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1.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445476

RESUMO

4,4'-Dimethylaminorex (4,4'-DMAR) is a new synthetic stimulant, and only a little information has been made available so far regarding its pharmaco-toxicological effects. The aim of this study was to investigate the effects of the systemic administration of both the single (±)cis (0.1-60 mg/kg) and (±)trans (30 and 60 mg/kg) stereoisomers and their co-administration (e.g., (±)cis at 1, 10 or 60 mg/kg + (±)trans at 30 mg/kg) in mice. Moreover, we investigated the effect of 4,4'-DMAR on the expression of markers of oxidative/nitrosative stress (8-OHdG, iNOS, NT and NOX2), apoptosis (Smac/DIABLO and NF-κB), and heat shock proteins (HSP27, HSP70, HSP90) in the cerebral cortex. Our study demonstrated that the (±)cis stereoisomer dose-dependently induced psychomotor agitation, sweating, salivation, hyperthermia, stimulated aggression, convulsions and death. Conversely, the (±)trans stereoisomer was ineffective whilst the stereoisomers' co-administration resulted in a worsening of the toxic (±)cis stereoisomer effects. This trend of responses was confirmed by immunohistochemical analysis on the cortex. Finally, we investigated the potentially toxic effects of stereoisomer co-administration by studying urinary excretion. The excretion study showed that the (±)trans stereoisomer reduced the metabolism of the (±)cis form and increased its amount in the urine, possibly reflecting its increased plasma levels and, therefore, the worsening of its toxicity.


Assuntos
Comportamento Animal/efeitos dos fármacos , Oxazóis/toxicidade , Transtornos Psicofisiológicos/metabolismo , Transtornos Psicofisiológicos/patologia , Psicotrópicos/toxicidade , Animais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Oxazóis/classificação , Oxazóis/urina , Transtornos Psicofisiológicos/induzido quimicamente , Psicotrópicos/classificação , Psicotrópicos/urina , Estereoisomerismo
2.
Exp Neurol ; 345: 113836, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34384790

RESUMO

Methoxetamine (MXE) is a dissociative substance of the arylcyclohexylamine class that has been present on the designer drug market as a ketamine-substitute since 2010. We have previously shown that MXE (i) possesses ketamine-like discriminative and positive rewarding effects in rats, (ii) affects brain processing involved in cognition and emotional responses, (iii) causes long-lasting behavioral abnormalities and neurotoxicity in rats and (iv) induces neurological, sensorimotor and cardiorespiratory alterations in mice. To shed light on the mechanisms through which MXE exerts its effects, we conducted a multidisciplinary study to evaluate the various neurotransmitter systems presumably involved in its actions on the brain. In vivo microdialysis study first showed that a single administration of MXE (0.25 and 0.5 mg/kg, i.v.) is able to significantly alter serotonin levels in the rat medial prefrontal cortex (mPFC) and nucleus accumbens. Then, we observed that blockade of the serotonin 5-HT2 receptors through two selective antagonists, ketanserin (0.1 mg/kg, i.p.) and MDL 100907 (0.03 mg/kg, i.p.), at doses not affecting animals behavior per se, attenuated the facilitatory motor effect and the inhibition on visual sensory responses induced by MXE (3 mg/kg, i.p.) and ketamine (3 mg/kg, i.p.), and prevented MXE-induced reduction of the prepulse inhibition in rats, pointing to the 5-HT2 receptors as a key target for the recently described MXE-induced sensorimotor effects. Finally, in-vitro electrophysiological studies revealed that the GABAergic and glutamatergic systems are also likely involved in the mechanisms through which MXE exerts its central effects since MXE inhibits, in a concentration-dependent manner, NMDA-mediated field postsynaptic potentials and GABA-mediated spontaneous currents. Conversely, MXE failed to alter both the AMPA component of field potentials and presynaptic glutamate release, and seems not to interfere with the endocannabinoid-mediated effects on mPFC GABAergic synapses. Altogether, our results support the notion of MXE as a NMDA receptor antagonist and shed further lights into the central mechanisms of action of this ketamine-substitute by pointing to serotonin 5-HT2 receptors as crucial players in the expression of its sensorimotor altering effects and to the NMDA and GABA receptors as potential further important targets of action.

