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1.
Emerg Med Clin North Am ; 40(2): 265-281, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35461623

RESUMO

Over the last decade, the use of novel psychoactive substances (NPS) has increased. Some substances are derived from plants but an increasing number are synthetically produced. Examples include synthetic cannabinoids, synthetic cathinones, kratom, phenibut, designer opioids, and benzodiazepines. These substances have a wide variety of effects due to the varied potency with which they bind their targeted receptors. Routine immunoassay urine drug screens do not detect these substances and it is, therefore, important for clinicians to be aware of these substances to make accurate clinical diagnoses.


Assuntos
Canabinoides , Drogas Desenhadas , Drogas Ilícitas , Transtornos Relacionados ao Uso de Substâncias , Benzodiazepinas , Humanos , Psicotrópicos , Transtornos Relacionados ao Uso de Substâncias/diagnóstico
2.
Sci Rep ; 12(1): 6595, 2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35449195

RESUMO

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) have become a premier neuroscience research tool for enabling reversible manipulations of cellular activity following experimenter-controlled delivery of a DREADD-specific ligand. However, several DREADD ligands, e.g., clozapine-N-oxide (CNO), have metabolic and off-target effects that may confound experimental findings. New DREADD ligands aim to reduce metabolic and potential off-target effects while maintaining strong efficacy for the designer receptors. Recently a novel DREADD ligand, deschloroclozapine (DCZ), was shown to induce chemogenetic-mediated cellular and behavioral effects in mice and monkeys without detectable side effects. The goal of the present study was to examine the effectiveness of systemic DCZ for DREADD-based chemogenetic manipulations in behavioral and slice electrophysiological applications in rats. We demonstrate that a relatively low dose of DCZ (0.1 mg/kg) supports excitatory DREADD-mediated cFos induction, DREADD-mediated inhibition of a central amygdala-dependent behavior, and DREADD-mediated inhibition of neuronal activity in a slice electrophysiology preparation. In addition, we show that this dose of DCZ does not alter gross locomotor activity or induce a place preference/aversion in control rats without DREADD expression. Together, our findings support the use of systemic DCZ for DREADD-based manipulaations in rats, and provide evidence that DCZ is a superior alternative to CNO.


Assuntos
Drogas Desenhadas , Animais , Comportamento Animal , Drogas Desenhadas/metabolismo , Drogas Desenhadas/farmacologia , Ligantes , Locomoção , Camundongos , Neurônios/metabolismo , Ratos
3.
J Neurosci ; 42(12): 2552-2561, 2022 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-35110390

RESUMO

The chemogenetic technology referred to as designer receptors exclusively activated by designer drugs (DREADDs) offers reversible means to control neuronal activity for investigating its functional correlation with behavioral action. Deschloroclozapine (DCZ), a recently developed highly potent and selective DREADD actuator, displays a capacity to expand the utility of DREADDs for chronic manipulation without side effects in nonhuman primates, which has not yet been validated. Here we investigated the pharmacokinetics and behavioral effects of orally administered DCZ in female and male macaque monkeys. Pharmacokinetic analysis and PET occupancy examination demonstrated that oral administration of DCZ yielded slower and prolonged kinetics, and that its bioavailability was 10%-20% of that in the case of systemic injection. Oral DCZ (300-1000 µg/kg) induced significant working memory impairments for at least 4 h in monkeys with hM4Di expressed in the dorsolateral prefrontal cortex (Brodmann's area 46). Repeated daily oral doses of DCZ consistently caused similar impairments over two weeks without discernible desensitization. Our results indicate that orally delivered DCZ affords a less invasive strategy for chronic but reversible chemogenetic manipulation of neuronal activity in nonhuman primates, and this has potential for clinical application.SIGNIFICANCE STATEMENT The use of designer receptors exclusively activated by designer drugs (DREADDs) for chronic manipulation of neuronal activity for days to weeks may be feasible for investigating brain functions and behavior on a long time-scale, and thereby for developing therapeutics for brain disorders, such as epilepsy. Here we performed pharmacokinetics and in vivo occupancy study of orally administered deschloroclozapine to determine a dose range suitable for DREADDs studies. In monkeys expressing hM4Di in the prefrontal cortex, single and repeated daily doses significantly induced working-memory impairments for hours and over two weeks, respectively, without discernible desensitization. These results indicate that orally delivered deschloroclozapine produces long-term stable chemogenetic effects, and holds great promise for the translational use of DREADDs technology.


