RESUMEN
2,5-dimethoxy-4-methylamphetamine (DOM) is a kind of hallucinogen of phenylalkylamine. Psychedelic effects mainly include audiovisual synesthesia, complex imagery, disembodiment etc. that can impair control and cognition leading to adverse consequences such as suicide. By now, there are no specific drugs regarding the management of classic hallucinogen use clinically. We evaluated the effects of three 5-HT 2A receptor antagonists ketanseirn, M100907 and olanzapine on hallucination-like behavior in therapeutic and preventive administration with male C57BL/6J mice. Two models were used to evaluate the therapeutic potential of antagonists, one is head-twitch response (HTR) and the other is locomotion. Effects of ketanserin, M100907 and olanzapine on DOM-induced HTR were studied in preventive and therapeutic administration, respectively. In the preventive administration, the ID 50 values of ketanseirn, M100907 and olanzapine were 0.4 mg/kg, 0.005 mg/kg and 0.25 mg/kg. In the therapeutic administration, the ID 50 values of ketanseirn, M100907 and olanzapine were 0.04 mg/kg, 0.005 mg/kg and 0.03 mg/kg. Secondly, locomotor activity induced by DOM was performed to further evaluate the efficacy of three compounds. In locomotion, M100907(0.005 mg/kg) whenever in preventive or therapeutic administration, reduced the increase of movement distance induced by DOM. Although ketanserin (0.4 mg/kg) in the preventive administration also decreased the movement distance induced by DOM, it was alone administrated to influence the locomotor activity. Through HTR and locomotion, we compared the efficacy and latent side effects of ketanserin, M100907 and olanzapine against hallucinogenic like action induced by DOM. Our study provided additional experimental evidence on specific therapeutic drugs against hallucinogenic behavior induce by representative hallucinogen DOM.
Asunto(s)
Alucinógenos , Metanfetamina , Ratones , Animales , Masculino , Ketanserina/farmacología , 2,5-Dimetoxi-4-Metilanfetamina/farmacología , Alucinógenos/farmacología , Olanzapina/farmacología , Ratones Endogámicos C57BL , Receptor de Serotonina 5-HT2ARESUMEN
There has been increasing interest in the potential therapeutic effects of drugs with agonist properties at serotonin 2A subtype (5-HT2A) receptors (e.g., psychedelics), including treatment of substance use disorders. Studying interactions between 5-HT2A receptor agonists and other drugs is important for understanding potential therapeutic effects as well as adverse interactions. Direct-acting 5-HT2A receptor agonists such as 2,5-dimethoxy-4-methylamphetamine (DOM) and 2-piperazin-1-yl-quinoline (quipazine) enhance some (e.g., antinociceptive) effects of opioids; however, it is unclear whether they alter the abuse-related effects of opioids. This study examined whether DOM and quipazine alter the reinforcing effects of fentanyl in rhesus monkeys (n = 6) responding under a food versus drug choice procedure. Responding on one lever delivered sucrose pellets and responding on the other lever delivered intravenous (i.v.) infusions. In one set of experiments, fentanyl (0.1-3.2 µg/kg/infusion) versus food choice sessions were preceded by noncontingent i.v. pretreatments with DOM (0032-0.32 mg/kg), quipazine (0.32-1.0 mg/kg), naltrexone (0.032 mg/kg), or heroin (0.1 mg/kg). In another set of experiments, fentanyl was available during choice sessions in combination with DOM (0.32-100 µg/kg/infusion) or quipazine (3.2-320 µg/kg/infusion) in varying dose ratios. Naltrexone decreased and heroin increased fentanyl choice, demonstrating sensitivity of responding to pharmacological manipulation. However, whether given as a pretreatment or made available in combination with fentanyl as a mixture, neither DOM nor quipazine significantly altered fentanyl choice. These results suggest that 5-HT2A receptor agonists do not enhance the reinforcing effects of opioids and, thus, will not likely enhance abuse potential. SIGNIFICANCE STATEMENT: Serotonin 2A subtype receptor agonists enhance some (e.g., antinociceptive) effects of opioids, suggesting they could be combined with opioids in some therapeutic contexts such as treating pain. However, it is unclear whether they also enhance adverse effects of opioids, including abuse. Results of this study indicate that serotonin 2A subtype receptor agonists do not reliably enhance opioid self-administration and, thus, are unlikely to enhance the abuse potential of opioids.