3.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299015

RESUMO

Synthetic cathinones have gained popularity among young drug users and are widely used in the clandestine market. While the cathinone-induced behavioral profile has been extensively investigated, information on their neuroplastic effects is still rather fragmentary. Accordingly, we have exposed male mice to a single injection of MDPV and α-PVP and sacrificed the animals at different time points (i.e., 30 min, 2 h, and 24 h) to have a rapid readout of the effect of these psychostimulants on neuroplasticity in the frontal lobe and hippocampus, two reward-related brain regions. We found that a single, low dose of MDPV or α-PVP is sufficient to alter the expression of neuroplastic markers in the adult mouse brain. In particular, we found increased expression of the transcription factor Npas4, increased ratio between the vesicular GABA transporter and the vesicular glutamate transporter together with changes in the expression of the neurotrophin Bdnf, confirming the widespread impact of these cathinones on brain plasticity. To sum up, exposure to low dose of cathinones can impair cortical and hippocampal homeostasis, suggesting that abuse of these cathinones at much higher doses, as it occurs in humans, could have an even more profound impact on neuroplasticity.


Assuntos
Alcaloides/farmacologia , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Benzodioxóis/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Lobo Frontal/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Pentanonas/farmacologia , Pirrolidinas/farmacologia , Ácido gama-Aminobutírico/metabolismo
4.
Int J Mol Sci ; 22(14)2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34299276

RESUMO

1-cyclohexyl-x-methoxybenzene is a novel psychoactive substance (NPS), first discovered in Europe in 2012 as unknown racemic mixture of its three stereoisomers: ortho, meta and para. Each of these has structural similarities with the analgesic tramadol and the dissociative anesthetic phencyclidine. In light of these structural analogies, and based on the fact that both tramadol and phencyclidine are substances that cause toxic effects in humans, the aim of this study was to investigate the in vitro and in vivo pharmacodynamic profile of these molecules, and to compare them with those caused by tramadol and phencyclidine. In vitro studies demonstrated that tramadol, ortho, meta and para were inactive at mu, kappa and delta opioid receptors. Systemic administration of the three stereoisomers impairs sensorimotor responses, modulates spontaneous motor activity, induces modest analgesia, and alters thermoregulation and cardiorespiratory responses in the mouse in some cases, with a similar profile to that of tramadol and phencyclidine. Naloxone partially prevents only the visual sensorimotor impairments caused by three stereoisomers, without preventing other effects. The present data show that 1-cyclohexyl-x-methoxybenzene derivatives cause pharmaco-toxicological effects by activating both opioid and non-opioid mechanisms and suggest that their use could potentially lead to abuse and bodily harm.


Assuntos
Analgésicos Opioides/toxicidade , Anisóis/toxicidade , Derivados de Benzeno/toxicidade , Alucinógenos/toxicidade , Fenciclidina/toxicidade , Psicotrópicos/toxicidade , Receptores Opioides/metabolismo , Tramadol/toxicidade , Analgésicos Opioides/química , Animais , Anisóis/química , Derivados de Benzeno/química , Células Cultivadas , Cricetinae , Alucinógenos/química , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modelos Animais , Fenciclidina/química , Psicotrópicos/química , Tramadol/química
5.
Psychopharmacology (Berl) ; 238(8): 2275-2295, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33881584

RESUMO

N-methyl-2-pyrrolidone (NMP) and γ-hydroxybutyrate acid (GHB) are synthetic solvents detected in the recreational drug market. GHB has sedative/hypnotic properties and is used for criminal purposes to compromise reaction ability and commit drug-facilitated sexual assaults and other crimes. NMP is a strong solubilizing solvent that has been used alone or mixed with GHB in case of abuse and robberies. The aim of this experimental study is to compare the acute pharmaco-toxicological effects of NMP and GHB on neurological signs (myoclonia, convulsions), sensorimotor (visual, acoustic, and overall tactile) responses, righting reflex, thermoregulation, and motor activity (bar, drag, and accelerod test) in CD-1 male mice. Moreover, since cardiorespiratory depression is one of the main adverse effects related to GHB intake, we investigated the effect of NMP and GHB on cardiorespiratory changes (heart rate, breath rate, oxygen saturation, and pulse distension) in mice. The present study demonstrates that NMP inhibited sensorimotor and motor responses and induced cardiorespiratory depression, with a lower potency and efficacy compared to GHB. These results suggest that NMP can hardly be used alone as a substance to perpetrate sexual assault or robberies.