Assuntos
Clozapina , Drogas Desenhadas , Animais , Controle Comportamental , Clozapina/farmacologia , Drogas Desenhadas/farmacologia , Feminino , Macaca mulatta , Masculino , Neurônios
4.
Biomed Pharmacother ; 146: 112295, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34980551

RESUMO

BACKGROUND: 5-HT2A receptor (e.g. 25I-NBOMe) agonists not only pose risks of acute intoxication but also long-term effects and significant adverse reactions, e.g. hallucinogen persisting perception disorder (HPPD), derealization, and depersonalization. AIMS: We evaluated the risk associated with single and repeated use of 25I-NBOMe. We aimed to identify factors that may increase the risk of HPPD, increase its severity and determine the time when the first symptoms appear. Herein, we report the first extensive evaluation of 25I-NBOMe-induced HPPD. METHOD: We assessed all reports (58) collected by The Pomeranian Pharmacovigilance Centre (PPC) from 2013 to 2020. RESULTS: The study included a total of 58 reports of adverse reactions caused by 25I-NBOMe. In the case of 15 reports (in patients aged 19-26 years), symptoms persisted many months after the discontinuation of 25I-NBOMe. The most common were: pseudohallucinations, bizarre delusions, derealizations and in some cases development or worsening of depression has been diagnosed. HPPD-like symptoms were most common in patients who took the drug regularly (i.e., several times a month). The risk of HPPD-like symptoms is higher in patients who have severe visual pseudohallucinations, severe bizarre delusions, derealization and/or depersonalization onset immediately after taking the drug. Recurrence of HPPD symptoms may be provoked by many factors, however, there is some cases there is no apparent reason. HPPD after 25I-NBOMe use can last from 2 months up to 2 years. In some patients, pharmacological treatment was necessary due to 25I-NBOMe-induced HPPD and depression. CONCLUSIONS: The study showed long-lasting effects after 25I-NBOMe administration and allowed for the determination of HPPD risk factors.


Assuntos
Despersonalização/induzido quimicamente , Drogas Desenhadas/efeitos adversos , Dimetoxifeniletilamina/análogos & derivados , Alucinações/induzido quimicamente , Alucinógenos/efeitos adversos , Transtorno de Pânico/induzido quimicamente , Agonistas do Receptor 5-HT2 de Serotonina/efeitos adversos , Adolescente , Adulto , Doença Crônica , Dimetoxifeniletilamina/efeitos adversos , Feminino , Humanos , Masculino , Receptor 5-HT2A de Serotonina , Adulto Jovem
5.
J Anal Toxicol ; 46(3): 246-256, 2022 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33575738

RESUMO

Abuse of new psychoactive substances (NPS) has become a health and social issue of global concern. p-Methoxyamphetamine (PMA)/p-methoxymethamphetamine (PMMA) with fluoro- or chloro-derivatives of amphetamine and methamphetamine were among the most common drugs found in specimens from fatal cases in Taiwan during the January 2011 to December 2018 period. A liquid-liquid extraction sample preparation protocol with highly sensitive ultra-high performance liquid chromatography-tandem mass spectrometry approach was developed for the simultaneous analysis of seven phenethylamine-type drugs-PMA, PMMA, p-methoxyethylamphetamine, 4-fluoroamphetamine (4-FA), 4-fluoromethamphetamine (4-FMA), 4-chloroamphetamine (4-CA) and 4-chloromethamphetamine (4-CMA)-in postmortem blood and urine specimens. Separation by liquid chromatography was performed by Agilent Zorbax SB-Aq column. Tandem mass spectrometry was operated in Agilent Jet Stream Technology electrospray ionization in positive-ion multiple reaction monitoring mode. An analytical methodology was evaluated using drug-free blood and urine after fortification with 100-2,000 ng/mL of the seven target analytes. Average extraction recoveries were >80%; slightly higher ion suppression was observed for PMA and 4-CA; intra-/inter-day precision (% coefficient of variation) and accuracy were in the ranges of 0.52-12.3% and 85-110%, respectively. Limit of detection and lower limit of quantitation for these seven analytes were both in the 0.5-5 ng/mL range. Interference and carryover were not significant. This relatively simple methodology was found effective and reliable for routine identification and quantitation of these seven analytes in postmortem and antemortem blood and urine specimens received in 2018. Analytical data obtained from these actual cases indicated the following: (i) compared to findings reported during the 2007-2011 period, the use of substituted phenethylamine-type drugs decreased in 2018; (ii) ketamine and 7-aminonimetazepam (the main metabolite of nimetazepam) were the most common co-ingested substances in specimens containing PMA/PMMA, 4-FA/4-FMA, or 4-CA/4-CMA; and (iii) in drug fatalities, the concentration of PMA was significantly higher than the concentration of PMMA in both urine and blood, while the reverse was true in urine specimens from antemortem cases.


