Hallucinogenic activity, neurotransmitters release, anxiolytic and neurotoxic effects in Rat's brain following repeated administration of novel psychoactive compound 25B-NBOMe.

2-(4-Bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)etanoamine (25B-NBOMe) is a highly selective 5-HT2A receptor agonist, exhibiting a potent hallucinogenic activity. In the present study, we investigated the effect of a 7-day treatment with 25B-NBOMe in a dose of 0.3 mg/kg on the following: the neurotransmitter release in vivo using microdialysis in freely moving animals, hallucinogenic activity measured in the Wet Dog Shake (WDS) test, anxiety level as measured in the light/dark box (LDB) and locomotor activity in the open field (OF) test, DNA damage with the comet assay, and on a number of neuronal and glial cells with immunohistochemistry. Repeated administration of 25B-NBOMe decreased the response to a challenge dose (0.3 mg/kg) on DA, 5-HT and glutamatergic neurons in the rats' frontal cortex, striatum, and nucleus accumbens. The WDS response dropped drastically after the second day of treatment, suggesting a rapid development of tolerance. LDB and OF tests showed that the effect of 25B-NBOMe on anxiety depends on the treatment and environmental settings. Results obtained with the comet assay indicate a genotoxic properties in the frontal cortex and hippocampus. An increase in immunopositive glial but not neuronal cells was observed in the cortical regions but not in the hippocampus. In conclusion, our study showed that a chronic administration of 25B-NBOMe produces the development of tolerance observed in the neurotransmitters release and hallucinogenic activity. The oxidative damage of cortical and hippocampal DNA implies the generation of free radicals by the drug, resulting in genotoxicity but rather not in neurotoxic tissue damage. Behavioral tests show that 25B-NBOMe exerts anxiogenic effect after single and repeated treatment.

Limbic System Response to Psilocybin and Ketamine Administration in Rats: A Neurochemical and Behavioral Study.

The pathophysiology of depression is related to the reduced volume of the hippocampus and amygdala and hypertrophy of the nucleus accumbens. The mechanism of these changes is not well understood; however, clinical studies have shown that the administration of the fast-acting antidepressant ketamine reversed the decrease in hippocampus and amygdala volume in depressed patients, and the magnitude of this effect correlated with the reduction in depressive symptoms. In the present study, we attempted to find out whether the psychedelic substance psilocybin affects neurotransmission in the limbic system in comparison to ketamine. Psilocybin and ketamine increased the release of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens of naive rats as demonstrated using microdialysis. Both drugs influenced glutamate and GABA release in the nucleus accumbens, hippocampus and amygdala and increased ACh levels in the hippocampus. The changes in D2, 5-HT1A and 5-HT2A receptor density in the nucleus accumbens and hippocampus were observed as a long-lasting effect. A marked anxiolytic effect of psilocybin in the acute phase and 24 h post-treatment was shown in the open field test. These data provide the neurobiological background for psilocybin's effect on stress, anxiety and structural changes in the limbic system and translate into the antidepressant effect of psilocybin in depressed patients.

Molecular and Medical Aspects of Psychedelics.

Psychedelics belong to the oldest psychoactive drugs. They arouse recent interest due to their therapeutic applications in the treatment of major depressive disorder, substance use disorder, end-of-life anxiety,= and anxiety symptoms, and obsessive-compulsive disorder. In this review, the current state of preclinical research on the mechanism of action, neurotoxicity, and behavioral impact of psychedelics is summarized. The effect of selective 5-HT2A receptor agonists, 25I- and 25B-NBOMe, after acute and repeated administration is characterized and compared with the effects of a less selective drug, psilocybin. The data show a significant effect of NBOMes on glutamatergic, dopaminergic, serotonergic, and cholinergic neurotransmission in the frontal cortex, striatum, and nucleus accumbens. The increases in extracellular levels of neurotransmitters were not dose-dependent, which most likely resulted from the stimulation of the 5-HT2A receptor and subsequent activation of the 5-HT2C receptors. This effect was also observed in the wet dog shake test and locomotor activity. Chronic administration of NBOMes elicited rapid development of tolerance, genotoxicity, and activation of microglia. Acute treatment with psilocybin affected monoaminergic and aminoacidic neurotransmitters in the frontal cortex, nucleus accumbens, and hippocampus but not in the amygdala. Psilocybin exhibited anxiolytic properties resulting from intensification of GABAergic neurotransmission. The data indicate that NBOMes as selective 5-HT2A agonists exert a significant effect on neurotransmission and behavior of rats while also inducing oxidative DNA damage. In contrast to NBOMes, the effects induced by psilocybin suggest a broader therapeutic index of this drug.