Asunto(s)
Metanfetamina , Quinolinas , Animales , Quipazina/farmacología , Fentanilo/farmacología , 2,5-Dimetoxi-4-Metilanfetamina/farmacología , Macaca mulatta , Receptor de Serotonina 5-HT2A , Heroína , Serotonina , Naltrexona , Analgésicos Opioides/farmacología , Relación Dosis-Respuesta a DrogaRESUMEN
In recent years, rigid analogs of phenylalkylamine hallucinogens have appeared as recreational drugs. Examples include 2-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)ethan-1-amine (2C-B-FLY) and 1-(8-bromobenzo[1,2-b;4,5-b']difuran-4-yl)-2-aminopropane (Bromo-DragonFLY, DOB-DFLY). Although some rigid compounds such as DOB-DFLY reportedly have higher potency than their non-rigid counterparts, it is not clear whether the same is true for 2C-B-FLY and other tetrahydrobenzodifurans. In the present study, the head twitch response (HTR), a 5-HT2A receptor-mediated behavior induced by serotonergic hallucinogens, was used to assess the effects of 2,5-dimethoxy-4-bromoamphetamine (DOB) and its α-desmethyl homologue 2,5-dimethoxy-4-bromophenethylamine (2C-B), as well as their benzodifuranyl and tetrahydrobenzodifuranyl analogs, in C57BL/6J mice. DOB (ED50 = 0.75 µmol/kg) and 2C-B (ED50 = 2.43 µmol/kg) induced the HTR. The benzodifurans DOB-DFLY (ED50 = 0.20 µmol/kg) and 2C-B-DFLY (ED50 = 1.07 µmol/kg) had significantly higher potency than DOB and 2C-B, respectively. The tetrahydrobenzodifurans DOB-FLY (ED50 = 0.67 µmol/kg) and 2C-B-FLY (ED50 = 1.79 µmol/kg), by contrast, were approximately equipotent with their non-rigid counterparts. Three novel tetrahydrobenzodifurans (2C-I-FLY, 2C-E-FLY and 2C-EF-FLY) were also active in the HTR assay but had relatively low potency. In summary, the in vivo potency of 2,5-dimethoxyphenylalkylamines is enhanced when the 2- and 5-methoxy groups are incorporated into aromatic furan rings, whereas potency is not altered if the methoxy groups are incorporated into dihydrofuran rings. The potency relationships for these compounds in mice closely parallel the human hallucinogenic data. The high potency of DOB-DFLY is probably linked to the presence of two structural features (a benzodifuran nucleus and an α-methyl group) known to enhance the potency of phenylalkylamine hallucinogens.
Asunto(s)
2,5-Dimetoxi-4-Metilanfetamina/análogos & derivados , Alucinógenos/farmacología , 2,5-Dimetoxi-4-Metilanfetamina/química , 2,5-Dimetoxi-4-Metilanfetamina/farmacología , Animales , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Alucinógenos/química , Movimientos de la Cabeza/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Estructura MolecularRESUMEN
There has been increasing use of novel synthetic hallucinogenic compounds, 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25B-NBOMe), 2-(4-chloro-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25C-NBOMe), 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25I-NBOMe), and N,N-diallyl-5-methoxy tryptamine (5-MeO-DALT), which have been associated with severe toxicities. These four compounds were tested for discriminative stimulus effects similar to a prototypical hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM) and the entactogen (±)-3,4-methylenedioxymethamphetamine (MDMA). Locomotor activity in mice was tested to obtain dose range and time-course information. 25B-NBOMe, 25C-NBOMe, and 25I-NBOMe decreased locomotor activity. 5-MeO-DALT dose dependently increased locomotor activity, with a peak at 10 mg/kg. A higher dose (25 mg/kg) suppressed activity. 25B-NBOMe fully substituted (≥80%) in both DOM-trained and MDMA-trained rats at 0.5 mg/kg. However, higher doses produced much lower levels of drug-appropriate responding in both DOM-trained and MDMA-trained rats. 25C-NBOMe fully substituted in DOM-trained rats, but produced only 67% drug-appropriate responding in MDMA-trained rats at doses that suppressed responding. 25I-NBOMe produced 74-78% drug-appropriate responding in DOM-trained and MDMA-trained rats at doses that suppressed responding. 5-MeO-DALT fully substituted for DOM, but produced few or no MDMA-like effects. All of the compounds, except 25I-NBOMe, fully substituted for DOM, whereas only 25B-NBOMe fully substituted for MDMA. However, the failure of 25I-NBOMe to fully substitute for either MDMA or DOM was more likely because of its substantial rate-depressant effects than weak discriminative stimulus effects. All of the compounds are likely to attract recreational users for their hallucinogenic properties, but probably of much less interest as substitutes for MDMA. Although no acute adverse effects were observed at the doses tested, the substantial toxicities reported in humans, coupled with the high likelihood for illicit use, suggests that these compounds have the same potential for abuse as other, currently scheduled compounds.
Asunto(s)
Anisoles/farmacología , Bencilaminas/farmacología , Dimetoxifeniletilamina/análogos & derivados , Fenetilaminas/farmacología , 2,5-Dimetoxi-4-Metilanfetamina/farmacología , Animales , Anisoles/metabolismo , Bencilaminas/metabolismo , Dimetoxifeniletilamina/metabolismo , Dimetoxifeniletilamina/farmacología , Alucinógenos/metabolismo , Alucinógenos/farmacología , Locomoción/efectos de los fármacos , Masculino , Ratones , N-Metil-3,4-metilenodioxianfetamina/farmacología , Fenetilaminas/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
RATIONALE: The synthetic phenethylamines are recreational drugs known to produce psychostimulant effects. However, their abuse potential has not been widely studied. OBJECTIVES: Here, we investigated the rewarding and the hallucinatory effects of 2,5-dimetoxy-4-bromo-amphetamine hydrobromide (DOB) and para-methoxyamphetamine (PMA) in comparison with the classical 3,4-methylenedioxymethamphetamine (MDMA). In addition, the role of serotonin 5-HT2-like receptor on the abovementioned effects was evaluated. METHODS: Zebrafish were intramuscularly (i.m.) treated with a wide range of doses of DOB (0.1-20 mg/kg), PMA (0.0005-2 mg/kg), or MDMA (0.5-160 mg/kg). Animals were submitted to a conditioned place preference (CPP) task, to investigation of the rewarding properties, and to the evaluation of hallucinatory behavior in terms of appearance of a trance-like behavior. The serotonin 5-HT2 subtype receptor antagonist ritanserin (0.025-2.5 mg/kg) in association with the maximal effective dose of MDMA, DOB, and PMA was given i.m., and the effect on CPP or hallucinatory behavior was evaluated. RESULTS: MDMA and its derivatives exhibited CPP in a biphasic fashion, being PMA the most potent. This effect was accompanied, for DOB (2 mg/kg) and PMA (0.1 mg/kg), by a trance-like hallucinatory behavior. MDMA at a high dose as 160 mg/kg did not induce any hallucinatory behavior. Ritanserin significantly blocked the rewarding and hallucinatory effects suggesting the involvement of serotonin 5HT2 subtype receptor. CONCLUSION: Collectively, these findings demonstrate for the first time that the rewarding properties of DOB and PMA are accompanied by hallucinatory behavior through a serotonergic system and reinforce zebrafish as an emerging experimental model for screening new hallucinogens.