Assuntos
Drogas Desenhadas , Ketamina , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida , Ketamina/urina , Limite de Detecção , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
6.
Med Clin North Am ; 106(1): 113-129, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34823725

RESUMO

Benzodiazepine and related sedative use has been increasing. There has been a growing number of unregulated novel psychoactive substances, including designer benzodiazepines. Benzodiazepines have neurobiological and pharmacologic properties that result in a high potential for misuse and physical dependence. Options for discontinuing long-term benzodiazepine use include an outpatient benzodiazepine taper or inpatient withdrawal management at a hospital or detoxification facility. The quality of evidence on medications for benzodiazepine discontinuation is overall low, whereas cognitive behavioral therapy has shown the most benefit in terms of behavioral treatments. Benzodiazepines may also have significant adverse effects, increasing the risk of overdose and death.


Assuntos
Benzodiazepinas/efeitos adversos , Redução da Medicação/métodos , Hipnóticos e Sedativos/efeitos adversos , Síndrome de Abstinência a Substâncias/prevenção & controle , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adulto , Benzodiazepinas/farmacologia , Drogas Desenhadas , Feminino , Humanos , Hipnóticos e Sedativos/farmacologia , Inativação Metabólica/fisiologia , Masculino , Neurobiologia , Receptores de GABA-A/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/terapia , Transtornos Relacionados ao Uso de Substâncias/complicações , Transtornos Relacionados ao Uso de Substâncias/etnologia , Adulto Jovem
7.
Lab Anim (NY) ; 51(1): 3, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34949842
8.
Genes (Basel) ; 12(12)2021 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-34946924

RESUMO

The use of 'new psychoactive substances' appears to be increasingly common. The aim of this study was to examine biological and personality determinants in individuals who choose to use these substances, which may help in the prevention and treatment of psychoactive substance use disorders. The study group consisted of 374 male volunteers; all were users of 'new psychoactive substances' (NPS). The NPS users were recruited after they had abstained-for at least 3 months-from any substance of abuse in addiction treatment facilities. The NPS patients and the control subjects were examined by a psychiatrist using the Mini-International Neuropsychiatric Interview (M.I.N.I.), the NEO Five-Factor Personality Inventory (NEO-FFI), and the State-Trait Anxiety Inventory (STAI) scales. The real-time PCR method was used for genotyping. When we compared the controls with the study group, statistically significant interactions were found between DAT1 polymorphism, neuroticism, and NPS use. NPS use and DAT1 polymorphism were associated with a higher level of neuroticism on the NEO-FFI scale. The study group of NPS users showed a higher severity of anxiety symptoms, both in terms of trait and state, compared to the control group. The results may support the idea that neuroticism and anxiety correlate strongly with coping motives for using NPS.


Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/genética , Drogas Desenhadas/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Personalidade/genética , Polimorfismo Genético/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Adulto , Feminino , Genótipo , Humanos , Masculino , Motivação/genética , Inventário de Personalidade , Adulto Jovem
9.
Pharmacol Res Perspect ; 9(6): e00822, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34676988

RESUMO

Engineered G protein-coupled receptors (GPCRs) are commonly used in chemogenetics as designer receptors exclusively activated by designer drugs (DREADDs). Although several GPCRs have been studied in astrocytes using a chemogenetic approach, the functional role of the astrocytic Gi pathway is not clear, as the literature is conflicting depending on the brain regions or behaviors investigated. In this study, we evaluated the role of the astrocytic Gi pathway in neuroinflammation using a Gi -coupled DREADD (hM4Di). Gi -DREADD was expressed in hippocampal astrocytes of a lipopolysaccharide (LPS)-induced neuroinflammation mouse model using adeno-associated viruses. We found that astrocyte Gi -DREADD stimulation using clozapine N-oxide (CNO) inhibits neuroinflammation, as characterized by decreased levels of proinflammatory cytokines, glial activation, and cognitive impairment in mice. Subsequent experiments using primary astrocyte cultures revealed that Gi -DREADD stimulation significantly downregulated LPS-induced expression of Nos2 mRNA and nitric oxide production. Similarly, in vitro calcium imaging showed that activation of the astrocytic Gi pathway attenuated intracellular calcium transients triggered by LPS treatment, suggesting a positive correlation between enhanced calcium transients and the inflammatory phenotype of astrocytes observed in the inflamed brain. Taken together, our results indicate that the astrocytic Gi pathway plays an inhibitory role in neuroinflammation, providing an opportunity to identify potential cellular and molecular targets to control neuroinflammation.