Assuntos
Drogas Ilícitas/toxicidade , Locomoção/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Pirrolidinonas/toxicidade , Reflexo de Sobressalto/efeitos dos fármacos , Oxibato de Sódio/toxicidade , Adjuvantes Anestésicos/toxicidade , Animais , Relação Dose-Resposta a Droga , Hipnóticos e Sedativos/toxicidade , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modelos Animais , Desempenho Psicomotor/fisiologia , Estupro , Reflexo de Sobressalto/fisiologia , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/fisiopatologia
6.
Psychopharmacology (Berl) ; 238(7): 1847-1856, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33770233

RESUMO

Recreational use of illicit methiopropamine (MPA) is a public health concern because it produces neurochemical effects comparable with those induced by methamphetamine (METH). The present study investigated the effects of MPA on the expression of an aggressive behaviour. Eighty CD-1 male mice, after receiving intraperitoneal injection of saline, MPA (0.01-10 mg/kg), METH (0.01-10 mg/kg), or AMPH (0.01-10 mg/kg), once a week over a 5-week period, underwent the resident-intruder test and spontaneous locomotor activity measurement. Results showed that all psychostimulants induce aggressive behaviour even at low doses, with a dose-dependent increase and a time-dependent sensitisation. MPA potency was similar to METH and superior to AMPH. Therefore, MPA-induced aggressive behaviour may appear even at MPA dosages free of cardiovascular or other behavioural adverse effects and could become a non-intentional side effect that users experience after increasing and repeating MPA consumption.


Assuntos
Agressão/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Metanfetamina/análogos & derivados , Tiofenos/administração & dosagem , Tiofenos/toxicidade , Agressão/fisiologia , Animais , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/química , Estimulantes do Sistema Nervoso Central/toxicidade , Relação Dose-Resposta a Droga , Locomoção/fisiologia , Masculino , Metanfetamina/administração & dosagem , Metanfetamina/química , Metanfetamina/toxicidade , Camundongos , Camundongos Endogâmicos ICR , Tiofenos/química
7.
Metabolites ; 11(2)2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578841

RESUMO

The diffusion of new psychoactive substances (NPS) is highly dynamic and the available substances change over time, resulting in forensic laboratories becoming highly engaged in NPS control. In order to manage NPS diffusion, efficient and innovative legal responses have been provided by several nations. Metabolic profiling is also part of the analytical fight against NPS, since it allows us to identify the biomarkers of drug intake which are needed for the development of suitable analytical methods in biological samples. We have recently reported the characterization of two new analogs of fentanyl, i.e., 4-fluoro-furanylfentanyl (4F-FUF) and isobutyrylfentanyl (iBF), which were found for the first time in Italy in 2019; 4F-FUF was identified for the first time in Europe and was notified to the European Early Warning System. The goal of this study was the characterization of the main metabolites of both drugs by in vitro and in vivo experiments. To this end, incubation with mouse hepatocytes and intraperitoneal administration to mice were carried out. Samples were analyzed by means of liquid chromatography-high resolution mass spectrometry (LC-HRMS), followed by untargeted data evaluation using Compound Discoverer software with a specific workflow, designed for the identification of the whole metabolic pattern, including unexpected metabolites. Twenty metabolites were putatively annotated for 4-FFUF, with the dihydrodiol derivative appearing as the most abundant, whereas 22 metabolites were found for iBF, which was mainly excreted as nor-isobutyrylfentanyl. N-dealkylation of 4-FFUF dihydrodiol and oxidation to carbonyl metabolites for iBF were also major biotransformations. Despite some differences, in general there was a good agreement between in vitro and in vivo samples.