Asunto(s)
Anfetaminas/farmacología , Conducta Animal/efectos de los fármacos , 2,5-Dimetoxi-4-Metilanfetamina/análogos & derivados , Alucinógenos/farmacología , N-Metil-3,4-metilenodioxianfetamina/farmacología , Receptores de Serotonina 5-HT2/metabolismo , Agonistas de Receptores de Serotonina/farmacología , 2,5-Dimetoxi-4-Metilanfetamina/farmacología , Animales , Condicionamiento Psicológico/efectos de los fármacos , Femenino , Masculino , Refuerzo en Psicología , Recompensa , Ritanserina/farmacología , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Pez CebraRESUMEN
5,6-Methylenedioxy-2-aminoindane (MDAI) has become a common substitute for (±)-3,4-methylenedioxymethamphetamine (MDMA) in Ecstasy. MDAI is known to produce MDMA-like discriminative stimulus effects, but it is not known whether MDAI has psychostimulant or hallucinogen-like effects. MDAI was tested for locomotor stimulant effects in mice and subsequently for discriminative stimulus effects in rats trained to discriminate cocaine (10 mg/kg, intraperitoneally), methamphetamine (1 mg/kg, intraperitoneally), ±MDMA (1.5 mg/kg, intraperitoneally), or (-)-2,5-dimethoxy-4-methylamphetamine hydrochloride (0.5 mg/kg, intraperitoneally) from saline. The ability of MDAI to produce conditioned place preference was also tested in mice. MDAI (3 to 30 mg/kg) depressed locomotor activity from 10 to 60 min. A rebound stimulant effect was observed at 1 to 3.5 h following 30 mg/kg. Lethality occurred in 8/8 mice following 100 mg/kg MDAI. Similarly, MDMA depressed locomotor activity immediately following the administration of 0.25 mg/kg and stimulant effects were observed 50-70 min following the administration of 0.5 and 1 mg/kg. MDAI fully substituted for the discriminative stimulus effects of MDMA (2.5 mg/kg), (-)-2,5-dimethoxy-4-methylamphetamine hydrochloride (5 mg/kg), and cocaine (7.5 mg/kg), but produced only 73% methamphetamine-appropriate responding at a dose that suppressed responding (7.5 mg/kg). MDAI produced tremors at 10 mg/kg in one methamphetamine-trained rat. MDAI produced conditioned place preference from 0.3 to 10 mg/kg. The effects of MDAI on locomotor activity and drug discrimination were similar to those produced by MDMA, having both psychostimulant-like and hallucinogen-like effects; thus, MDAI may have similar abuse potential as MDMA.
Asunto(s)
Aprendizaje Discriminativo/efectos de los fármacos , Alucinógenos/farmacología , Indanos/farmacología , Locomoción/efectos de los fármacos , 2,5-Dimetoxi-4-Metilanfetamina/farmacología , Animales , Estimulantes del Sistema Nervioso Central/farmacología , Cocaína/farmacología , Condicionamiento Psicológico/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Masculino , Metanfetamina/farmacología , Ratones , N-Metil-3,4-metilenodioxianfetamina/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
(1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (lorcaserin) is approved by the United States Food and Drug Administration for treating obesity, and its therapeutic effects are thought to result from agonist activity at serotonin (5-HT)2C receptors. Lorcaserin has affinity for other 5-HT receptor subtypes, although its activity at those subtypes is not fully described. The current study compared the behavioral effects of lorcaserin (0.0032-32.0 mg/kg) to the effects of other 5-HT receptor selective agonists in rats (n = 8). The 5-HT2C receptor selective agonist 1-(3-chlorophenyl)piperazine (mCPP, 0.032-1.0 mg/kg) and lorcaserin induced yawning which was attenuated by the 5-HT2C receptor selective antagonist 6-chloro-5-methyl-N-(6-[(2-methylpyridin-3-yl)oxy]pydidin-3-yl)indoline-1-carboxamide (1.0 mg/kg). The 5-HT2A receptor selective agonist 2,5-dimethoxy-4-methylamphetamine (0.1-3.2 mg/kg) induced head twitching, which was attenuated by the 5-HT2A receptor selective antagonist R-(+)-2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol] (MDL 100907, 0.01 mg/kg), lorcaserin (3.2 mg/kg), and mCPP (3.2 mg/kg). In rats pretreated with MDL 100907 (1.0 mg/kg), lorcaserin also induced head twitching. At larger doses, lorcaserin produced forepaw treading, which was attenuated by the 5-HT1A receptor selective antagonist N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridyl)cyclohexanecarboxamide (0.178 mg/kg). While the behavioral effects of lorcaserin in rats are consistent with it having agonist activity at 5-HT2C receptors, these data suggest that at larger doses it also has agonist activity at 5-HT2A and possibly 5-HT1A receptors. Mounting evidence suggests that 5-HT2C receptor agonists might be effective for treating drug abuse. A more complete description of the activity of lorcaserin at 5-HT receptor subtypes will facilitate a better understanding of the mechanisms that mediate its therapeutic effects.
