The effect of repeated-intermittent exposure to 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) during adolescence on learning and memory in adult rats.

BACKGROUND: According to the European Drug Report, the use of novel psychoactive substances (NPS) is constantly growing. NPS are widely abused by human adolescent subjects. 5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) is one of the most frequently used hallucinogenic NPS. 5-MeO-DIPT intoxication results in hallucinations, vomiting, and tachycardia. Long-term exposure to 5-MeO-DIPT was reported to lead to development of post-hallucinogenic perception disorder. The aim of the present study was to determine whether repeated-intermittent administration of 5-MeO-DIPT during adolescence affects learning and memory in adult rats. METHODS: Rats were treated with 5-MeO-DIPT in a dose of 2.5mg/kg from 30 to 33 and 37 to 40 Postnatal Day (PND). The experiments were conducted when the animals reached 90 PND. The effect of 5-MeO-DIPT on cognitive functions was assessed using the novel object recognition, open field, and serial pattern learning (SPL) tests. RESULTS: Repeated-intermittent exposure to 5-MeO-DIPT during adolescence decreased the number of crossings in the open field test at adulthood. Moreover, 5-MeO-DIPT treatment impaired adult rats' learning in the SPL test. There was no change in the novel object recognition test. CONCLUSIONS: The present results show that the performance of adult rats treated with 5-MeO-DIPT during adolescence was impaired in the open field test, which indicates the attenuated exploratory activity. 5-MeO-DIPT treatment undermined adult rats' performance in the serial pattern learning test, suggesting impairment of long term memory and cognitive flexibility. The present study showed that the exposure to 5-MeO-DIPT during adolescence might lead to long-lasting behavioral changes which persisted long after the exposure period.

Neurotoxic Effects of 5-MeO-DIPT: A Psychoactive Tryptamine Derivative in Rats.

5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT, 'foxy') is one of the most popular tryptamine hallucinogens in the illicit drug market. It produces serious adverse effects, but its pharmacological profile is not well recognized. In vitro data have shown that 5-MeO-DIPT acts as a potent serotonin transporter (SERT) inhibitor and displays high affinity at serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors. In this study, using microdialysis in freely moving rats, we examined the effect of 5-MeO-DIPT on dopamine (DA), serotonin (5-HT), and glutamate release in the rat striatum, nucleus accumbens, and frontal cortex. In search of a possible neurotoxic effect of 5-MeO-DIPT, we measured DA and 5-HT tissue content in the above rat brain regions and also determined the oxidative DNA damage with the comet assay. Moreover, we tested drug-elicited head-twitch response and a forepaw treading induced by 8-OH-DPAT. 5-MeO-DIPT at doses of 5, 10, and 20 mg/kg increased extracellular DA, 5-HT, and glutamate level but the differences in the potency were found between brain regions. 5-MeO-DIPT increased 5-HT and decreased 5-HIAA tissue content which seems to result from SERT inhibition. On the other hand, a decrease in DA, DOPAC, and HVA tissue contents suggests possible adaptive changes in DA turnover or damage of DA terminals by 5-MeO-DIPT. DNA single and double-strand breaks persisted up to 60 days after the treatment, indicating marked neurotoxicity of 5-MeO-DIPT. The induction of head-twitch response and potentiation of forepaw treading induced by 8-OH-DPAT indicate that hallucinogenic activity seems to be mediated through the stimulation of 5-HT2A and 5-HT1A receptors by 5-MeO-DIPT.

Developmental exposure to a serotonin agonist produces subsequent behavioral and neurochemical changes in the adult male prairie vole.