Assuntos
Astrócitos/metabolismo , Disfunção Cognitiva/fisiopatologia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , /fisiopatologia , Animais , Astrócitos/efeitos dos fármacos , Encéfalo/metabolismo , Clozapina/análogos & derivados , Clozapina/farmacologia , Citocinas/metabolismo , Drogas Desenhadas/farmacologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Receptores Acoplados a Proteínas G/metabolismo
10.
Molecules ; 26(20)2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34684770

RESUMO

The Sterling Research Group identified pravadoline as an aminoalkylindole (AAI) non-steroidal anti-inflammatory pain reliever. As drug design progressed, the ability of AAI analogs to block prostaglandin synthesis diminished, and antinociceptive activity was found to result from action at the CB1 cannabinoid receptor, a G-protein-coupled receptor (GPCR) abundant in the brain. Several laboratories applied computational chemistry methods to ultimately conclude that AAI and cannabinoid ligands could overlap within a common binding pocket but that WIN55212-2 primarily utilized steric interactions via aromatic stacking, whereas cannabinoid ligands required some electrostatic interactions, particularly involving the CB1 helix-3 lysine. The Huffman laboratory identified strategies to establish CB2 receptor selectivity among cannabimimetic indoles to avoid their CB1-related adverse effects, thereby stimulating preclinical studies to explore their use as anti-hyperalgesic and anti-allodynic pharmacotherapies. Some AAI analogs activate novel GPCRs referred to as "Alkyl Indole" receptors, and some AAI analogs act at the colchicine-binding site on microtubules. The AAI compounds having the greatest potency to interact with the CB1 receptor have found their way into the market as "Spice" or "K2". The sale of these alleged "herbal products" evades FDA consumer protections for proper labeling and safety as a medicine, as well as DEA scheduling as compounds having no currently accepted medical use and a high potential for abuse. The distribution to the public of potent alkyl indole synthetic cannabimimetic chemicals without regard for consumer safety contrasts with the adherence to regulatory requirements for demonstration of safety that are routinely observed by ethical pharmaceutical companies that market medicines.


Assuntos
Canabinoides/química , Canabinoides/farmacologia , Drogas Desenhadas/química , Drogas Desenhadas/farmacologia , Analgésicos/química , Analgésicos/farmacologia , Animais , Benzoxazinas/farmacologia , Sítios de Ligação , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Desenho de Fármacos , Humanos , Indóis/química , Indóis/farmacologia , Ligantes , Morfolinas/farmacologia , Naftalenos/farmacologia , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/química , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/química , Eletricidade Estática , Relação Estrutura-Atividade
11.
Artigo em Inglês | MEDLINE | ID: mdl-34678705

RESUMO

We have investigated the metabolic profile of N-ethyl heptedrone, a new designer synthetic stimulant drug, by using data independent acquisition mass spectrometry. Phase I and phase II metabolism was studied by in vitro models, followed by liquid-chromatography coupled to mass spectrometry, to characterize and pre-select the most diagnostic markers of intake. N-ethyl heptedrone was incubated in the presence of pooled human liver microsomes. The contribution of individual enzymatic isoforms in the formation of the phase I and phase II metabolites was further investigated by using human recombinant cDNA-expressed cytochrome P450 enzymesand uridine 5'-diphospho glucuronosyltransferases. The analytical workflow consisted of liquid-liquid extraction with tert-butyl-methyl-ether at alkaline pH, performed before (to investigate the phase I metabolic profile) and after (to investigate the glucuronidation profile) enzymatic hydrolysis. The separation, identification, and determination of the compounds formed in the in vitro experiments were carried out by using liquid chromatography coupled to either high- or low-resolution mass spectrometry. Data independent acquisition method, namely sequential window acquisition of all theoretical fragment-ion spectra (SWATH®) and product ion scan were selected for high-resolution mass spectrometry, whereas multiple reaction monitoring was used for low-resolution mass spectrometry. Thirteen phase-I metabolites were isolated, formed from reactions being catalyzed mainly by CYP1A2, CYP2C9, CYP2C19 and CYP2D6 and, to a lesser degree, by CYP3A4 and CYP3A5. The phase I biotransformation pathways included hydroxylation in different positions, reduction of the ketone group, carbonylation, N-dealkylation, and combinations of the above. Most of the hydroxylated metabolites underwent conjugation reactions to form the corresponding glucurono-conjugated metabolites. Based on our in vitro observation, the metabolic products resulting from reduction of the keto group, N-dealkylation and hydroxylation of the aliphatic chain appear to be the most diagnostic target analytes to be selected as markers of exposure to N-ethyl heptedrone.