Asunto(s)
Fármacos Antiobesidad/farmacología , Conducta Animal/efectos de los fármacos , Benzazepinas/farmacología , 2,5-Dimetoxi-4-Metilanfetamina/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Anfetaminas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Movimientos de la Cabeza/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Receptor de Serotonina 5-HT2C/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Bostezo/efectos de los fármacosRESUMEN
Serotonergic hallucinogens, such as lysergic acid diethylamide (LSD) and dimethoxy-bromoamphetamine (DOB), provoke stereotype-like shaking behaviour in rodents, which is hypothesised to engage frontocortical glutamate receptor activation secondary to serotonin2A (5-HT2A) related glutamate release. Challenging this hypothesis, we here investigate whether tolerance to LSD and DOB correlates with frontocortical adaptations of 5-HT2A and/or overall-glutamate binding sites. LSD and DOB (0.025 and 0.25 mg/kg, i.p.) induce a ketanserin-sensitive (0.5 mg/kg, i.p., 30-min pretreatment) increase in shaking behaviour (including head twitches and wet dog shakes), which with repeated application (7× in 4 ds) is undermined by tolerance. Tolerance to DOB, as indexed by DOB-sensitive [(3)H]spiroperidol and DOB induced [(35)S]GTP-gamma-S binding, is accompanied by a frontocortical decrease in 5-HT2A binding sites and 5-HT2 signalling, respectively; glutamate-sensitive [(3)H]glutamate binding sites, in contrast, remain unchanged. As to LSD, 5-HT2 signalling and 5-HT2A binding, respectively, are not or only marginally affected, yet [(3)H]glutamate binding is significantly decreased. Correlation analysis interrelates tolerance to DOB to the reduced 5-HT2A (r=.80) as well as the unchanged [(3)H]glutamate binding sites (r=.84); tolerance to LSD, as opposed, shares variance with the reduction in [(3)H]glutamate binding sites only (r=.86). Given that DOB and LSD both induce tolerance, one correlating with 5-HT2A, the other with glutamate receptor adaptations, it might be inferred that tolerance can arise at either level. That is, if a hallucinogen (like LSD in our study) fails to induce 5-HT2A (down-)regulation, glutamate receptors (activated postsynaptic to 5-HT2A related glutamate release) might instead adapt and thus prevent further overstimulation of the cortex.
Asunto(s)
2,5-Dimetoxi-4-Metilanfetamina/análogos & derivados , Lóbulo Frontal/metabolismo , Alucinógenos/farmacología , Dietilamida del Ácido Lisérgico/farmacología , Actividad Motora/efectos de los fármacos , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Receptores de Glutamato/efectos de los fármacos , 2,5-Dimetoxi-4-Metilanfetamina/farmacología , Animales , Sitios de Unión/efectos de los fármacos , Tolerancia a Medicamentos , Lóbulo Frontal/efectos de los fármacos , Ácido Glutámico/metabolismo , Ketanserina/farmacología , Masculino , Ratas , Antagonistas de la Serotonina/farmacologíaRESUMEN
Feeding conditions can impact sensitivity to drugs acting on dopamine receptors; less is known about the impact of feeding conditions on the effects of drugs acting on serotonin (5-HT) receptors. This study examined the effects of feeding conditions on sensitivity to the direct-acting 5-HT(2A/2C) receptor agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM; 0.1-3.2 mg/kg) and the direct-acting dopamine D3/D2 receptor agonist quinpirole (0.0032-0.32 mg/kg). Male Sprague-Dawley rats had free access (11 weeks), followed by restricted access (6 weeks), to high fat (34.3%, n=8) or standard (5.7% fat; n=7) chow. Rats eating high fat chow became insulin resistant and gained more weight than rats eating standard chow. Free access to high fat chow did not alter sensitivity to DOM-induced head twitch but increased sensitivity to quinpirole-induced yawning. Restricting access to high fat or standard chow shifted the DOM-induced head twitch dose-response curve to the right and shifted the quinpirole-induced yawning dose-response curve downward in both groups of rats. Some drugs of abuse and many therapeutic drugs act on 5-HT and dopamine systems; these results show that feeding conditions impact sensitivity to drugs acting on these systems, thereby possibly affecting vulnerability to abuse, as well as the therapeutic effectiveness of drugs.
Asunto(s)
2,5-Dimetoxi-4-Metilanfetamina/farmacología , Dieta Alta en Grasa , Conducta Alimentaria/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Animales , Glucemia/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Agonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Movimientos de la Cabeza/efectos de los fármacos , Insulina/farmacología , Resistencia a la Insulina/fisiología , Masculino , Quinpirol/farmacología , Ratas , Factores de Tiempo , Bostezo/efectos de los fármacosRESUMEN
RATIONALE: The serotonin (5-HT) system is involved in pain modulation, and 5-HT receptor agonists can enhance antinociceptive effects of mu opioid receptor agonists. Less is known about the actions of 5-HT receptor agonists on other effects of opioids. OBJECTIVE: This study examined the effects of non-contingent and contingent administration of the 5-HT(2A) receptor agonists DOM and quipazine on i.v. heroin self-administration in rhesus monkeys. RESULTS: Heroin (0.0001-0.1 mg/kg/infusion) generated an inverted U-shaped dose-response function. Non-contingent administration of DOM (0.1-0.32 mg/kg) flattened the dose-response function in three monkeys and eliminated heroin self-administration in a fourth monkey. Contingent DOM (0.0032-0.032 mg/kg/infusion) alone did not maintain responding above that maintained by saline, and, when added to self-administered heroin, monkeys responded less than for the same unit doses of heroin alone. Non-contingent (0.32-3.2 mg/kg) and contingent (0.0032-0.56 mg/kg/infusion) administration of quipazine flattened the dose-response function in two monkeys, increasing responding maintained by small unit doses of heroin and saline, but failed to enhance responding for heroin in two other monkeys. CONCLUSION: This study shows that DOM does not enhance, and might attenuate, the positive reinforcing effects of the mu opioid receptor agonist heroin. Quipazine increased responding for saline and small doses of heroin; those effects were modest and observed in only two subjects. Taken together, these data suggest that 5-HT(2A) receptor agonists do not significantly enhance the reinforcing effectiveness of mu opioid receptor agonists and support the view that administering 5-HT drugs in combination with opioids to treat pain might not enhance abuse liability.