Autistic spectrum disorders (ASDs) are classified as pervasive developmental disorders characterized by abnormalities in various cognitive and behavioral functions. Although exact underlying causes are still unknown, nearly 30% of autistic patients show elevated blood levels of serotonin (5-HT) and, therefore, various genetic and environmental factors that are known to elevate 5-HT levels may play a role in the development of ASDs. In the present study, we used the socially monogamous male prairie vole (Microtus ochrogaster) as an animal model to examine the effects of perinatal exposure to 5-methoxytryptamine (5-MT), a non-selective serotonin agonist, on subsequent behavioral and neurochemical changes in the brain. 5-MT treated males showed a decrease in affiliation and an increase in anxiety-related behavior, as well as a decrease in the density of 5-HT immunoreactive (ir) fibers in the amygdala and oxytocin-ir and vasopressin-ir cells in the paraventricular nucleus of the hypothalamus, compared to saline treated controls. These data indicate that exposure to 5-HT during early development can induce abnormalities in various neurochemical systems which, in turn, may underlie deficits in social and anxiety-related behaviors. In addition, these data will help to establish the prairie vole model to study the neurobiological underpinnings of complex neuropsychiatric disorders such as ASDs.

Inhibition of itch-related responses at spinal level in rats.

The goal was to develop a rat model for determination of the effects of intrathecally administered drugs on the peripherally induced pruritic behaviors. After chronic intrathecal catheterization, a serotonin derivative (5-methoxytryptamine: MeOT, 200 µg on both sides) was injected into the lower leg skin. After the first period (phase 0: 0-30 min) MeOT injection was repeated and opioid antagonist naltrexone (10 µg), NMDA receptor antagonists ketamine (10-100 µg), kynurenic acid (1-10 µg) or their combinations were injected intrathecally. The second observational period lasted for 60 min (phases I and II, 30-60 and 60-90 min, respectively). MeOT produced pruritic behavior with high degree of interindividual differences. The second MeOT injection caused an enhanced pruritic behavior in Phase I. Naltrexone decreased the pruritic activity, while neither doses of ketamine influenced the effects of MeOT. The higher doses of kynurenic acid resulted in notable decreases in the pruritic behavior. The combinations of naltrexone with ketamine or kynurenic acid produced a prolonged antipruritic effect. Our data suggest an important direction for the development of a new itch model in rats that focuses on the spinal mechanism of itching. Besides, the results revealed the role of the spinal opioid and NMDA receptors in this process.

Glucose and corticosterone changes in developing and adult rats following exposure to (+/-)-3,4-methylendioxymethamphetamine or 5-methoxydiisopropyltryptamine.

The use of the club drugs 3,4-methylenedioxymethamphetamine (MDMA) and 5-methoxy-n,n-diisopropyltryptamine (Foxy) is of growing concern, especially as many of the effects, particularly during development, are unknown. The effects of these drugs upon homeostasis may be important since both are known to stimulate the hypothalamic-pituitary-adrenal axis. The purpose of this experiment was to examine alterations in rats in corticosterone and glucose following an acute exposure to these drugs at different stages of development: preweaning, juvenile, and adulthood. Both MDMA and Foxy increased corticosterone levels significantly at all ages examined, while glucose was elevated at all stages except at the juvenile time point (postnatal day 28). For both measures, there were no differences between the sexes with either drug. The data indicate that an acute exposure to these drugs alters CORT and glucose levels, raising the possibility that these changes may have effects on behavioral and cognitive function, as we and others have previously demonstrated.

Neuropsychotoxicity of abused drugs: molecular and neural mechanisms of neuropsychotoxicity induced by methamphetamine, 3,4-methylenedioxymethamphetamine (ecstasy), and 5-methoxy-N,N-diisopropyltryptamine (foxy).

Psychostimulants including amphetamines and cocaine, opioids including morphine, and some recreational drugs share the ability to cause drug dependence and addiction. Although these drugs of abuse primarily act on distinct molecular targets, such as monoamine transporters or receptors, they finally converge to common neural pathways. Several lines of evidence suggest that their chronic treatment leads to the enhancement of the mesocorticolimbic dopaminergic neurons from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and the medial prefrontal cortex (mPFC) and leads to abnormal glutamatergic function from the mPFC to the NAc and VTA. The neural adaptation of dopaminergic-glutamatergic system is considered to be critically implicated in neuropsychotoxic effects of these drugs of abuse. In addition, recent studies suggest that the serotonergic neurons from the raphe nuclei to limbic areas modulate the mesocorticolimbic dopaminergic-glutamatergic system and participate in the neuropsychotoxicity. In this review, our recent in vitro studies on the molecular targets and neural adaptation of methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"), and 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DiPT, "foxy") using Xenopus oocytes, organotypic slice cultures of the mesocorticolimbic dopaminergic-glutamatergic system, and the raphe serotonergic system are introduced.