Assuntos
Cromatografia Líquida/métodos , Cetonas/química , Cetonas/urina , Espectrometria de Massas/métodos , Biotransformação , Citocromo P-450 CYP3A/metabolismo , Drogas Desenhadas/análise , Drogas Desenhadas/metabolismo , Feminino , Humanos , Hidroxilação , Masculino , Metaboloma , Metabolômica , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Psicotrópicos/química , Psicotrópicos/urina , Quinazolinas/química , Quinazolinas/metabolismo
12.
Neuropharmacology ; 200: 108820, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34619165

RESUMO

Clandestine chemists are currently exploiting the pyrrolidinophenone scaffold to develop new designer drugs that carry the risk of abuse and overdose. These drugs promote addiction through the rewarding effects of increased dopaminergic neurotransmission. 3,4-Methylenedioxypyrovalerone (MDPV) and its analogs are illicit psychostimulants of this class that are ∼50-fold more potent than cocaine at inhibiting the human dopamine transporter (hDAT). In contrast, MDPV is a weak inhibitor at both the human serotonin transporter (hSERT) and, as it is shown here, the Drosophila melanogaster DAT (dDAT). We studied three conserved residues between hSERT and dDAT that are unique in hDAT (A117, F318, and P323 in dDAT), and one residue that is different in all three transporters (D121 in dDAT). hDAT residues were replaced in the dDAT sequence at these positions using site-directed mutagenesis and stable cell lines were generated expressing these mutant transporters. The potencies of MDPV and two of its analogs were determined using a Ca2+-mobilization assay. In this assay, voltage-gated Ca2+ channels are expressed to sense the membrane electrical depolarization evoked when dopamine is transported through DAT. Each individual mutant slightly improved MDPV's potency, but the combination of all four increased its potency ∼100-fold (2 log units) in inhibiting dDAT activity. Molecular modeling and docking studies were conducted to explore the possible mode of interaction between MDPV and DAT in silico. Two of the studied residues (F318 and P323) are at the entrance of the S1 binding site, whereas the other two (A117 and D121) face the aryl moiety of MDPV when bound to this site. Therefore, these four non-conserved residues can influence MDPV selectivity not only by stabilizing binding, but also by controlling access to its binding site at DAT.


Assuntos
Benzodioxóis/farmacologia , Drogas Desenhadas/química , Drogas Desenhadas/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Pirrolidinas/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Animais , Benzodioxóis/química , Transporte Biológico/efeitos dos fármacos , Canais de Cálcio/efeitos dos fármacos , Linhagem Celular , Inibidores da Captação de Dopamina/farmacologia , Drosophila melanogaster , Simulação de Acoplamento Molecular , Pirrolidinas/química
13.
Anal Chem ; 93(40): 13467-13474, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34582178

RESUMO

Illicit drug use causes over half a million deaths worldwide every year. Drugs of abuse are commonly smuggled through customs and border checkpoints and, increasingly, through parcel delivery services. Improved methods for detection of trace drug residues from surfaces are needed. Such methods should be robust, fieldable, sensitive, and capable of detecting a wide range of drugs. In this work, commercially produced paper with a pressure-sensitive adhesive coating was utilized for the collection and analysis of trace drug residues by paper spray mass spectrometry (MS). This modified substrate was used to combine sample collection of drug residues from surfaces with rapid detection using a single paper spray ticket. The all-in-one ticket was used to probe different surfaces commonly encountered in forensic work including clothing, cardboard, glass, concrete, asphalt, and aluminum. A total of 10 drugs (acetyl fentanyl, fentanyl, clonazolam, cocaine, heroin, ketamine, methamphetamine, methylone, U-47700, and XLR-11) were evaluated and found to be detectable in the picogram range using a benchtop mass spectrometer and in the low nanogram range using a portable ion trap MS. The novel approach demonstrates a simple yet effective sampling strategy, allowing for rapid identification from difficult surfaces via paper spray mass spectrometry.