Effect of Psilocybin and Ketamine on Brain Neurotransmitters, Glutamate Receptors, DNA and Rat Behavior.

Clinical studies provide evidence that ketamine and psilocybin could be used as fast-acting antidepressants, though their mechanisms and toxicity are still not fully understood. To address this issue, we have examined the effect of a single administration of ketamine and psilocybin on the extracellular levels of neurotransmitters in the rat frontal cortex and reticular nucleus of the thalamus using microdialysis. The genotoxic effect and density of glutamate receptor proteins was measured with comet assay and Western blot, respectively. An open field test, light-dark box test and forced swim test were conducted to examine rat behavior 24 h after drug administration. Ketamine (10 mg/kg) and psilocybin (2 and 10 mg/kg) increased dopamine, serotonin, glutamate and GABA extracellular levels in the frontal cortex, while psilocybin also increased GABA in the reticular nucleus of the thalamus. Oxidative DNA damage due to psilocybin was observed in the frontal cortex and from both drugs in the hippocampus. NR2A subunit levels were increased after psilocybin (10 mg/kg). Behavioral tests showed no antidepressant or anxiolytic effects, and only ketamine suppressed rat locomotor activity. The observed changes in neurotransmission might lead to genotoxicity and increased NR2A levels, while not markedly affecting animal behavior.

Effect of -NBOMe Compounds on Sensorimotor, Motor, and Prepulse Inhibition Responses in Mice in Comparison With the 2C Analogs and Lysergic Acid Diethylamide: From Preclinical Evidence to Forensic Implication in Driving Under the Influence of Drugs.

In the last decade, the market for new psychoactive substances has been enriched by numerous psychedelic phenethylamines, which mimic the psychoactive effect of lysergic acid diethylamide (LSD). In particular, the -NBOMe series, which are more potent than their 2C compounds analogs, are considered worthy substitutes for LSD by users. The purpose of this study was to assess the effects of 25H-NBOMe and its halogenated derivatives (25I-NBOMe and 25B-NBOMe) in comparison to their 2C compounds analogs and LSD on the sensorimotor (visual, acoustic, and overall tactile), reaction time, spontaneous (total distance traveled) and stimulated (drag, accelerod test) motor activity, grip strength test, and prepulse inhibition (PPI) responses in mice. Systemic administration of -NBOMe, 2C compounds analogs, and LSD (0.001-10 mg/kg) differently impaired the sensorimotor, reaction time, motor, and PPI responses in mice. In particular, halogenated (25I and 25B)-NBOMe derivatives appear to be more effective than the entire class of 2C compounds analogs in altering visual and acoustic responses, affecting reaction time, and motor and sensory gating in PPI test. In fact, the specific rank order of compounds potency for nearly all of the experiments showed that (25I and 25B)-NBOMe were more potent than 2C compounds analogs and LSD. -NBOMe and 2C compounds analogs impaired not only the reception of incoming sensory stimuli (visual and acoustic), but their correct brain processing (PPI) in an equal and sometimes stronger way than LSD. This sensory impairment directly affected the spontaneous motor response and reaction time of mice, with no change in performance in stimulated motor activity tests. These aspects should be carefully considered to better understand the potential danger that psychedelic phenethylamines, in particular -NBOMe, may pose to public health, with particular reference to decreased performance in driving and hazardous works that require special sensorimotor skills.