An examination of the effects of 5-Methoxy-n, n-di(ISO)propyltryptamine hydrochloride (Foxy) on cognitive development in rats.

The hallucinogenic "designer drug" known as Foxy or Methoxy Foxy and formally know as 5-Methoxy-N,N-di(iso)propyltryptamine hydrochloride (5-MeO-DIPT) is rapidly gaining popularity among recreational users. However, little is known about the consequences of its use on neuropsychological development or behavior. During one of two adolescent periods, the rats were given repeated injections of either saline or 5 mg/kg of 5-MeO-DIPT. Once the animals reached 80 days of age, they were trained and tested on a number of tasks designed to assess the effects of 5-MeO-DIPT, if any, on memory tasks with spatial components that presumably involve declarative memory systems and on a nonspatial task that is considered sensitive to disruptions in nondeclarative memory. With one exception, both the 5-MeO-DIPT- and saline-treated rats were able to master the spatial navigation tests at comparable rates. However, the performance of the drug-treated rats was markedly inferior to that of the control animals on a response-learning task, suggesting a lack of flexibility in adapting their responses to changing task demands. This could indicate reductions in serotonin activity in the forebrain similar to the effects of studied drugs such as methylenedioxymethamphetamine (MDMA), suggesting 5-MeO-DIPT may act as a toxin compromising serotoninergic systems in the brain.

[Evaluation of the toxicity of indorenate on reproduction]. / Evaluación de la toxicidad del indorrenato sobre la reproduccion.

Indorenate (TR3369) a new antihypertensive drug, was examined for effects upon general reproductive performance, for peri-postnatal and embryofetal toxicity in the rat at doses of 0, 10, 20, 40 and 60 mg/kg/day by oral administration. Excluding the 60 mg/kg dose, in the fertility study, any dose produced neither decrement of body weight gain of progenitors, fertility, fetal weight nor survival rate. Retardation of the surface righting, pinnal unfolding or startle response were not observed. On the other hand, 40 and 60 mg/kg significantly increased the number of resorptions. In the peri-postnatal study, doses of 40 and 60 mg/kg incremented the number of dead pups at birth, and the later also affected the survival rate, growing and air righting reflex. Reproductive performance of the F1 offsprings was unimpaired. Indorenate in contrast to serotonin, from which it is a structural derivative, gave no evidence of teratogenicity when administered during the period of organogenesis. It was concluded that the parameters of fetal development were not affected by doses of up to 20 mg/kg, which represents approximately 1200 times the proposed dose for hypertensive patients.

Evaluation of the teratological potential of the new antihypertensive 5-methoxytryptamine, beta-methylcarboxylate hydrochloride (indorenate) in mice.

5-Methoxytryptamine, beta-methylcarboxylate hydrochloride (indorenate), a new antihypertensive agent, was examined for teratogenic-embryotoxic effects in the mouse at doses of 0 (control), 10, 20, 40, and 80 mg/kg/day. The compound was administered by gastric intubation on days 6-15 of gestation. On day 17, the dams were sacrificed, the number of live, dead, and resorbed fetuses recorded and mean pup weight determined. Teratological evaluation was carried out by visual inspection, alizarin red staining of the skeleton and Wilson's sections. Signs of overtoxicity in mothers were found in the high-dose groups. There were no differences between control and indorenate-treated groups in the number of implantations, live fetuses or anomalies. However, an embryotoxic effect was observed at 40 and 80 mg/kg, shown by increased resorptions and lower weight of pups at the higher dose.

Development of pre-implantation mouse embryos under the influence of pineal indoles.

