Pharmacology, biochemistry, and behavior
August 1, 1990
N A Darmani, B R Martin, U Pandey et al.
245 citations
In mice, the drug (+/-)-DOI, which activates 5-HT2 receptors, causes a head-twitch response that increases with dose. The (-) isomer of DOI is twice as potent as the (+) isomer. Selective 5-HT2 blockers (ketanserin and spiperone) reduce this response in a dose-dependent way. A nonselective 5-HT agonist (5-MeO DMT) and a 5-HT1A-selective agonist (8-OH-DPAT) also reduce the response, but a 5-HT1B/5-HT1C-selective agonist (TFMPP) does not. The authors propose that 5-HT1A receptors inhibit the 5-HT2 receptor-mediated head-twitch response.
Pharmacology, biochemistry, and behavior
June 1, 1986
L M Smith, S J Peroutka
245 citations
Four drugs that bind to the same serotonin receptor subtype (5-HT1A) produce different behavioral effects in rats. 8-OH-DPAT, 5-MeODMT, buspirone, and isapirone all potently inhibit 3H-8-OH-DPAT binding to rat brain membranes (Ki values = 1.9-13 nM). However, only 8-OH-DPAT and 5-MeODMT induce forepaw treading, head-weaving, and tremor, while buspirone and isapirone actually block those behaviors when given alongside the full agonists. All four drugs induce hindlimb abduction, flattened body posture, and Straub tail. The findings suggest that specific components of the serotonin behavioral syndrome are mediated by 5-HT1A receptors.
Pharmacology, biochemistry, and behavior
January 1, 2006
W E Fantegrossi, A W Harrington, C L Kiessel et al.
144 citations
5-MeO-DIPT, a hallucinogenic drug similar to DMT, produced head-twitch responses in mice, an effect blocked by a serotonin 2A receptor antagonist. In rats trained to recognize LSD, 5-MeO-DIPT partially substituted for LSD (75% generalization) and suppressed response rates in a dose-dependent way; this effect was abolished by a 5-HT2A antagonist but not by a 5-HT1A antagonist. The drug showed micromolar affinity for 5-HT2A and 5-HT2C receptors and much higher affinity for 5-HT1A receptors in rat brain tissue. The results indicate that the 5-HT2A receptor is a key site of action for 5-MeO-DIPT, despite its in vitro selectivity for the 5-HT1A receptor.
Pharmacology, biochemistry, and behavior
October 1, 1991
E Yadin, E Friedman, W H Bridger
137 citations
Serotonergic drugs that activate certain receptors (5-HT1A) disrupt spontaneous alternation in rats, a behavior that may model the perseveration and indecisiveness seen in obsessive-compulsive disorder (OCD). Food-deprived rats given repeated choices in a T-maze normally alternate between goal boxes. Both the nonselective 5-HT agonist 5-MeODMT and the more selective 5-HT1A agonist 8-OH-DPAT reduced this alternation. Chronic treatment with the selective serotonin reuptake inhibitor fluoxetine protected against the disruption caused by 5-MeODMT. The findings suggest that serotonergic manipulation of spontaneous alternation could serve as a simple animal model for certain OCD symptoms.
Pharmacology, biochemistry, and behavior
November 1, 1995
A H Rezvani, D H Overstreet, Y W Lee
136 citations
Ibogaine, injected into the abdomen or given orally, but not under the skin, reduced alcohol intake in alcohol-preferring, Fawn-Hooded, and alcohol-accepting rats. The effect was dose-dependent and did not diminish with repeated oral doses over five days. Ibogaine did not affect blood alcohol levels or food and water intake. The results suggest that ibogaine or its metabolites may reduce alcohol consumption by modulating brain chemicals involved in alcohol intake regulation, though the exact mechanism is not fully understood.
Pharmacology, biochemistry, and behavior
August 1, 1987
J C Winter, D T Petti
128 citations
In a radial maze task, rats given various serotonergic drugs showed dose-related declines in response rate, except for a low dose of 8-OH-DPAT that increased responding. LSD, RU 24969, and 8-OH-DPAT also reduced efficiency, with 8-OH-DPAT being the most potent, producing efficiencies of 61%, 53%, and 44% at 0.3, 1.0, and 3.0 mg/kg, respectively. Given 8-OH-DPAT's selectivity for 5-HT1A receptors, the high density of these receptors in the hippocampus, and their reduction in Alzheimer's disease, the authors suggest this serotonin receptor subtype may play a role in memory.