Neurotoxicological profile of the hallucinogenic compound 25I-NBOMe.

4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25I-NBOMe) is a new psychoactive substance with strong hallucinogenic properties. Our previous data reported increased release of dopamine, serotonin, and glutamate after acute injections and a tolerance development in the neurotransmitters release and rats' behavior after chronic treatment with 25I-NBOMe. The recreational use of 25I-NBOMe is associated with severe intoxication and deaths in humans. There is no data about 25I-NBOMe in vivo toxicity towards the brain tissue. In this article 25I-NBOMe-crossing through the blood-brain barrier (BBB), the impact on DNA damage, apoptosis induction, and changes in the number of cortical and hippocampal cells were studied. The presence of 25I-NBOMe in several brain regions shortly after the drug administration and its accumulation after multiple injections was found. The DNA damage was detected 72 h after the chronic treatment. On the contrary, at the same time point apoptotic signal was not identified. A decrease in the number of glial but not in neural cells in the frontal (FC) and medial prefrontal cortex (mPFC) was observed. The obtained data indicate that 25I-NBOMe passes easily across the BBB and accumulates in the brain tissue. Observed oxidative DNA damage may lead to the glial cells' death.

Neurotoxicity of MDMA: Main effects and mechanisms.

Preclinical and clinical studies indicate that 3,4-methylenedioxymethamphetamine (MDMA; 'ecstasy'), in addition to having abuse potential, may elicit acute and persistent abnormalities of varying severity at the central level. Importantly, neurotoxic effects of MDMA have been demonstrated in experimental animals. Accordingly, central toxicity induced by MDMA may pose a serious harm for health, since MDMA is among the substances that are used for recreational purposes by young and adult people. This review provides a concise overview of recent findings from preclinical and clinical studies that evaluated the central effects of MDMA, and the mechanisms involved in the neurotoxicity induced by this amphetamine-related drug.

Tolerance to neurochemical and behavioral effects of the hallucinogen 25I-NBOMe.

RATIONALE: 4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25I-NBOMe) is a potent serotonin 5-HT2A/2C receptor agonist with hallucinogenic activity. There is no data on the 25I-NBOMe effect on brain neurotransmission and animal performance after chronic administration. OBJECTIVES: We examined the effect of a 7-day treatment with 25I-NBOMe (0.3 mg/kg/day) on neurotransmitters' release and rats' behavior in comparison to acute dose. METHODS: Changes in dopamine (DA), serotonin (5-HT), acetylcholine (ACh), and glutamate release were studied using microdialysis in freely moving rats. The hallucinogenic activity was measured in the wet dog shake (WDS) test. The animal locomotion was examined in the open field (OF) test, short-term memory in the novel object recognition (NOR) test. The anxiogenic/anxiolytic properties of the drug were tested using the light/dark box (LDB) test. RESULTS: Repeated administration of 25I-NBOMe decreased the response to a challenge dose of DA, 5-HT, and glutamatergic neurons in the frontal cortex as well as weakened the hallucinogenic activity in comparison to acute dose. In contrast, striatal and accumbal DA and 5-HT release and accumbal but not striatal glutamate release in response to the challenge dose of 25I-NBOMe was increased in comparison to acute treatment. The ACh release was increased in all brain regions. Behavioral tests showed a motor activity reduction and memory deficiency in comparison to a single dose and induction of anxiety after the drug's chronic and acute administration. CONCLUSIONS: Our findings suggest that multiple injections of 25I-NBOMe induce tolerance to hallucinogenic activity and produce alterations in neurotransmission. 25I-NBOMe effect on short-term memory, locomotor function, and anxiety seems to be the result of complex interactions between neurotransmitter pathways.

Neurochemical and Behavioral Effects of a New Hallucinogenic Compound 25B-NBOMe in Rats.