Asunto(s)
2,5-Dimetoxi-4-Metilanfetamina/farmacología , Heroína/administración & dosificación , Quipazina/farmacología , Agonistas del Receptor de Serotonina 5-HT2/farmacología , 2,5-Dimetoxi-4-Metilanfetamina/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Femenino , Macaca mulatta , Masculino , Quipazina/administración & dosificación , Esquema de Refuerzo , Autoadministración , Agonistas del Receptor de Serotonina 5-HT2/administración & dosificaciónRESUMEN
RATIONALE: Serotonergic hallucinogens such as (+)-lysergic acid diethylamide (LSD) and dimethyltryptamine (DMT) produce distinctive visual effects, whereas the synthetic hallucinogen N,N-diisopropyltryptamine (DiPT) is known for its production of auditory distortions. OBJECTIVE: This study compares the discriminative stimulus effects of DiPT to those of visual hallucinogens. METHODS: Adult male rats were trained to discriminate DiPT (5 mg/kg, 15 min) from saline under a FR10 schedule. A dose-effect and time course of DiPT's discriminative stimulus effects were established. DMT, (-)-2,5-dimethoxy-4-methylamphetamine (DOM), LSD, (±)-methylenedioxymethamphetamine (MDMA), and (+)-methamphetamine were tested for cross-substitution in DiPT-trained animals. RESULTS: Rats learned to discriminate DiPT from saline in an average of 60 training sessions (30 drug and 30 saline). DiPT (0.5-5 mg/kg) produced dose-dependent increases in drug-appropriate responding (DAR) to 99 % (ED(50) = 2.47 mg/kg). Onset of the discriminative stimulus effects was within 5 min, and the effects dissipated within 4 h. Full substitution for the discriminative stimulus effects of DiPT occurred with LSD, DOM, and MDMA. DMT only partially substituted for DiPT (65 % DAR), whereas (+)-methamphetamine failed to substitute for DiPT (29 % DAR). CONCLUSIONS: The discriminative stimulus effects of DiPT were similar those of a number of synthetic hallucinogens, only partially similar to those of DMT, but not similar to (+)-methamphetamine. The putative DiPT-induced auditory distortions do not lead to discriminative stimulus effects distinguishable from other hallucinogens.
Asunto(s)
Aprendizaje Discriminativo/efectos de los fármacos , Alucinógenos/farmacología , Triptaminas/farmacología , 2,5-Dimetoxi-4-Metilanfetamina/farmacología , Animales , Relación Dosis-Respuesta a Droga , Dietilamida del Ácido Lisérgico/farmacología , Masculino , Metanfetamina/farmacología , N-Metil-3,4-metilenodioxianfetamina/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
RATIONALE: Parenteral injections of d-lysergic acid diethylamide (LSD), a serotonin 5-HT(2A) receptor agonist, enhance eyeblink conditioning. Another hallucinogen, (±)-1(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), was shown to elicit a 5-HT(2A)-mediated behavior (head bobs) after injection into the hippocampus, a structure known to mediate trace eyeblink conditioning. OBJECTIVE: This study aims to determine if parenteral injections of the hallucinogens LSD, d,l-2,5-dimethoxy-4-methylamphetamine, and 5-methoxy-dimethyltryptamine elicit the 5-HT(2A)-mediated behavior of head bobs and whether intrahippocampal injections of LSD would produce head bobs and enhance trace eyeblink conditioning. MATERIALS AND METHODS: LSD was infused into the dorsal hippocampus just prior to each of eight conditioning sessions. One day after the last infusion of LSD, DOI was infused into the hippocampus to determine whether there had been a desensitization of the 5-HT(2A) receptor as measured by a decrease in DOI-elicited head bobs. RESULTS: Acute parenteral or intrahippocampal LSD elicited a 5-HT(2A) but not a 5-HT(2C)-mediated behavior, and chronic administration enhanced conditioned responding relative to vehicle controls. Rabbits that had been chronically infused with 3 or 10 nmol per side of LSD during Pavlovian conditioning and then infused with DOI demonstrated a smaller increase in head bobs relative to controls. CONCLUSIONS: LSD produced its enhancement of Pavlovian conditioning through an effect on 5-HT(2A) receptors located in the dorsal hippocampus. The slight, short-lived enhancement of learning produced by LSD appears to be due to the development of desensitization of the 5-HT(2A) receptor within the hippocampus as a result of repeated administration of its agonist (LSD).