Pharmacology, biochemistry, and behavior
June 1, 2003
Isabelle M. Maisonneuve, Stanley D. Glick
109 citations
18-Methoxycoronaridine (18-MC), a synthetic compound related to iboga, reduces self-administration of multiple addictive drugs in animal models. It decreased intravenous morphine, cocaine, methamphetamine, and nicotine self-administration, as well as oral alcohol and nicotine intake, and eased opioid withdrawal signs, without affecting responding for a nondrug reinforcer (water) or causing apparent toxicity. 18-MC also blocked sensitized dopamine responses to morphine and cocaine in the nucleus accumbens. Receptor studies identified it as a potent antagonist at alpha3beta4 nicotinic receptors. Low-dose combinations of 18-MC with other alpha3beta4 antagonists reduced drug self-administration at otherwise ineffective doses. The findings suggest that alpha3beta4 nicotinic receptor antagonists may offer a novel, broad-spectrum treatment for addiction.
Pharmacology, biochemistry, and behavior
June 1, 2003
Amir H Rezvani, David H Overstreet, Marina Perfumi et al.
95 citations
A review of studies in alcohol-preferring rats shows that extracts from St. John's wort, kudzu, and ibogaine, as well as purified compounds from these plants (puerarin, daidzin, daidzein, and ibogaine analogs), dose-dependently reduce alcohol intake after a single dose, with minimal effects on food intake. Puerarin and St. John's wort extract also remain effective with repeated dosing. The compounds appear to work by modulating multiple brain systems involved in drinking, though their exact mechanisms are not fully understood. Whether these compounds become treatments for alcoholism depends on future clinical trials.
Pharmacology, biochemistry, and behavior
December 1, 2009
Aashish S. Morani, Bronwyn Kivell, Thomas E. Prisinzano et al.
91 citations
Pretreatment with several kappa-opioid receptor agonists, including salvinorin A (Sal A), the active compound in Salvia divinorum, reduced cocaine-induced drug-seeking in rats. After learning to self-administer cocaine, rats underwent extinction and then received a cocaine priming injection. Cocaine-induced reinstatement of drug-seeking was attenuated by U69593, U50488H, spiradoline, and Sal A. Sal A did not affect sucrose-reinforced responding or cocaine-induced hyperactivity, suggesting its effects are specific to drug-seeking. These findings indicate that Sal A, like other kappa-opioid agonists, can suppress cocaine-seeking behavior.
Pharmacology, biochemistry, and behavior
January 1, 2000
J C Winter, R A Filipink, D Timineri et al.
80 citations
In rats trained to recognize the effects of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or (-)-2,5-dimethoxy-4-methylamphetamine (DOM), blocking specific serotonin receptors revealed which receptors mediate each drug's effects. Blocking 5-HT1A receptors strongly reduced 5-MeO-DMT's effects, while blocking 5-HT2 receptors had little effect. Conversely, DOM's effects were blocked by a 5-HT2 antagonist but not by 5-HT1A antagonists. 5-MeO-DMT partially mimicked DOM only when given subcutaneously, and this required both 5-HT1A and 5-HT2 receptor involvement. The findings indicate that 5-MeO-DMT's effects rely mainly on 5-HT1A receptors, but it also activates 5-HT2 receptors, a component revealed in animals trained with the 5-HT2-selective drug DOM.
Pharmacology, biochemistry, and behavior
October 1, 1997
A H Rezvani, D H Overstreet, Y Yang et al.
78 citations
A single injection of 18-methoxycoronaridine (18-MC), a nontoxic ibogaine analogue, dose dependently reduced alcohol consumption and preference in alcohol-preferring rats, while water intake increased correspondingly. Only the highest dose (40 mg/kg) also decreased food intake. The mechanism by which 18-MC suppresses alcohol intake is not yet fully understood but may involve modulation of neurotransmitters that regulate alcohol consumption.
Pharmacology, biochemistry, and behavior
January 1, 1994
H Sershen, A Hashim, A Lajtha
75 citations
Male C57BL/6By mice developed a preference for cocaine after forced exposure to it in drinking water. When given a choice, they consumed 71% of their fluid from the cocaine solution. Ibogaine administration reduced cocaine preference to 41% and daily cocaine intake by 38% for at least five days. Cocaine-challenged mice previously exposed to cocaine showed increased locomotor activity and stereotypy, which were reduced after ibogaine treatment. Brain cocaine levels were about 25% higher in ibogaine-treated mice, suggesting ibogaine may alter cocaine pharmacokinetics.
Pharmacology, biochemistry, and behavior
October 1, 2007
J C Winter, K C Rice, D J Amorosi et al.