4-Bromo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25B-NBOMe) is a hallucinogen exhibiting high binding affinity for 5-HT2A/C serotonin receptors. In the present work, we investigated its effect on dopamine (DA), serotonin (5-HT), acetylcholine (ACh), and glutamate release in the rat frontal cortex, striatum, and nucleus accumbens. Hallucinogenic activity, impact on cognitive and motor functions, and anxiogenic/anxiolytic properties of this compound were also tested. The release of DA, 5-HT, ACh, and glutamate was studied using microdialysis in freely moving animals. Hallucinogenic activity was investigated using head and body twitch response (WDS), cognitive functions were examined with the novel object recognition test (NOR), locomotor activity was studied in the open field (OF), while anxiogenic/anxiolytic effect was tested using the light/dark box (LDB). Neurotoxicity was evaluated with the comet assay. 25B-NBOMe increased DA, 5-HT, and glutamate release in all studied brain regions, induced hallucinogenic activity, and lowered the recognition index (Ri) vs. control in the NOR test. It also decreased locomotor activity of rats in the OF test. The effect of 25B-NBOMe in the NOR test was inhibited by scopolamine. In the LDB test, the time spent in the dark zone was longer in comparison to control and was dose-dependent. In contrast to MDMA, 25B-NBOMe showed subtle genotoxic effect observed in the comet assay.Our findings indicate that 25B-NBOMe shows hallucinogenic activity in the wide range of doses. The changes in neurotransmitter levels may be related to 25B-NBOMe affinity for 5-HT2A receptor. Alterations in the NOR, OF, and LDB indicate that 25B-NBOMe impacts short-term memory, locomotion, and may be anxiogenic.

Contribution of serotonin receptor subtypes to hallucinogenic activity of 25I-NBOMe and to its effect on neurotransmission.

BACKGROUND: 4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25I-NBOMe) is a potent serotonin (5-HT) receptor agonist with hallucinogenic properties. The aim of our research was to examine the role of the 5-HT2A, 5-HT2C and 5-HT1A serotonin receptor subtypes in 25I-NBOMe hallucinogenic activity and its effect on dopamine (DA), 5-HT and glutamate release in the rat frontal cortex. METHODS: Hallucinogenic activity was investigated using the wet dog shake (WDS) test. The release of DA, 5-HT and glutamate in the rat frontal cortex was studied using a microdialysis in freely moving rats. Neurotransmitter levels were analyzed by HPLC with electrochemical detection. The selective antagonists of the 5-HT2A, 5-HT2C and 5-HT1A serotonin receptor subtypes: M100907, SB242084 and WAY100635, respectively were applied through a microdialysis probe. RESULTS: The WDS response to 25I-NBOMe (1 and 3 mg/kg) was significantly reduced by local administration of M100907 and SB242084 (100 nM). The 25I-NBOMe-induced increase in glutamate, DA and 5-HT release was inhibited by M100907 and SB242084. WAY100635 had no effect on 25I-NBOMe-induced WDS and glutamate release, while it decreased DA and 5-HT release from cortical neuronal terminals. CONCLUSION: The obtained results suggest that 5-HT2A and 5-HT2C receptors play a role in 25I-NBOMe-induced hallucinogenic activity and in glutamate, DA and 5-HT release in the rat frontal cortex as their respective antagonists attenuated the effect of this hallucinogen. The disinhibition of GABA cells by the 5-HT1A receptor antagonist seems to underlie the mechanism of decreased DA and 5-HT release from neuronal terminals in the frontal cortex.

Functional characterization of a novel opioid, PZM21, and its effects on the behavioural responses to morphine.

