days produced an even stronger response than immobilization alone. Chronic immobilization did not affect shaking behavior induced by another serotonin precursor, 5-HTP. These findings suggest chronic stress selectively adapts the 5-HT1 serotonin site and activates an opioid mechanism likely involved in that adaptation.
European journal of pharmacology
November 21, 2005
Vishal Panchal, Olga D Taraschenko, Isabelle M Maisonneuve et al.
30 citations
18-Methoxyroconaridine (18-MC), a synthetic derivative of ibogaine, reduces morphine self-administration and alleviates several signs of acute opioid withdrawal in rats. The mechanism behind 18-MC's attenuation of opioid withdrawal was unknown. In vitro studies show 18-MC is a potent antagonist of alpha3beta4 nicotinic receptors, predominantly located in the medial habenula and interpeduncular nuclei. To test whether brain areas with high densities of these receptors are involved, 18-MC was locally administered into the medial habenula, interpeduncular nucleus, and locus coeruleus of morphine-dependent rats, followed by naltrexone to precipitate withdrawal.
European journal of pharmacology
September 3, 1984
A P Nisbet, C A Marsden
29 citations
Destroying serotonin-producing neurons in the brain with a chemical (5,7-DHT) made rats more sensitive to a drug that activates serotonin receptors (5-MeO-DMT). The stronger behavioral response matched how much serotonin was lost. But the same treatment did not increase the hyperactivity caused by a different drug (RU-24969) that targets a specific serotonin receptor subtype (5HT1). This suggests that different serotonin receptors control different behaviors and that losing serotonin neurons changes sensitivity to some, but not all, receptor-activating drugs.
European journal of pharmacology
January 20, 1987
T Nabeshima, K Ishikawa, K Yamaguchi et al.
27 citations
Withdrawal from chronic methysergide, a 5-HT2 receptor blocker, potentiates phencyclidine (PCP)-induced head-twitch behavior in rats, while repeated PCP treatment leads to tolerance that is blocked by methysergide. PCP-induced behaviors (head-twitch, head-weaving, turning, backpedalling) were attenuated after 12 days of daily PCP, but head-twitch increased significantly after stopping methysergide. Binding studies showed increased Bmax of 5-HT2 and PCP receptors after methysergide withdrawal, and decreased Bmax of 5-HT2 receptors after PCP tolerance, with no affinity changes. PCP displaced [3H]ketanserin at 5-HT2 but not [3H]5-HT at 5-HT1 sites, indicating PCP produces head-twitch through agonistic action at 5-HT2 receptors.
European journal of pharmacology
June 3, 1983
B L Jacobs, J Heym, K Rasmussen
25 citations
In unanesthetized and unrestrained cats, serotonergic neurons in several raphe nuclei showed a strong negative correlation between their spontaneous firing rate during waking and their response to systemic injections of the serotonin agonists 5-MeODMT or LSD. The authors propose that both the baseline activity of these neurons and the size of their response to serotonin-like drugs can be explained by the density of autoreceptors on each neuron.
European journal of pharmacology
December 15, 2006
Roman Paškulin, Polona Jamnik, Marko Živin et al.
24 citations
Ibogaine, an alkaloid from the Tabernanthe iboga plant, reduces withdrawal symptoms in animal models of drug addiction, and its effects outlast its presence in the body, suggesting lasting metabolic changes. In rats given a single 20 mg/kg dose, brain protein analysis at 24 and 72 hours revealed increased levels of key energy-metabolism enzymes: glyceraldehyde-3-phosphate dehydrogenase, aldolase A, pyruvate kinase, and malate dehydrogenase. These enzymes are involved in glycolysis and the tricarboxylic acid cycle. The findings indicate that ibogaine's anti-addiction effects may arise from enhanced energy availability, supporting cellular changes needed for detoxification and reversal of drug tolerance.
European journal of pharmacology
February 25, 2000
M E Alburges, B P Ramos, L Bush et al.
21 citations
Ibogaine, a compound from the West African shrub Tabernanthe iboga, and cocaine both increased substance P—a key signaling molecule—in brain regions associated with movement and reward, specifically the striatum and substantia nigra, 12 hours after the last drug treatment. Substance P levels were not significantly raised in the nucleus accumbens by either drug. These increases were blocked by antagonists of dopamine D1 or D2 receptors, indicating involvement of dopamine pathways. Unlike cocaine, multiple doses of ibogaine did not raise substance P in the frontal cortex. The findings suggest substance P systems may contribute to the effects of ibogaine and cocaine.