Asunto(s)
2,5-Dimetoxi-4-Metilanfetamina/farmacología , Dietilamida del Ácido Lisérgico/farmacología , Metoxidimetiltriptaminas/farmacología , Receptor de Serotonina 5-HT2A/efectos de los fármacos , 2,5-Dimetoxi-4-Metilanfetamina/administración & dosificación , Animales , Parpadeo/efectos de los fármacos , Condicionamiento Clásico/efectos de los fármacos , Alucinógenos/administración & dosificación , Alucinógenos/farmacología , Movimientos de la Cabeza/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Inyecciones , Aprendizaje/efectos de los fármacos , Dietilamida del Ácido Lisérgico/administración & dosificación , Metoxidimetiltriptaminas/administración & dosificación , Conejos , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2C/efectos de los fármacos , Agonistas de Receptores de Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
Although many drugs act by indirectly stimulating multiple receptors (e.g., reuptake inhibitors), relatively little is known about interactions between agonism at different receptors. This study compared the effect of serotonin (5-HT)(1A) receptor agonists with the discriminative stimulus effects of the 5-HT(2A) receptor agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) in rats and rhesus monkeys. Eight rats discriminated 0.56 mg/kg i.p. DOM and responded under a fixed ratio (FR) 10 schedule of food presentation, whereas three rhesus monkeys discriminated 0.32 mg/kg s.c. DOM and responded under an FR 5 schedule of stimulus shock termination. DOM and the 5-HT(2A) receptor agonists 2,5-dimethoxy-4-n-propylthiophenethylamine (2C-T-7) and dipropyltryptamine (DPT), but not the 5-HT(1A) receptor agonists 8-hydroxy-2-(di-n-propylamino) tetralin hydrochloride (8-OH-DPAT) and 3-chloro-4-fluorophenyl-(4-fluoro-4-([(5-methyl-6-methylaminopyridin-2-ylmethyl) amino) methyl] piperidin-1-yl) methanone (F13714), occasioned responding on the DOM-associated lever in rats and monkeys. Both 8-OH-DPAT and F13714 attenuated the discriminative stimulus effects of DOM in monkeys but not in rats; these effects of 8-OH-DPAT and F13714 were prevented by the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (WAY 100635). DPT and 2C-T-7 enhanced the discriminative stimulus effects of DOM in rats and monkeys in an additive manner. Taken together, the results suggest that the DOM discriminative stimulus is pharmacologically similar and mediated by 5-HT(2A) receptors in rats and monkeys; however, the ability of 5-HT(1A) receptor agonists to modify the effects of DOM is markedly different between these species. These results indicate possible differences in the neurobiology of 5-HT systems that could be important for studying drugs that have multiple mechanisms of action (e.g., reuptake inhibitors that indirectly stimulate multiple receptors).
Asunto(s)
2,5-Dimetoxi-4-Metilanfetamina/farmacología , Discriminación en Psicología/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT1 , Agonistas del Receptor de Serotonina 5-HT2 , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Aminopiridinas/farmacología , Animales , Interacciones Farmacológicas , Macaca mulatta , Masculino , Fenetilaminas/farmacología , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , Triptaminas/farmacologíaRESUMEN
Very little is known about constitutive activity in vivo. This study examined whether constitutive activity and inverse agonism contribute to discriminative stimulus effects of drugs acting at serotonin (5-HT)(2A) receptors. Rats were trained to discriminate between saline and either 0.56 mg/kg 5-HT(2) receptor agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), 1.0 mg/kg 5-HT(2A) receptor antagonist ketanserin, or 0.1 mg/kg purported 5-HT(2A) receptor inverse agonist (R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-pipidinemethanol (MDL100907). Discriminative control was established with each drug after 33 to 35 sessions. MDL100907 and ketanserin did not occasion DOM lever responding but attenuated the discriminative stimulus effects of DOM. DOM did not occasion responding on the drug-associated lever in rats discriminating MDL100907 or ketanserin, but attenuated the discriminative stimulus effects of both drugs. Ketanserin and ritanserin occasioned MDL100907-lever responding, whereas rats discriminating ketanserin responded only partially on the drug-associated lever after receiving MDL100907, ritanserin, or the alpha(1)-adrenergic antagonist prazosin. Combining prazosin with MDL100907 or ritanserin resulted in near-complete ketanserin-lever responding, indicating that the ketanserin stimulus involves both 5-HT(2A) and alpha(1)-adrenergic receptors. Administration of p-chlorophenylalanine methyl ester, then fenfluramine, significantly decreased cortical 5-HT, enhanced sensitivity to the discriminative stimulus effects of DOM, and occasioned partial MDL100907-lever responding. Collectively, these results show that DOM and MDL100907 discriminative stimulus effects are mediated by 5-HT(2A) receptors and that ketanserin discriminative stimulus effects involve both 5-HT(2A) and alpha(1)-adrenergic receptors. Results in 5-HT-depleted rats further suggest that the discriminative stimulus effects of MDL100907 might involve antagonism of endogenous 5-HT and/or inverse agonism at 5-HT(2A) receptors.