73 citations
Psilocybin produces a complex internal cue in rats that depends partly, but not entirely, on the 5-HT2A serotonin receptor. Blocking the 5-HT2A receptor with M100907 only partially reduced the drug's effect, while blocking the 5-HT1A/7 receptor or the dopamine D2 receptor had no effect. Rats trained to recognize psilocybin also recognized other hallucinogens such as LSD, psilocin, and DOM, and partially recognized mescaline and 2C-T-7. LSD and MDMA partly substituted for psilocybin, and those effects were fully blocked by M100907. Unlike the related hallucinogen 5-MeO-DMT, psilocybin's effects do not involve the 5-HT1A receptor.
Pharmacology, biochemistry, and behavior
January 1, 1997
K Matsumoto, M Mizowaki, H Takayama et al.
60 citations
Mitragynine, a compound from kratom leaves, suppresses head-twitch responses in mice induced by a serotonin receptor agonist, similar to a known 5-HT2A receptor antagonist. The effect was dose-dependent and not altered by depleting serotonin or dopamine systems, but was reduced by drugs that block alpha-2 adrenoceptors. This suggests mitragynine acts through stimulation of postsynaptic alpha-2 adrenoceptors, blockade of 5-HT2A receptors, or both.
Pharmacology, biochemistry, and behavior
August 1, 1997
S M Pearl, L B Hough, D L Boyd et al.
58 citations
Ibogaine, a substance studied for antiaddictive properties, produces stronger behavioral effects in female rats than in males, correlating with higher ibogaine levels in their brains and plasma. Five hours after a 40 mg/kg dose, ibogaine antagonized morphine-induced locomotor activity only in females. At 19 hours after 10-60 mg/kg ibogaine or one hour after 5-40 mg/kg noribogaine (a metabolite), antagonism was greater in females. Brain and plasma levels of ibogaine and noribogaine were higher in females given the same dose. Levels were much lower at 19 hours than earlier, unlike a prior human study. Subcutaneous injection produced greater antagonism than intraperitoneal, consistent with higher brain levels. Sex differences likely stem from lower ibogaine bioavailability in males.
Pharmacology, biochemistry, and behavior
January 1, 1990
M P Johnson, C A Mathis, A T Shulgin et al.
56 citations
A radiolabeled compound, [125I]-2C-I, was used to label low-density 5-HT2 agonist binding sites in brain tissue. The nonhydrolyzable GTP analog GppNHp inhibited high-affinity binding, and serotonin along with several 5-HT2 agonists and antagonists showed high affinity for the site. At 37°C, the number of binding sites (Bmax) decreased compared to 24°C, while binding affinity (KD) remained unchanged. Structure-activity relationships for displacing [125I]-2C-I supported the receptor's role in hallucinogen action. The findings demonstrate [125I]-2C-I as a useful radioligand and provide further evidence linking the 5-HT2 receptor to hallucinogenic activity.
Pharmacology, biochemistry, and behavior
March 1, 1985
G A Gudelsky, J I Koenig, H Y Meltzer
54 citations
Rats of the Fawn-Hooded (FH) strain show stronger behavioral responses to certain serotonin-related drugs compared to Sprague-Dawley (SD) rats. Specifically, FH rats exhibited significantly more "wet dog" shakes when given quipazine and a greater hyperthermic response to 5MeODMT. Conversely, the hypothermic effect of 8-OH-DPAT was significantly weaker in FH rats than in SD rats. These results suggest that central nervous system serotonergic mechanisms differ markedly between the two rat strains.
Pharmacology, biochemistry, and behavior
January 1, 1997
R A Glennon, R Young, M Dukat et al.
48 citations
The drug PMMA, a hybrid of PMA and methamphetamine, produces effects in rats similar to MDMA (Ecstasy) but lacks the stimulant or hallucinogen-like properties of amphetamine or DOM. Rats trained to distinguish PMMA from saline did not respond to amphetamine or DOM, but did respond to MDMA and its S(+) isomer. Partial responses occurred with several related compounds. These results suggest PMMA acts like MDMA without amphetamine-like stimulation, supporting the idea that PMMA is the structural parent of MDMA-like designer drugs.
Pharmacology, biochemistry, and behavior
March 1, 1992
N A Darmani, B R Martin, R A Glennon
48 citations
Cocaine acutely suppresses a serotonin-related behavior in mice (the head-twitch response) by activating other receptors, not by blocking 5-HT3 receptors. During withdrawal from chronic cocaine treatment, the same behavior becomes enhanced, indicating supersensitivity that can last up to 172 hours depending on the cocaine dose. Low-dose chronic cocaine withdrawal increases the response to a selective 5-HT2 agonist, while higher doses do not. Withdrawal also increases the inhibitory effect of a 5-HT1A agonist on the behavior.