The developmental toxicity of pineal hormones on mouse embryos was examined both in vitro and in vivo. Pregnant ICR mice were divided into groups which received at 1.5 days post-coitum (p.c.) and again at 2.5 days p.c. a subcutaneous injection of one of the following pineal indoles: hydroxyindoleacetic acid (HIAA), melatonin (MEL), methoxytryptophol (MTP) or methoxytryptamine (MTA). Mice treated with the injection vehicle served as the control. The animals were sacrificed at 17.5 days p.c. The pineal indole treatment did not cause changes in the gravid uterine weight, numbers of implants, early resorption, late resorption, dead fetuses and live fetuses, fetal weight or fetal crown-rump length, and did not produce embryos with external or visceral defects. However, some mice treated with MTP or MTA produced litters in which all embryos underwent resorption. Cultured embryos at the 4-cell stage were treated with the aforementioned pineal indoles and examined after 24, 48, 72 and 96 hours. It was found that MTA retarded embryonic development at all time points studied. HIAA also produced a slight inhibitory effect on embryonic development. Some embryos underwent degeneration in response to the MTA and HIAA treatments. However, MEL- and MTP-treated embryos were in general developmentally similar to control embryos. When cultured embryos were treated at the 8-cell to compacting stage, it was found that MTA exerted only a slight retarding effect on embryonic development, while other indoles were devoid of any conspicuous effects.

5-Hydroxytryptamine is emetogenic in the house musk shrew, Suncus murinus.

The emetic effects of 5-hydroxytryptamine (5-HT) and 5-HT3 receptor agonists were investigated in the house musk shrew, Suncus murinus. 5-Hydroxytryptamine (5-HT; i.p., i.v., s.c.) and 2-methyl-5-HT (2-Me-5-HT; i.p.) but not 5-hydroxyindoleacetic acid (i.p.) or 5-methoxytryptamine (i.p.) induced emesis with very short latency. Tropisetron (ICS 205-930, a 5-HT3 receptor antagonist, s.c.) blocked the emesis induced by 5-HT (10 mg/kg, i.p.) and 2-Me-5-HT (5 mg/kg, i.p.) with respective ID50 values of 7.8 and 70.9 micrograms/kg. Pindolol (5-HT1 receptor antagonist) and ketanserin (5-HT2 receptor antagonist) were about 100 times less potent than tropisetron. The emesis induced by 5-HT was prevented by surgical vagotomy but not by pretreatment with a combination of atropine (0.1 mg/kg, s.c.) and hexamethonium (10 mg/kg, s.c.). These results clearly indicate that 5-HT is emetogenic probably through a stimulation of peripheral 5-HT3 receptors.

Plasma concentrations of 5-methoxytryptamine, 5-methoxytryptophol and melatonin after 5-methoxytryptamine administration of golden hamsters: physiological implications.

5-Methoxytryptamine (5-MT), 5-methoxytryptophol (5-ML) and melatonin (Mel) were measured in the plasma after 2, 5, and 8 weeks administration of 25 micrograms 5-MT to golden hamsters kept under long photoperiod. 5-MT showed a one compartment kinetic profile in the plasma with half lives of 14.8 min after 2 weeks, 15 min after 5 weeks and 19.1 min after 8 weeks. A rapid metabolism of 5-MT was shown, Mel and 5-ML being detected in the plasma following 5-MT administration. However it was also shown that the gonadal atrophy observed after 5-MT administration cannot be due to its metabolism into these 2 compounds. Indeed when exogenously administered at a dose generating the same plasma concentration as that observed after 5-MT, the gonadal regression observed after the association of 5-ML and Mel is much less than that observed after 5-MT. 5-MT is thus a compound of great physiological interest.

[The radioprotective properties of the liposomal form of mexamine]. / Radiozashchitnye svoistva liposomnoi formy meksamina.

Encapsulation of mexamine (5 methoxytryptamine) in large monostratal lecithin-cholesterol liposomes was shown to cause a 1.4-fold reduction of acute toxicity of the preparation and to prolong its radioprotective efficacy from 15 min to 2 h.