Asunto(s)
2,5-Dimetoxi-4-Metilanfetamina/farmacología , Fluorobencenos/farmacología , Ketanserina/farmacología , Piperidinas/farmacología , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Analgésicos Opioides/farmacología , Anestésicos Disociativos/farmacología , Animales , Condicionamiento Operante/efectos de los fármacos , Discriminación en Psicología/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/farmacología , Ketamina/farmacología , Masculino , Morfina/farmacología , Fenciclidina/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Ritanserina/farmacologíaRESUMEN
RATIONALE: There has been increased recreational use of dimethyltryptamine (DMT), but little is known of its discriminative stimulus effects. OBJECTIVES: The present study assessed the similarity of the discriminative stimulus effects of DMT to other types of hallucinogens and to psychostimulants. METHODS: Rats were trained to discriminate DMT from saline. To test the similarity of DMT to known hallucinogens, the ability of (+)-lysergic acid diethylamide (LSD), (-)-2,5-dimethoxy-4-methylamphetamine (DOM), (+)-methamphetamine, or (+/-)3,4-methylenedioxymethyl amphetamine (MDMA) to substitute in DMT-trained rats was tested. The ability of DMT to substitute in rats trained to discriminate each of these compounds was also tested. To assess the degree of similarity in discriminative stimulus effects, each of the compounds was tested for substitution in all of the other training groups. RESULTS: LSD, DOM, and MDMA all fully substituted in DMT-trained rats, whereas DMT fully substituted only in DOM-trained rats. Full cross-substitution occurred between DMT and DOM, LSD and DOM, and (+)-methamphetamine and MDMA. MDMA fully substituted for (+)-methamphetamine, DOM, and DMT, but only partially for LSD. In MDMA-trained rats, LSD and (+)-methamphetamine fully substituted, whereas DMT and DOM did not fully substitute. No cross-substitution was evident between (+)-methamphetamine and DMT, LSD, or DOM. CONCLUSIONS: DMT produces discriminative stimulus effects most similar to those of DOM, with some similarity to the discriminative stimulus effects of LSD and MDMA. Like DOM and LSD, DMT seems to produce predominately hallucinogenic-like discriminative stimulus effects and minimal psychostimulant effects, in contrast to MDMA which produced hallucinogen- and psychostimulant-like effects.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Aprendizaje Discriminativo/efectos de los fármacos , Alucinógenos/farmacología , N,N-Dimetiltriptamina/farmacología , 2,5-Dimetoxi-4-Metilanfetamina/farmacología , Animales , Conducta Animal/efectos de los fármacos , Dietilamida del Ácido Lisérgico/farmacología , Masculino , Metanfetamina/farmacología , N-Metil-3,4-metilenodioxianfetamina/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Co-administration of the 5-HT1A 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-HT1A 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-HT1A serotonin receptor mechanism might contribute to this phenomenon.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , 2,5-Dimetoxi-4-Metilanfetamina/farmacología , Aprendizaje Discriminativo/efectos de los fármacos , Discriminación en Psicología/efectos de los fármacos , Alucinógenos/farmacología , N-Metil-3,4-metilenodioxianfetamina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Animales , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Generalización del Estimulo/efectos de los fármacos , Isomerismo , Masculino , Piperazinas/farmacología , Ratas , Ratas Sprague-Dawley , Antagonistas de la SerotoninaRESUMEN
Discriminative stimulus effects of the serotonin (5-HT) receptor agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) have been studied in rats and, more recently, in rhesus monkeys. This study examined DOM, 2,5-dimethoxy-4-(n)-propylthiophenethylamine (2C-T-7), and dipropyltryptamine hydrochloride (DPT) alone and in combination with three antagonists, MDL100907 [(+/-)2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol]], ketanserin [3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-1H-quinazoline-2,4-dione], and ritanserin [6-[2-[4-[bis(4-fluorophenyl)methylidene]piperidin-1-yl]ethyl]-7-methyl-[1,3]thiazolo[2,3-b]pyrimidin-5-one], to identify the 5-HT receptor subtype(s) that mediates the discriminative stimulus effects of these 5-HT receptor agonists. Four adult rhesus monkeys discriminated between 0.32 mg/kg s.c. DOM and vehicle while responding under a fixed ratio 5 schedule of stimulus shock termination. DOM, 2C-T-7, and DPT dose-dependently increased responding on the DOM-associated lever. MDL100907 (0.001-0.01 mg/kg), ketanserin (0.01-0.1 mg/kg), and ritanserin (0.01-0.1 mg/kg) each shifted the dose-response curves of DOM, 2C-T-7, and DPT rightward in a parallel manner. Schild analysis of each drug combination was consistent with a simple, competitive, and reversible interaction. Similar apparent affinity (pA(2)) values were obtained for MDL100907 in combination with DOM (8.61), 2C-T-7 (8.58), or DPT (8.50), for ketanserin with DOM (7.67), 2C-T-7 (7.75), or DPT (7.71), and for ritanserin with DOM (7.65), 2C-T-7 (7.75), or DPT (7.65). Potency of antagonists in this study was correlated with binding affinity at 5-HT(2A) receptors and not at 5-HT(2C) or alpha(1) adrenergic receptors. This study used Schild analysis to examine receptor mechanisms mediating the discriminative stimulus effects of hallucinogenic drugs acting at 5-HT receptors; results provide quantitative evidence for the predominant, if not exclusive, role of 5-HT(2A) receptors in the discriminative stimulus effects of DOM, 2C-T-7, and DPT in rhesus monkeys.