Pharmacology, biochemistry, and behavior
November 1, 1994
P A Broderick, F T Phelan, F Eng et al.
46 citations
Ibogaine reduced cocaine-induced increases in dopamine release in the nucleus accumbens and amplified cocaine-induced decreases in serotonin release in male rats. It also diminished cocaine-stimulated ambulation and central ambulation, behaviors that had habituated over time in the test chamber. Rearing and fine movements, which did not habituate, were not affected by ibogaine. Ibogaine alone did not significantly alter dopamine release over two hours but did increase serotonin release and acted as a weak psychostimulant. The findings highlight a modulatory role for serotonin in ibogaine-cocaine interactions and show ibogaine's efficacy when cocaine responses are reduced by environmental habituation.
Pharmacology, biochemistry, and behavior
September 1, 2010
Bryan A Killinger, Mary M Peet, Lisa E Baker
41 citations
Salvinorin A, the active compound in Salvia divinorum, is an atypical hallucinogen that selectively binds to kappa opioid receptors and is structurally distinct from other opioids. In a drug discrimination study, 16 male rats trained to recognize either LSD or ketamine did not generalize to salvinorin A, meaning the rats did not treat it as similar to those hallucinogens. This supports evidence that salvinorin A is pharmacologically distinct from traditional hallucinogens like LSD and ketamine, offering a unique tool for studying the neurochemical mechanisms of hallucination.
Pharmacology, biochemistry, and behavior
August 1, 1989
J F Nash, H Y Meltzer, G A Gudelsky
40 citations
Repeated administration of 5-MeODMT (3 mg/kg, twice daily for 14 days) in animals reduced the hypothermia and corticosterone secretion caused by an acute challenge with the 5-HT1A agonist 8-OH-DPAT, compared to vehicle-treated animals. Chronic 5-MeODMT did not affect hyperthermia or corticosterone secretion from the 5-HT2 agonist MK-212. Repeated administration of DOI (1 mg/kg daily for 7 days) reduced corticosterone but not body temperature increases from MK-212, and did not alter responses to 8-OH-DPAT. These results suggest that chronic 5-MeODMT selectively reduces 5-HT1A receptor-mediated responses, while chronic DOI selectively reduces 5-HT2 receptor-mediated corticosterone secretion without affecting thermoregulatory responses, supporting the independence of these receptor systems.
Pharmacology, biochemistry, and behavior
February 1, 1998
S Helsley, D Fiorella, R A Rabin et al.
35 citations
In rats trained to recognize the hallucinogen ibogaine, two other hallucinogens—LSD and DOM—partially substituted for ibogaine (63% and 66.4% of responses, respectively). This partial substitution was completely blocked by the 5-HT2A antagonist pirenpirone, indicating that LSD and DOM produce ibogaine-like effects through the 5-HT2A receptor. However, pirenpirone did not block ibogaine itself or its effects from harmaline and noribogaine. Ibogaine, noribogaine, and harmaline showed only micromolar affinity for the 5-HT2A receptor (92.5, 34.5, and 42.5 µM). Ibogaine and harmaline, but not noribogaine, protected the receptor from alkylation. The findings suggest that while ibogaine interacts with 5-HT2A receptors, these interactions are not essential for its discriminative stimulus effects.
Pharmacology, biochemistry, and behavior
January 1, 1975
M A Geyer, J D Warbritton, D B Menkes et al.
34 citations
Rat startle responses to air puffs were measured during infusion of serotonin (5-HT), a hallucinogenic compound (5-HDMT), or saline. Serotonin reduced startle magnitude in a dose-dependent way, while the hallucinogen increased startle responses. Neither compound specifically affected sensitization or habituation. The findings suggest a central serotonin system that promotes behavioral inhibition, which indoleamine hallucinogens may oppose.
Pharmacology, biochemistry, and behavior
April 1, 2016
Adam L Halberstadt
33 citations
Combining 5-MeO-DMT with monoamine oxidase inhibitors (MAOIs) changes how the drug affects behavior in rats. 5-MeO-DMT alone did not disrupt prepulse inhibition (PPI), a measure of sensorimotor gating, but when rats were pretreated with the MAO-A inhibitor clorgyline or the MAO-A/B inhibitor pargyline, the drug disrupted PPI. This disruption was blocked by antagonists of either 5-HT1A or 5-HT2A receptors, indicating both receptor types are involved. MAO-A inhibition increased levels of 5-MeO-DMT in plasma and whole brain but did not affect its conversion to bufotenine, which was negligible. The findings suggest that MAOIs enhance the drug's effects by increasing its accumulation in the central nervous system.