Assuntos
Resíduos de Drogas , Drogas Ilícitas , Adesivos , Benzodiazepinas , Drogas Desenhadas , Drogas Ilícitas/análise , Limite de Detecção , Espectrometria de Massas , Papel
14.
Neuropharmacology ; 200: 108795, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34555367

RESUMO

Previous studies in rodents have repeatedly demonstrated that the centrally-projecting Edinger-Westphal nucleus (EWcp) is highly sensitive to alcohol and is also involved in regulating alcohol intake and body temperature. Historically, the EWcp has been known as the main site of Urocortin 1 (Ucn1) expression, a corticotropin-releasing factor-related peptide, in the brain. However, the EWcp also contains other populations of neurons, including neurons that express the vesicular glutamate transporter 2 (Vglut2). Here we transduced the EWcp with adeno-associated viruses (AAVs) encoding Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to test the role of the EWcp in alcohol drinking and in the regulation of body temperature. Activation of the EWcp with excitatory DREADDs inhibited alcohol intake in a 2-bottle choice procedure in male C57BL/6J mice, whereas inhibition of the EWcp with DREADDs had no effect. Surprisingly, analysis of DREADD expression indicated Ucn1-containing neurons of the EWcp did not express DREADDs. In contrast, AAVs transduced non-Ucn1-containing EWcp neurons. Subsequent experiments showed that the inhibitory effect of EWcp activation on alcohol intake was also present in male Ucn1 KO mice, suggesting that a Ucn1-devoid population of EWcp regulates alcohol intake. A final set of chemogenetic experiments showed that activation of Vglut2-expressing EWcp neurons inhibited alcohol intake and induced hypothermia in male and female mice. These studies expand on previous literature by indicating that a glutamatergic, Ucn1-devoid subpopulation of the EWcp regulates alcohol consumption and body temperature.


Assuntos
Temperatura Corporal/efeitos dos fármacos , Drogas Desenhadas/farmacologia , Núcleo de Edinger-Westphal/efeitos dos fármacos , Etanol/farmacologia , Proteína Vesicular 2 de Transporte de Glutamato/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/patologia , Animais , Regulação da Temperatura Corporal/efeitos dos fármacos , Dependovirus , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Urocortinas/efeitos dos fármacos
15.
Mol Brain ; 14(1): 144, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34544455

RESUMO

Astrocytes express a plethora of G protein-coupled receptors (GPCRs) that are crucial for shaping synaptic activity. Upon GPCR activation, astrocytes can respond with transient variations in intracellular Ca2+. In addition, Ca2+-dependent and/or Ca2+-independent release of gliotransmitters can occur, allowing them to engage in bidirectional neuron-astrocyte communication. The development of designer receptors exclusively activated by designer drugs (DREADDs) has facilitated many new discoveries on the roles of astrocytes in both physiological and pathological conditions. They are an excellent tool, as they can target endogenous GPCR-mediated intracellular signal transduction pathways specifically in astrocytes. With increasing interest and accumulating research on this topic, several discrepancies on astrocytic Ca2+ signalling and astrocyte-mediated effects on synaptic plasticity have emerged, preventing a clear-cut consensus about the downstream effects of DREADDs in astrocytes. In the present study, we performed a side-by-side evaluation of the effects of bath application of the DREADD agonist, clozapine-N-oxide (10 µM), on Gq- and Gi-DREADD activation in mouse CA1 hippocampal astrocytes. In doing so, we aimed to avoid confounding factors, such as differences in experimental procedures, and to directly compare the actions of both DREADDs on astrocytic intracellular Ca2+ dynamics and synaptic plasticity in acute hippocampal slices. We used an adeno-associated viral vector approach to transduce dorsal hippocampi of male, 8-week-old C57BL6/J mice, to drive expression of either the Gq-DREADD or Gi-DREADD in CA1 astrocytes. A viral vector lacking the DREADD construct was used to generate controls. Here, we show that agonism of Gq-DREADDs, but not Gi-DREADDs, induced consistent increases in spontaneous astrocytic Ca2+ events. Moreover, we demonstrate that both Gq-DREADD as well as Gi-DREADD-mediated activation of CA1 astrocytes induces long-lasting synaptic potentiation in the hippocampal CA1 Schaffer collateral pathway in the absence of a high frequency stimulus. Moreover, we report for the first time that astrocytic Gi-DREADD activation is sufficient to elicit de novo potentiation. Our data demonstrate that activation of either Gq or Gi pathways drives synaptic potentiation through Ca2+-dependent and Ca2+-independent mechanisms, respectively.