Asunto(s)
2,5-Dimetoxi-4-Metilanfetamina/farmacología , Fluorobencenos/farmacología , Alucinógenos/farmacología , Piperidinas/farmacología , Receptores de Serotonina/fisiología , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , 2,5-Dimetoxi-4-Metilanfetamina/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Electrochoque , Alucinógenos/administración & dosificación , Ketanserina/farmacología , Macaca mulatta , Fenetilaminas/farmacología , Tiempo de Reacción/efectos de los fármacos , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Receptor de Serotonina 5-HT2C/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Análisis de Regresión , Ritanserina/farmacologíaRESUMEN
AL-38022A is a novel synthetic serotonergic (5-HT) ligand that exhibited high affinity for each of the 5-HT2 receptor subtypes (Ki
Asunto(s)
Benzopiranos/farmacología , Discriminación en Psicología/efectos de los fármacos , Indazoles/farmacología , Agonistas del Receptor de Serotonina 5-HT2 , Agonistas de Receptores de Serotonina/farmacología , 2,5-Dimetoxi-4-Metilanfetamina/farmacología , Agonistas de Receptores Adrenérgicos beta 2 , Animales , Señalización del Calcio/efectos de los fármacos , Química Física , Clonación Molecular , AMP Cíclico/biosíntesis , AMP Cíclico/genética , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Fluorobencenos/farmacología , Humanos , Técnicas In Vitro , Macaca mulatta , Masculino , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Receptor de Serotonina 5-HT2C/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/química , Estómago/efectos de los fármacosRESUMEN
The designer drugs 4-methyl-2,5-dimethoxy-amphetamine (DOM), 4-iodo-2,5-dimethoxy-amphetamine (DOI), 4-chloro-2,5-dimethoxy-amphetamine (DOC), 4-bromo-2,5-dimethoxy-amphetamine (DOB), 4-bromo-2,5-dimethoxy-methamphetamine (MDOB), and 2,4,5-trimethoxy-amphetamine (TMA-2) are potent serotonin 5HT(2) receptor agonists and have appeared on the illicit drug market. These drugs are mainly metabolized by O-demethylation or in case of DOM by hydroxylation of the methyl moiety. In an initial activity screening using microsomes of insect cells heterologously expressing human CYPs, CYP2D6 was found to be the only CYP isoenzyme involved in the above-mentioned main metabolic steps whereas the amounts of metabolites formed were very small. As inhibition of CYP2D6 by other amphetamines had been described, the inhibitory effects of the 2,5-dimethoxyamphetamine derivatives were studied using insect cell microsomes with heterologously expressed human CYP2D6 and pooled human liver microsomes (HLM) as enzyme sources and dextromethorphan O-demethylation as probe reaction. All studied drugs were observed to be non-mechanism-based competitive inhibitors of CYP2D6 with inhibition constants (K(i)) from 7.1 to 296microM using recombinant CYP2D6 and 2.7-19.9microM using HLM. For comparison, the K(i) values for quinidine and fluoxetine were 0.0092 and 8.2microM using recombinant CYP2D6 and 0.019 and 0.93microM using HLM. As the K(i) values of the drugs were much higher than that of quinidine and, with the exception of DOI, higher than that of fluoxetine, interactions with other CYP2D6 substrates are possible but rather unlikely.
Asunto(s)
Anfetaminas/farmacología , Inhibidores Enzimáticos del Citocromo P-450 , Drogas de Diseño/farmacología , 2,5-Dimetoxi-4-Metilanfetamina/análogos & derivados , 2,5-Dimetoxi-4-Metilanfetamina/química , 2,5-Dimetoxi-4-Metilanfetamina/metabolismo , 2,5-Dimetoxi-4-Metilanfetamina/farmacología , Algoritmos , Anfetaminas/química , Anfetaminas/metabolismo , Animales , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Inhibidores del Citocromo P-450 CYP2D6 , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Drogas de Diseño/química , Drogas de Diseño/metabolismo , Fluoxetina/química , Fluoxetina/metabolismo , Fluoxetina/farmacología , Cromatografía de Gases y Espectrometría de Masas , Humanos , Hidroxilación , Insectos/citología , Insectos/metabolismo , Cinética , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Estructura Molecular , Quinidina/química , Quinidina/metabolismo , Quinidina/farmacología , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
RATIONALE: The hallucinogenic tea known as ayahuasca is made from a combination of psychoactive plants that contribute the active components N,N-dimethyltryptamine (DMT) and 5-methoxy-DMT (5-MeO-DMT), as well as the monoamine oxidase (MAO) inhibitors (MAOIs) harmine and harmaline for oral activity. OBJECTIVE: The present study examined the effects of 5-MeO-DMT in combination with MAOIs in rats using the behavioral pattern monitor, which enables analyses of patterns of locomotor activity and exploration. Interaction studies using the serotonin (5-HT)(1A) antagonist WAY-100635 (1.0 mg/kg) and the 5-HT(2A) antagonist MDL 11,939 (1.0 mg/kg) were also performed to assess the respective contributions of these receptors to the behavioral effects of 5-MeO-DMT in MAOI-treated animals. RESULTS: 5-MeO-DMT (0.01, 0.1, and 1.0 mg/kg) decreased locomotor activity and investigatory behavior. In rats pretreated with a behaviorally inactive dose of harmaline (0.1 mg/kg), 1.0 mg/kg 5-MeO-DMT had biphasic effects on locomotor activity, initially reducing locomotion and then increasing activity as time progressed. The ability of harmaline to shift 5-MeO-DMT to a biphasic locomotor pattern was shared by the selective MAO(A) inhibitor clorgyline, whereas the selective MAO(B) inhibitor (-)-deprenyl was ineffective. The late hyperactivity induced by the combination of 1.0 mg/kg 5-MeO-DMT and 0.3 mg/kg clorgyline was blocked by pretreatment with MDL 11,939. Pretreatment with WAY-100635 failed to attenuate either the early hypoactivity or the late hyperactivity. CONCLUSIONS: The ability of harmaline to modify the behavioral effects of 5-MeO-DMT is mediated by the inhibition of MAO(A). Furthermore, 5-HT(2A) receptors are responsible for the late hyperactivity induced by 5-MeO-DMT in the presence of MAO(A) inhibitors.