BACKGROUND AND PURPOSE: The concept of opioid ligands biased towards the G protein pathway with minimal recruitment of ß-arrestin-2 is a promising approach for the development of novel, efficient, and potentially nonaddictive opioid therapeutics. A recently discovered biased µ-opioid receptor agonist, PZM21, showed analgesic effects with reduced side effects. Here, we aimed to further investigate the behavioural and biochemical properties of PZM21. EXPERIMENT APPROACH: We evaluated antinociceptive effects of systemic and intrathecal PZM21 administration. Its addiction-like properties were determined using several behavioural approaches: conditioned place preference, locomotor sensitization, precipitated withdrawal, and self-administration. Also, effects of PZM21 on morphine-induced antinociception, tolerance, and reward were assessed. Effects of PZM21 on striatal release of monoamines were evaluated using brain microdialysis. KEY RESULTS: PZM21 caused long-lasting dose-dependent antinociception. It did not induce reward- and reinforcement-related behaviour; however, its repeated administration led to antinociceptive tolerance and naloxone-precipitated withdrawal symptoms. Pretreatment with PZM21 enhanced morphine-induced antinociception and attenuated the expression of morphine reward. In comparison to morphine, PZM21 administration induced a moderate release of dopamine and a robust release of 5-HT in the striatum. CONCLUSIONS AND IMPLICATIONS: PZM21 exhibited antinociceptive efficacy, without rewarding or reinforcing properties. However, its clinical application may be restricted, as it induces tolerance and withdrawal symptoms. Notably, its ability to diminish morphine reward implies that PZM21 may be useful in treatment of opioid use disorders.

Hallucinogen-Like Action of the Novel Designer Drug 25I-NBOMe and Its Effect on Cortical Neurotransmitters in Rats.

NBOMes are N-benzylmethoxy derivatives of the 2C family hallucinogens. 4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25I-NBOMe) is one of the commonly used illicit drugs. It exhibits high binding affinity for 5-HT2A/C and 5-HT1A serotonin receptors. Activation of 5-HT2A receptor induces head-twitch response (HTR) in rodents, a behavioral marker of hallucinogen effect in humans. There is not much data on neurochemical properties of NBOMes. Therefore, we aimed to investigate the effect of 25I-NBOMe on extracellular level of dopamine (DA), serotonin (5-HT), and glutamate (GLU) in the rat frontal cortex, tissue contents of monoamines, and hallucinogenic activity in rats. The extracellular levels of DA, 5-HT, and GLU were studied using microdialysis in freely moving animals. The tissue contents of DA, 5-HT and their metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were determined in the rat frontal cortex. We also tested a drug-elicited HTR. 25I-NBOMe at doses 1, 3, and 10 mg/kg (sc) increased extracellular DA, 5-HT, and GLU levels, enhanced tissue content of 5-HT and 5-HIAA, but did not affect tissue level of DA and its metabolites. The compound exhibited an inverted U-shaped dose-response curve with respect to the effect on extracellular DA and 5-HT levels, but a U-shaped dose-response curve was observed for its effect on GLU release and HTR. The data from our study suggest that hallucinogenic activity of 25I-NBOMe seems to be related with the increase in extracellular GLU level-mediated via cortical 5-HT2A receptors. The influence of 25I-NBOMe on 5-HT2C and 5-HT1A receptors may modulate its effect on neurotransmitters and HTR.

Correction to: the Effects of Exposure to Mephedrone During Adolescence on Brain Neurotransmission and Neurotoxicity in Adult Rats.

Acknowledgments: This study was supported by the Grant No 2013/09/B/NZ7/04104 from the National Science Center (Poland).

Effects of exposure to 5-MeO-DIPT during adolescence on brain neurotransmission and neurotoxicity in adult rats.