In vivo and in vitro genotoxic evaluation of indorenate.

5-Methoxytryptamine, beta-methylcarboxylate hydrochloride (indorenate) is a new antihypertensive serotonin derivative. We evaluated its genotoxic activity using the mouse bone marrow and cytogenetic test and the human lymphocyte culture cytogenetic assay. As endpoints we measured chromosomal aberrations, sister-chromatid exchanges and cellular proliferation kinetics. Our results agree in both systems showing that indorenate is a non-genotoxic agent in these assays.

[Radioprotective effectiveness and toxicity of 4,5-disubstituted tryptamines]. / Radiozashchitnaia éffektivnost' i toksichnost' 4,5-dizameshchennykh triptaminov.

In experiments on mice a study was made of different substituents in the 4th position of the indole ring of 5-methoxytryptamines (5-MOT) on toxicity and radioprotective efficiency of the compounds of this class. It was shown that the administration of the amino-group to a mexamine molecule increased the preparation toxicity; the nitro-group somewhat diminished the toxic properties, and the acetylamino group did not change 5-MOT toxicity. A 5-MOT derivative with a nitro group possessed the strongest radioprotective action. The radioprotective efficiency of these compounds persisted for 1-2 h.

[Blastomogenic activity of biogenic methoxyindoles]. / Blastomogennaia aktivnost' biogennykh metoksiindolov.

A considerable blastogenic activity of biogenic methoxyindoles--melatonin, 5-methoxytryptamine (5-MOT) and their common metabolite--5-methoxyindolyl-3-acetic acid (5-MIAA) was established by prolonged s.c. injection in C57BL/6 mice. However, the blastogenic effect of 5-MOT decreased by 26% when its further metabolism to 5-MIAA was blocked for some time and the synthesis of its carcinogenic metabolite was inhibited. These results showed that the blastogenic effect of 5-MOT is not direct; and it is mediated by its transformation to 5-MIAA in the body.

[Carcinogenic action of 5-methoxytryptamine related to its transformation into 5-methoxyindolyl-3-acetic acid]. / Kantserogennoe deistvie 5-metoksitriptamina, sviazannoe s ego prevrashcheniem v 5-metoksiindolil-3-uksusnuiu kisloty.

A considerable blastomogenic effect of metabolite serotonin 5-methoxytryptamine (5-MOT) subcutaneously administered for a long time to C57BL/6 mice was established. This effect was decreased noticeably if the further metabolism of 5-MOT into 5-methoxyindolyl-3-acetic acid (5-MIAA) was blocked by pyrazidol. These results explain the fact that the blastomogenic effect of 5-MOT is not direct but is caused by the transformation of 5-MOT into its final carcinogenic metabolite 5-MIAA.

[Study of antihypoxic properties and toxicity of mexamine (5-methoxytryptamine)]. / Izuchenie antigipoksicheskikh svoistv i toksichnosti meksamina (5-metoksitriptamina).

On its introduction to mongrel albino mice in doses of 1 to 200 mg/kg mexamine (5-methoxytryptamine) exerted a marked antihypoxic action in conditions of hypoxic hypoxia (a "rise" in the pressure chamber to an altitude of 8000 to 10 000 m) 5--180 minutes after administration of the drug. The possibility of reducing the toxicity of mexamine through preventive introduction of the agent in a dose of 1 mg/kg was established. With such a modification of the toxicity no mitigation of the antihypoxic effectiveness of the basic dose of the agent is observed.

[A pool hemopoietic stem cells and resistance of mice to toxic substances depending upon food rations]. / Pul krovetvornykh stvolovykh kletok i ustoichivost' myshei k toksicheskim veshchestvam v zavisnmosti ot kachestva pischevykh ratsionov

Tests set up on male-mice of the CBA/I lineage demonstrated that fat carbohydrate rations of 1:7.3 and 1:3.8 in granulated combined fodder tend to increase the number of stem cells in a statistically fashion. Among mongrel mice kept on a ration with 7 per cent of fat a combination of mexamine with AET was found to loose some of its toxicity.