8.
J Anal Toxicol ; 45(5): 475-483, 2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32860694

RESUMO

Since the widespread diffusion of new psychoactive substances, forensic laboratories are often required to identify new drugs and their metabolites for which information or reference standards are lacking. We performed a study on N-methyl-2-aminoindane (NM2AI) metabolism in silico and in vivo, in order to identify the main metabolites to be screened in the different biological samples. We performed the in silico metabolism prediction of NM2AI using MetaSiteTM software and subsequently verified the presence of metabolites in the blood, urine and hair of mice after NM2AI administration. The samples were analyzed by liquid chromatography-high-resolution mass spectrometry (LC-HRMS) with a benchtop Orbitrap Exactive mass detector. This allowed the evaluation of the agreement between software prediction and experimental results in biological samples. LC-HRMS analysis identified seven main metabolites in the urine. They were identified, by their accurate masses and fragmentation patterns, as 2-aminoindane (2AI), two hydroxy-2AI and four hydroxy-NM2AI; one of the hydroxy-NM2AI and one of the hydroxy-2AI underwent also to conjugation. NM2AI and 2AI were also detected by LC-HRMS in the hair and blood. Based on these findings, we developed an LC-HRMS method for the screening of NM2AI and metabolites in urine, blood and hair samples. This can be of primary effectiveness to uncover the abuse of NM2AI and related possible intoxications.


Assuntos
Indanos , Detecção do Abuso de Substâncias , Animais , Cromatografia Líquida , Espectrometria de Massas , Camundongos
9.
Brain Sci ; 10(9)2020 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-32847111

RESUMO

The drastic increase in hallucinogenic compounds in illicit drug markets of new psychoactive substances (NPS) is a worldwide threat. Among these, 2, 5-dimetoxy-4-bromo-amphetamine (DOB) and paramethoxyamphetamine (PMA; marketed as "ecstasy") are frequently purchased on the dark web and consumed for recreational purposes during rave/dance parties. In fact, these two substances seem to induce the same effects as MDMA, which could be due to their structural similarities. According to users, DOB and PMA share the same euphoric effects: increasing of the mental state, increasing sociability and empathy. Users also experienced loss of memory, temporal distortion, and paranoia following the repetition of the same thought. The aim of this study was to investigate the effect of the acute systemic administration of DOB and PMA (0.01-30 mg/kg; i.p.) on motor, sensorimotor (visual, acoustic, and tactile), and startle/PPI responses in CD-1 male mice. Moreover, the pro-psychedelic effect of DOB (0.075-2 mg/kg) and PMA (0.0005-0.5 mg/kg) was investigated by using zebrafish as a model. DOB and PMA administration affected spontaneous locomotion and impaired behaviors and startle/PPI responses in mice. In addition, the two compounds promoted hallucinatory states in zebrafish by reducing the hallucinatory score and swimming activity in hallucinogen-like states.

10.
Int J Legal Med ; 134(5): 1695-1711, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32356113

RESUMO

Methiopropamine is a structural analog of methamphetamine that is categorized as a novel psychoactive substance. It primarily acts as a norepinephrine-dopamine reuptake inhibitor and, secondarily, as a serotonin reuptake inhibitor. In humans, methiopropamine induces stimulation and alertness and increases focus and energy. However, significant side effects are reported, such as tachycardia, anxiety, panic attacks, perspiration, headache, and difficulty in breathing. To date, little data is available regarding its pharmacodynamic effects, thereby we aimed to investigate the acute in vivo effects induced by this drug on sensorimotor responses, body temperature, pain thresholds, motor activity, and cardiovascular and respiratory systems in CD-1 male mice. We selected a range of doses that correspond to the whole range of human reported use, in order to evaluate the threshold of adverse effects presentation. This study demonstrates that methiopropamine acts as a dopaminergic and noradrenergic stimulating drug and that the highest doses (10-30 mg/kg) impair the visual placing response, facilitate the acoustic and tactile response, induce hypothermia, increase mechanical and thermal analgesia, stimulate locomotor activity, induce motor stereotypies, and strongly affected cardiovascular and respiratory parameters, increasing heart rate, breath rate, and blood pressure but reducing oxygen saturation. On the contrary, lower doses do not show any of those effects. We hypothesize that there is a range of doses that do enhance performance but do not seem hazardous to users: this gap could induce the perception of safety and increase the abuser population.