Assuntos
Astrócitos/fisiologia , Região CA1 Hipocampal/fisiologia , Sinalização do Cálcio/fisiologia , Clozapina/análogos & derivados , Drogas Desenhadas/farmacologia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/fisiologia , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Animais , Astrócitos/efeitos dos fármacos , Região CA1 Hipocampal/citologia , Clozapina/farmacologia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/efeitos dos fármacos , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/efeitos dos fármacos , Vetores Genéticos/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/fisiologia , Receptores Acoplados a Proteínas G/efeitos dos fármacos
16.
Neuropharmacology ; 197: 108746, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34371079

RESUMO

Increasing evidence indicates that the melanocortin and mesolimbic dopamine (DA) systems interact to regulate feeding and body weight. Because melanocortin-3 receptors (MC3R) are highly expressed in the ventral tegmental area (VTA), we tested whether VTA neurons expressing these receptors (VTA MC3R neurons) control feeding and body weight in vivo. We also tested whether there were sex differences in the ability of VTA MC3R neurons to control feeding, as MC3R -/- mice show sex-dependent alterations in reward feeding and DA levels, and there are clear sex differences in multiple DA-dependent behaviors and disorders. Designer receptors exclusively activated by designer drugs (DREADD) were used to acutely activate and inhibit VTA MC3R neurons and changes in food intake and body weight were measured. Acutely altering the activity of VTA MC3R neurons decreased feeding in an activity- and sex-dependent manner, with acute activation decreasing feeding, but only in females, and acute inhibition decreasing feeding, but only in males. These differences did not appear to be due to sex differences in the number of VTA MC3R neurons, the ability of hM3Dq to activate VTA MC3R neurons, or the proportion of VTA MC3R neurons expressing tyrosine hydroxylase (TH). These studies demonstrate an important role for VTA MC3R neurons in the control of feeding and reveal important sex differences in behavior, whereby opposing changes in neuronal activity in male and female mice cause similar changes in behavior.


Assuntos
Atividade Motora/fisiologia , Neurônios/fisiologia , Receptor Tipo 3 de Melanocortina/fisiologia , Área Tegmentar Ventral/fisiologia , Animais , Peso Corporal , Drogas Desenhadas/farmacologia , Dopamina/metabolismo , Comportamento Alimentar , Feminino , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Receptor Tipo 3 de Melanocortina/genética , Recompensa , Caracteres Sexuais , Área Tegmentar Ventral/citologia
17.
Drug Alcohol Depend ; 227: 108910, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34332176

RESUMO

The α-pyrrolidino-phenone cathinone stimulants first came to widespread attention because of bizarre behavior consequent to the use of α-pyrrolidinopentiophenone (α-PVP, "flakka") reported in popular press. As with other designer drugs, diversification of cathinones has been driven by desirable subjective effects, but also by attempts to stay ahead of legal controls of specific molecules. The α-pyrrolidinohexiophenone (α-PHP) and α-pyrrolidinopropiophenone (α-PPP) compounds have been relatively under-investigated relative to α-PVP and provide a key opportunity to also investigate structure-activity relationships, i.e., how the extension of the alpha carbon chain may affect potency or efficacy. Female rats were used to contrast the effects of α-PHP and α-PPP with those of α-PVP in altering wheel activity and effects on spontaneous locomotion, temperature and intracranial self-stimulation reward. The α-PPP, α-PHP and α-PVP compounds (5, 10 mg/kg, i.p.) suppressed wheel activity. Inhalation of α-PHP or α-PVP also suppressed wheel activity, but for an abbreviated duration compared with the injection route. Spontaneous activity was increased, and brain reward thresholds decreased, in a dose-dependent manner by all three compounds; only small decrements in body temperature were observed. These data show that all three of the α-pyrrolidino-phenone cathinones exhibit significant stimulant-like activity in female rats. Differences were minor and abuse liability is therefore likely to be equivalent for all three α-pyrrolidino-phenones.


Assuntos
Alcaloides , Estimulantes do Sistema Nervoso Central , Drogas Desenhadas , Alcaloides/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Drogas Desenhadas/farmacologia , Relação Dose-Resposta a Droga , Feminino , Locomoção , Pirrolidinas/farmacologia , Ratos
18.
Emerg Med Clin North Am ; 39(3): 677-687, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34215409

RESUMO

In recent years, there has been an emergence of numerous novel drugs. Such toxicity may occur in both adolescents and adults. This article discusses the opioid epidemic and several emerging opioids, including buprenorphine, loperamide, fentanyl, fentanyl derivatives, and others. Kratom, a plant occasionally used for opiate detoxification, along with the sedatives etizolam and phenibut, will be discussed. Lastly, this article discusses the phenethylamines and marijuana.