PURPOSE: Tryptamine hallucinogen 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) is a serotonin transporter inhibitor with high affinity for serotonin 5-HT1A and 5-HT2A/C receptors. We showed previously that 5-MeO-DIPT in a single dose increased neurotransmitter release in brain regions of rats and elicited single- and double-strand DNA breaks. Herein we investigated the effects of repeated-intermittent 5-MeO-DIPT administration in adolescence on dopamine (DA), serotonin (5-HT) and glutamate release in brain regions of adult rats. Furthermore, we examined caspase-3 activity, oxidative DNA damage, the Gpx3, Sod1, Ht1a and Ht2a mRNA expression levels, and cell viability. METHODS: Neurotransmitter release was measured by microdialysis in freely moving animals. Caspase-3 activity was assessed colorimetrically, and oxidative DNA damage with the comet assay, while the Gpx3, Sod1, Ht1a and Ht2a mRNA expression levels were assessed by real-time polymerase chain reaction. Cell viability was studied in SH-SY5Y and Hep G2 cells by the MTT test. RESULTS: We observed changed responses of DA, 5-HT and glutamate neurons to a challenge dose of 5-MeO-DIPT when animals were treated repeatedly in adolescence with this hallucinogen. The basal extracellular levels of DA and 5-HT were decreased in the striatum and nucleus accumbens, while glutamate level was increased in the nucleus accumbens and frontal cortex. The damage of cortical DNA, increased Gpx3 and Sod1 mRNA expression and affected caspase-3 activity were also observed. Furthermore, decreased Ht1a and Ht2a mRNA expression in the frontal cortex and marked cytotoxicity of 5-MeO-DIPT were found. CONCLUSIONS: These results suggest that 5-MeO-DIPT given repeatedly during adolescence affects brain neurotransmission and shows neurotoxic potential observed in adult animals.

Methcathinone and 3-Fluoromethcathinone Stimulate Spontaneous Horizontal Locomotor Activity in Mice and Elevate Extracellular Dopamine and Serotonin Levels in the Mouse Striatum.

Methcathinone (MC) and 3-fluoromethcathinone (3-FMC) are well-known members of the synthetic cathinone derivatives, the second most abused group of novel psychoactive substances (NPS). They are considered as methamphetamine-like cathinones, as they elicit their psychostimulatory effects via inhibition of monoamine uptake and enhanced release. The present study examines the effects of MC and 3-FMC on the spontaneous locomotor activity of mice and extracellular levels of dopamine and serotonin in the mouse striatum. Both MC and 3-FMC produced a dose-dependent increase of horizontal locomotor activity, but no significant changes in rearing behavior were observed. The locomotor stimulation induced by MC and 3-FMC is mediated by activation of dopaminergic neurotransmission, as selective D1-dopamine receptor antagonist, SCH 23390, abolished the effects of both drugs. In line with pharmacological data obtained by previous in vitro studies, MC and 3-FMC produced potent increases of extracellular dopamine and serotonin levels in the mouse striatum. Taken together, results presented within this study confirm previous findings and expand our knowledge on the pharmacology of MC and 3-FMC along with their behavioral effects.

The effect of chronic co-treatment with risperidone and novel antidepressant drugs on the dopamine and serotonin levels in the rats frontal cortex.

BACKGROUND: Preclinical and clinical studies have suggested a beneficial effect of combination treatment with atypical antipsychotic drugs and antidepressants (ADs) in schizophrenia and in drug-resistant depression. METHODS: In the present study, we investigated the effect of chronic administration of risperidone and ADs (escitalopram or mirtazapine), given separately or jointly on the extracellular levels of dopamine (DA) and serotonin (5-HT) in the rat frontal cortex. The animals were administered risperidone (0.2mg/kg) and escitalopram (5mg/kg) or mirtazapine (10mg/kg) repeatedly for 14days. The release of monoamines in the rat frontal cortex was evaluated using a microdialysis, and DA and 5-HT levels were assayed by HPLC. We also measured the locomotor activity, catalepsy and recognition memory in these rats. RESULTS: Chronic risperidone treatment (0.2mg/kg) increased the extracellular levels of DA and 5-HT. Co-treatment with risperidone and escitalopram (5mg/kg) or mirtazapine (10mg/kg) more efficiently increased the release of 5-HT but not DA in the rat frontal cortex, as compared to drugs given alone. Moreover, risperidone, escitalopram and mirtazapine given alone or in combination significantly decreased the locomotor activity and only mirtazapine increased the catalepsy evoked by risperidone. Combined treatment with risperidone and ADs impaired recognition memory in these rats. CONCLUSIONS: The obtained results suggest that chronic co-administration of risperidone and escitalopram or mirtazapine more efficiently increased 5-HT release in the rat frontal cortex as compared to drugs given alone and suggest that this effect may be of importance to the pharmacotherapy of schizophrenia and drug-resistant depression.