Assuntos
Metanfetamina/análogos & derivados , Tiofenos/farmacologia , Animais , Relação Dose-Resposta a Droga , Masculino , Metanfetamina/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Modelos Animais , Psicotrópicos/farmacologia
11.
Neurotoxicology ; 78: 36-46, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32050087

RESUMO

The increased diffusion of the so-called novel psychoactive substances (NPS) and their continuous change in structure andconceivably activity has led to the need of a rapid screening method to detect their biological effects as early as possible after their appearance in the market. This problem is very felt in forensic pathology and toxicology, so the preclinical study is fundamental in the approach to clinical and autopsy cases of difficult interpretation intoxication. Zebrafish is a high-throughput suitable model to rapidly hypothesize potential aversive or beneficial effects of novel molecules. In the present study, we measured and compared the behavioral responses to two novel neuroactive drugs, namely APINAC, a new cannabimimetic drug, and methiopropamine (MPA), a methamphetamine-like compound, on zebrafish larvae (ZL) and adult mice. By using an innovative statistical approach (general additive models), it was found that the spontaneous locomotor activity was impaired by the two drugs in both species: the disruption extent varied in a dose-dependent and time-dependent manner. Sensorimotor function was also altered: i) the visual object response was reduced in mice treated with APINAC, whereas it was not after exposure to MPA; ii) the visual placing responses were reduced after treatment with both NPS in mice. Furthermore, the visual motor response detected in ZL showed a reduction after treatment with APINAC during light-dark and dark-light transition. The same pattern was found in the MPA exposed groups only at the dark-light transition, while at the transition from light to dark, the individuals showed an increased response. In conclusion, the present study highlighted the impairment of spontaneous motor and sensorimotor behavior induced by MPA and APINAC administration in both species, thus confirming the usefulness of ZL as a model for a rapid behavioural-based drug screening.


Assuntos
Comportamento Animal/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Toxicologia Forense/métodos , Psicotrópicos/toxicidade , Peixe-Zebra , Adamantano/análogos & derivados , Adamantano/toxicidade , Animais , Indazóis/toxicidade , Masculino , Metanfetamina/análogos & derivados , Metanfetamina/toxicidade , Camundongos Endogâmicos ICR , Tiofenos/toxicidade
12.
Int J Mol Sci ; 21(3)2020 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-32050487

RESUMO

Novel Psychoactive Substances (NPS) include several classes of substances such as synthetic cannabinoids (SCBs), an emerging alternative to marijuana, easily purchasable on internet. SCBs are more dangerous than Δ9-Tetrahydrocannabinol as a consequence of their stronger affinities for the CB1 and CB2 receptors, which may result in longer duration of distinct effects, greater potency, and toxicity. The information on SCBs cytotoxicity, genotoxicity, mutagenicity, and long-term effects is scarce. This fact suggests the urgent need to increase available data and to investigate if some SCBs have an impact on the stability of genetic material. Therefore, the aim of the present study was the evaluation of the mutagenic effect of different SCBs belonging to indole- and indazole-structures. The analyzes were conducted in vitro on human TK6 cells and mutagenicity were measured as micronucleus fold increase by flow cytometry. Our results have highlighted, for the first time, the mutagenic capacity of four SCBs, in particular in terms of chromosomal damage induction. We underline the serious potential toxicity of SCBs that suggests the need to proceed with the studies of other different synthetic compounds. Moreover, we identified a method that allows a rapid but effective screening of NPS placed on the market increasingly faster.