Assuntos
Drogas Desenhadas/efeitos adversos , Drogas Ilícitas/efeitos adversos , Transtornos Relacionados ao Uso de Substâncias/complicações , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Buprenorfina/administração & dosagem , Buprenorfina/efeitos adversos , Canabinoides/efeitos adversos , Drogas Desenhadas/administração & dosagem , Overdose de Drogas/tratamento farmacológico , Fentanila/administração & dosagem , Fentanila/efeitos adversos , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Loperamida/administração & dosagem , Loperamida/efeitos adversos , Mitragyna/efeitos adversos , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Fenetilaminas/efeitos adversos
19.
Environ Int ; 156: 106760, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34256299

RESUMO

The major human cytochrome P450 CYP2D6 isoform enzyme plays important roles in the liver and in the brain with regards to xenobiotic metabolism. Xenobiotics as CYP2D6 substrates include a whole range of pharmaceuticals, pesticides and plant alkaloids to cite but a few. In addition, a number of endogenous compounds have been shown to be substrates of CYP2D6 including trace amines in the brain such as tyramine and 5-methoxytryptamine as well as anandamide and progesterone. Because of the polymorphic nature of CYP2D6, considerable inter-phenotypic and inter-ethnic differences in the pharmaco/toxicokinetics (PK/TK) and metabolism of CYP2D6 substrates exist with potential consequences on the pharmacology and toxicity of chemicals. Here, large extensive literature searches have been performed to collect PK data from published human studies for a wide range of pharmaceutical probe substrates and investigate human variability in CYP2D6 metabolism. The computed kinetic parameters resulted in the largest open source database, quantifying inter-phenotypic differences for the kinetics of CYP2D6 probe substrates in Caucasian and Asian populations, to date. The database is available in supplementary material (CYPD6 DB) and EFSA knowledge junction (DOI to added). Subsequently, meta-analyses using a hierarchical Bayesian model for markers of chronic oral exposure (oral clearance, area under the plasma concentration time curve) and acute oral exposure (maximum plasma concentration (Cmax) provided estimates of inter-phenotypic differences and CYP2D6-related uncertainty factors (UFs) for chemical risk assessment in Caucasian and Asian populations classified as ultra-rapid (UM), extensive (EMs), intermediate (IMs) and poor metabolisers (PMs). The model allowed the integration of inter-individual (i.e. inter-phenotypic and inter-ethnic), inter-compound and inter-study variability together with uncertainty in each PK parameter. Key findings include 1. Higher frequencies of PMs in Caucasian populations compared to Asian populations (>8% vs 1-2%) for which EM and IM were the most frequent phenotype. 2. Large inter-phenotypic differences in PK parameters for Caucasian EMs (coefficients of variation (CV) > 50%) compared with Caucasian PMs and Asian EMs and IMs (i.e CV < 40%). 3. Inter-phenotypic PK differences between EMs and PMs in Caucasian populations increase with the quantitative contribution of CYP2D6 for the metabolism (fm) for a range of substrates (fmCYP2D6 range: 20-95% of dose) (range: 1-54) to a much larger extent than those for Asian populations (range: 1-4). 4. Exponential meta-regressions between FmCYP2D6 in EMs and inter-phenotypic differences were also shown to differ between Caucasian and Asian populations as well as CYP2D6-related UFs. Finally, implications of these results for the risk assessment of food chemicals and emerging designer drugs of public health concern, as CYP2D6 substrates, are highlighted and include the integration of in vitro metabolism data and CYP2D6-variability distributions for the development of quantitative in vitro in vivo extrapolation models.


Assuntos
Citocromo P-450 CYP2D6 , Drogas Desenhadas , Teorema de Bayes , Citocromo P-450 CYP2D6/metabolismo , Humanos , Medição de Risco , Toxicocinética
20.
Behav Neurosci ; 135(2): 89-107, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34060867

RESUMO

Technological advances over the last decade are changing the face of behavioral neuroscience research. Here we review recent work on the use of one such transformative tool in behavioral neuroscience research, chemogenetics (or Designer Receptors Exclusively Activated by Designer Drugs, DREADDS). As transformative technologies such as DREADDs are introduced, applied, and refined, their utility in addressing complex questions about behavior and cognition becomes clear and exciting. In the behavioral neuroscience field, remarkable new findings now regularly appear as a result of the ability to monitor and intervene in neural processes with high anatomical precision as animals behave in complex task environments. As these new tools are applied to behavioral questions, individualized procedures for their use find their way into diverse labs. Thus, "tips of the trade" become important for wide dissemination not only for laboratories that are using the tools but also for those who are interested in incorporating them into their own work. Our aim is to provide an up-to-date perspective on how the DREADD technique is being used for research on learning and memory, decision making, and goal-directed behavior, as well as to provide suggestions and considerations for current and future users based on our collective experience. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Drogas Desenhadas , Neurociências , Animais , Aprendizagem
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