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.

Effects of the new generation α-pyrrolidinophenones on spontaneous locomotor activities in mice, and on extracellular dopamine and serotonin levels in the mouse striatum.

PURPOSE: Pyrovalerone derivatives (α-pyrrolidinophenones) form a distinct branch of synthetic cathinones, a popular group of novel psychoactive substances, and exert strong psychostimulatory effects resulting from their high potency to inhibit dopamine (DA) and norepinephrine transporters, with negligible activity at the serotonin (5-HT) transporter. In contrast to the old generation α-pyrrolidinophenones, 3,4-MDPV and α-PVP, there is limited data on the pharmacology and toxicology of the novel analogs. Therefore, the present study assesses the in vivo effects of two new pyrovalerones, PV8 and PV9, along with those of α-PVP, on spontaneous locomotor activities of mice and extracellular DA and 5-HT levels in the mouse striatum. METHODS: Spontaneous locomotor activity was measured using Opto-Varimex Auto-Track. Effects of tested compounds on extracellular levels of DA and 5-HT in the striatum were studied by an in vivo microdialysis technique; their concentrations in dialysate fractions were analyzed by high-performance liquid chromatography with electrochemical detection. RESULTS: α-PVP, PV8 and PV9 stimulated mice locomotor activity (an effect being blocked by D1-dopamine receptor antagonist, SCH 23390), and increased extracellular levels of DA and 5-HT in the striatum. Observed effects depend on dose, time and compound under investigation, with α-PVP being more potent than PV8 and PV9. When used at the same dose, the pyrovalerones produced effects significantly weaker than a model, old generation psychostimulant, methamphetamine. CONCLUSIONS: Enhancement of dopaminergic neurotransmission plays a dominant role in the psychomotor stimulation caused by α-PVP, PV8 and PV9. Extending an aliphatic side chain beyond a certain point leads to the decrease in their potency in vivo.

The Effects of Exposure to Mephedrone During Adolescence on Brain Neurotransmission and Neurotoxicity in Adult Rats.

According to the European Drug Report (2016), the use of synthetic cathinones, such as mephedrone, among young people has rapidly increased in the last years. Studies in humans indicate that psychostimulant drug use in adolescence increases risk of drug abuse in adulthood. Mephedrone by its interaction with transporters for dopamine (DAT) and serotonin (SERT) stimulates their release to the synaptic cleft. In animal studies, high repeated doses of mephedrone given to adolescent but not adult mice or rats induced toxic changes in 5-hydroxytryptamine (5-HT) neurons. The aim of our study was to investigate the effects of mephedrone given in adolescence on brain neurotransmission and possible neuronal injury in adult rats. Adolescent male rats were given mephedrone (5 mg/kg) for 8 days. In vivo microdialysis in adult rats showed an increase in dopamine (DA), 5-HT, and glutamate release in the nucleus accumbens and frontal cortex but not in the striatum in response to challenge dose in animals pretreated with mephedrone in adolescence. The 5-HT and 5-hydroxyindoleacetic acid contents decreased in the striatum and nucleus accumbens while DA turnover rates were decreased in the striatum and nucleus accumbens. The oxidative damage of DNA assessed with the alkaline comet assay was found in the cortex of adult rats. Therefore, the administration of repeated low doses of mephedrone during adolescence does not seem to induce injury to 5-HT and DA neurons. The oxidative stress seems to be responsible for possible damage of cortical cell bodies which causes maladaptive changes in serotonergic and dopaminergic neurons.