Assuntos
Canabinoides/toxicidade , Mutagênicos/toxicidade , Psicotrópicos/toxicidade , Canabinoides/química , Linhagem Celular , Citometria de Fluxo , Humanos , Testes para Micronúcleos , Testes de Mutagenicidade , Mutagênicos/química , Psicotrópicos/química
13.
Neurotoxicology ; 76: 17-32, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610187

RESUMO

JWH-018-Cl, JWH-018-Br and AM-2201 (JWH-018 halogenated-derivatives; JWH-018-R compounds) are synthetic cannabinoid agonists illegally marketed as "Spice", "K2", "herbal blend" and research chemicals for their cannabis-like psychoactive effects. In rodents, JWH-018 and its halogenated derivatives reproduce the typical effects of Δ9-tetrahydrocannabinol (Δ9-THC), i.e. hypothermia, analgesia, hypolocomotion and akinesia. Yet, the effects of JWH-018-R compounds on sensorimotor functions are still unknown. This study was designed to investigate the effect of an acute intraperitoneal (i.p.) administration of JWH-018-R compounds (0.01-6 mg/kg) on sensorimotor functions in mice and to compare them to those caused by the reference compound JWH-018 and Δ9-THC. A well validated battery of behavioral tests was used to investigate the effects of these synthetic cannabinoids on the visual, auditory and tactile responses in mice, while the pre-pulse inhibition (PPI) test was used to investigate their effect on sensorimotor gating. The effect of the synthetic cannabinoids on spontaneous locomotion was also measured by a video tracking analysis to assess potential cannabinoid-induced motor impairment. Results showed that, similarly to JWH-018, systemic administration of JWH-018-R compounds inhibits sensorimotor and PPI responses at lower doses (0.01-0.1 mg/kg) and reduced spontaneous locomotion at intermediate/high doses (1-6 mg/kg). All effects were prevented by the administration of the selective cannabinoid CB1 receptor antagonist/inverse agonist AM-251 thus confirming a CB1 receptor-mediated action. Finding that lower doses of JWH-018-R compounds selectively impair sensorimotor and PPI responses without affecting locomotion should be carefully considered to better understand the potential danger that halogenated-derivatives of JWH-018 may pose to public health, with particular reference to decreased performance in driving and hazardous works.


Assuntos
Canabinoides/toxicidade , Drogas Ilícitas/toxicidade , Indóis/toxicidade , Naftalenos/toxicidade , Desempenho Psicomotor/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Canabinoides/química , Halogenação , Indóis/química , Masculino , Camundongos Endogâmicos ICR , Naftalenos/química
15.
Front Neurosci ; 13: 1163, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31736697

RESUMO

AKB48 is a designer drug belonging to the indazole synthetic cannabinoids class, illegally sold as herbal blend, incense, or research chemicals for their psychoactive cannabis-like effects. In the present study, we investigated the in vivo pharmacological and behavioral effects of AKB48 in male rats and measured the pharmacodynamic effects of AKB48 and simultaneously determined its plasma pharmacokinetic. AKB48 at low doses preferentially stimulated dopamine release in the nucleus accumbens shell (0.25 mg/kg) and impaired visual sensorimotor responses (0.3 mg/kg) without affecting acoustic and tactile reflexes, which are reduced only to the highest dose tested (3 mg/kg). Increasing doses (0.5 mg/kg) of AKB48 impaired place preference and induced hypolocomotion in rats. At the highest dose (3 mg/kg), AKB48 induced hypothermia, analgesia, and catalepsy; inhibited the startle/pre-pulse inhibition test; and caused cardiorespiratory changes characterized by bradycardia and mild bradipnea and SpO2 reduction. All behavioral and neurochemical effects were fully prevented by the selective CB1 receptor antagonist/inverse agonist AM251. AKB48 plasma concentrations rose linearly with increasing dose and were correlated with changes in the somatosensory, hypothermic, analgesic, and cataleptic responses in rats. For the first time, this study shows the pharmacological and behavioral effects of AKB48 in rats, correlating them to the plasma levels of the synthetic cannabinoid. Chemical Compound Studied in This Article: AKB48 (PubChem CID: 57404063); AM251 (PubChem CID: 2125).

16.
Int J Legal Med ; 133(6): 1797-1808, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31154497

RESUMO

MDPV is a synthetic cathinone illegally marketed and consumed for its psychostimulant effects, which are similar to those produced by cocaine, amphetamines, and MDMA. Clinical reports indicate that MDPV produces euphoria, increases alertness, and at high doses causes agitation, psychosis, tachycardia and hypertension, hallucinations, delirium, hyperthermia, rhabdomyolysis, and even death. In rodents, MDPV reproduces the typical physiological effects of psychostimulant drugs, demonstrating greater potency than cocaine. Nevertheless, its role in aggressive behavior has been reported but not yet experimentally confirmed. Therefore, the aim of this study was to evaluate the effects of acute and repeated MDPV (0.01-10 mg/kg i.p.) administration on aggressive behavior in mice and to compare them with those of cocaine (0.01-10 mg/kg i.p.) administration. To this purpose, the resident-intruder test in isolated mice and the spontaneous and stimulated aggressiveness tests for group-housed mice were employed. The present study shows for the first time that MDPV enhances aggressive behavior and locomotion in mice with greater potency and efficacy than cocaine treatment. Moreover, the aggressive and locomotor responses are enhanced after repeated administration, indicating that a sensitization mechanism comes into play. These results, although from preclinical investigation, are suggestive that human MDPV intake could be a problem for public health and the criminal justice system. Thus, investigation by police officers and medical staff is needed to prevent interpersonal violence induced by the consumption of synthetic cathinones.


Assuntos
Agressão , Benzodioxóis/toxicidade , Psicotrópicos/toxicidade , Pirrolidinas/toxicidade , Animais , Cocaína/toxicidade , Toxicologia Forense , Locomoção/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Modelos Animais , Entorpecentes/toxicidade , Medicamentos Sintéticos/toxicidade
17.
Int J Legal Med ; 133(3): 811-820, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30056621

RESUMO

Methiopropamine (MPA) is a structural analogue of methamphetamine and belongs to the category of the novel psychoactive substances. To the best of our knowledge, no experimental study has been performed to evaluate the organ damage evoked by MPA administration in an animal model. Therefore, the main purpose of the present study was to investigate the histological changes in CD-1 male mice following the chronic administration of MPA. MPA-chronically treated mice showed myocardial damage with features consistent with repeated episodes of ischemia and a pattern of kidney damage and gastrointestinal ischemia, with ischemic-necrotic lesions of variable extent. In agreement with the analogies between MPA and methamphetamine, we link organ damage secondary to MPA administration to the vasoconstrictive effect exhibited by both compounds. Chronically MPA-treated mice did not show changes in body weight, food intake, thermoregulation, muscular strength and motor coordination in the accelerod test. However, acute MPA administration significantly increased their heart rate and promoted vasoconstriction, which were associated with the sudden death of a subset of animals (40% of all chronically treated mice). In conclusion, the present study demonstrates that MPA consumption could induce health hazards, highlighting the risk of sudden catastrophic events; therefore, clinicians should be aware of these data and consider MPA screening when no other drug is identified by a urine drug screen.


Assuntos
Drogas Ilícitas/toxicidade , Metanfetamina/análogos & derivados , Tiofenos/toxicidade , Animais , Morte Súbita/etiologia , Frequência Cardíaca/efeitos dos fármacos , Intestinos/irrigação sanguínea , Intestinos/patologia , Isquemia/induzido quimicamente , Isquemia/patologia , Rim/patologia , Masculino , Metanfetamina/toxicidade , Camundongos Endogâmicos ICR , Modelos Animais , Miocárdio/patologia , Psicotrópicos/toxicidade , Vasoconstrição/efeitos dos fármacos
18.
Brain Sci ; 8(9)2018 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-30200549

RESUMO

BACKGROUND: New Psychoactive Substances (NPS) constitute a broad range of hundreds of natural and synthetic drugs, including synthetic opioids, synthetic cannabinoids, synthetic cathinones, and other NPS classes, which were not controlled from 1961 to 1971 by the United Nations drug control conventions. Among these, synthetic opioids represent a major threat to public health. METHODS: A literature search was carried out using public databases (such as PubMed, Google Scholar, and Scopus) to survey fentanyl-, fentanyl analogs-, and other synthetic opioid-related deaths. Keywords including "fentanyl", "fentanyl analogs", "death", "overdose", "intoxication", "synthetic opioids", "Novel Psychoactive Substances", "MT-45", "AH-7921", and "U-47700" were used for the inquiry. RESULTS: From our literature examination, we inferred the frequent implication of fentanyls and synthetic opioids in side effects, which primarily affected the central nervous system and the cardiovascular and pulmonary systems. The data showed a great variety of substances and lethal concentrations. Multidrug-related deaths appeared very common, in most reported cases. CONCLUSIONS: The investigation of the contribution of novel synthetic opioid intoxication to death should be based on a multidisciplinary approach aimed at framing each case and directing the investigation towards targeted toxicological analyses.

19.
Neuropharmacology ; 141: 167-180, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30165078

RESUMO

Novel psychoactive substances are intoxicating compounds developed to mimic the effects of well-established drugs of abuse. They are not controlled by the United Nations drug convention and pose serious health concerns worldwide. Among them, the dissociative drug methoxetamine (MXE) is structurally similar to ketamine (KET) and phencyclidine (PCP) and was created to purposely mimic the psychotropic effects of its "parent" compounds. Recent animal studies show that MXE is able to stimulate the mesolimbic dopaminergic transmission and to induce KET-like discriminative and rewarding effects. In light of the renewed interest in KET and PCP analogs, we decided to deepen the investigation of MXE-induced effects by a battery of behavioral tests widely used in studies of "safety-pharmacology" for the preclinical characterization of new molecules. To this purpose, the acute effects of MXE on neurological and sensorimotor functions in mice, including visual, acoustic and tactile responses, thermal and mechanical pain, motor activity and acoustic startle reactivity were evaluated in comparisons with KET and PCP to better appreciate its specificity of action. Cardiorespiratory parameters and blood pressure were also monitored in awake and freely moving animals. Acute systemic administrations of MXE, KET and PCP (0.01-30 mg/kg i.p.) differentially alter neurological and sensorimotor functions in mice depending in a dose-dependent manner specific for each parameter examined. MXE and KET (1 and 30 mg/kg i.p.) and PCP (1 and 10 mg/kg i.p.) also affect significantly cardiorespiratory parameters, systolic and diastolic blood pressure in mice.


Assuntos
Cicloexanonas/efeitos adversos , Cicloexilaminas/efeitos adversos , Avaliação Pré-Clínica de Medicamentos , Ketamina/efeitos adversos , Fenciclidina/efeitos adversos , Animais , Comportamento Animal/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Frequência Cardíaca/efeitos dos fármacos , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Oxigênio/sangue , Medição da Dor/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Respiração/efeitos dos fármacos
20.
Int J Mol Sci ; 19(5)2018 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-29783748

RESUMO

Cholesterol metabolism is crucial for cells and, in particular, its biosynthesis in the central nervous system occurs in situ, and its deregulation involves morphological changes that cause functional variations and trigger programmed cell death. The pathogenesis of rare diseases, such as Mevalonate Kinase Deficiency or Smith⁻Lemli⁻Opitz Syndrome, arises due to enzymatic defects in the cholesterol metabolic pathways, resulting in a shortage of downstream products. The most severe clinical manifestations of these diseases appear as neurological defects. Expanding the knowledge of this biological mechanism will be useful for identifying potential targets and preventing neuronal damage. Several studies have demonstrated that deregulation of the cholesterol pathway induces mitochondrial dysfunction as the result of respiratory chain damage. We set out to determine whether mitochondrial damage may be prevented by using protective mitochondria-targeted compounds, such as MitoQ, in a neuronal cell line treated with a statin to induce a biochemical block of the cholesterol pathway. Evidence from the literature suggests that mitochondria play a crucial role in the apoptotic mechanism secondary to blocking the cholesterol pathway. Our study shows that MitoQ, administered as a preventive agent, could counteract the cell damage induced by statins in the early stages, but its protective role fades over time.


Assuntos
Colesterol/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Compostos Organofosforados/farmacologia , Ubiquinona/análogos & derivados , Anticolesterolemiantes/efeitos adversos , Linhagem Celular Tumoral , Transporte de Elétrons , Humanos , Lovastatina/efeitos adversos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ubiquinona/farmacologia
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