Opióides são substâncias de origem endógena ou sintética, referindo-se a todos os compostos relacionados ao ópio, sendo o protótipo dos agonistas opióides, a morfina, conhecida pela sua capacidade de aliviar a dor intensa com eficácia. A morfina se liga a pelo menos três tipos de receptores conhecidos como &#181;, <font face=\"symbol\">k e <font face=\"symbol\">d. Os opióides parecem ter relação a comportamentos reprodutivos, dentre estes o comportamento maternal (CM). O CM é complexo, instintivo e com características espécie-específicas determinadas por modificações fisiológicas que ocorrem pouco antes ou logo após o parto e deve ajustar-se à uma série de variáveis como disponibilidade de alimentos, por exemplo, e influencia diretamente nos desenvolvimentos físico, neurológico e comportamental das proles, garantindo ou não a perpetuação dessas espécies. Trabalhos mostraram que os estados fisiológico, reprodutivo e a manipulação farmacológica com morfina ao final da gestação de ratas, por si só, são capazes de alterar a habilidade materna, comprometendo o desenvolvimento das proles, bem como podem modular a expressão dos genes que codificam para os receptores opióides em regiões implicadas com o controle do CM, porém são desconhecidos os resultados de ratas tratadas com esse opióide nas fases iniciais da gestação, objetivo deste trabalho, bem como os parâmetros físico e neurocomportamental das proles e na biologia molecular de receptores opióides em diferentes regiões encefálicas tanto nas proles quanto nas mães. Os resultados mostraram que tratamento com morfina no primeiro e segundo terços da gestação de ratas alterou alguns parâmetros do CM como a recuperação dos filhotes, e alterou alguns parâmetros do desenvolvimento físico como o ganho de peso e o desenvolvimento dos órgãos sexuais e desenvolvimento neurocomportamental em ambas as proles, bem como os padrões de expressão gênica e produtos protéicos nas mães e em suas proles no estriado, hipotálamo e PAG. Conclui-se, portanto que o tratamento com morfina durante a gestação de ratas pode alterar o estado fisiológico das mães com implicações diretas nas proles. / Opioids are substances of endogenous or synthetic origin, referring to all related opiate compounds, the prototype of the opioid agonists, morphine, known for its ability to relieve severe pain effectively. Morphine binds to at least three types of receptors known as &#181;, <font face=\"symbol\">d and <font face=\"symbol\">k. Opioids appear to be related to reproductive behaviors among this maternal behavior (CM). The CM is complex, instinctive and species-specific characteristics determined by physiological changes that occur shortly before or after delivery and must adjust to a number of variables such as food availability, for example, and directly influences the physical developments, neurological and behavior of the offspring, or not ensuring the perpetuation of the species. Studies have shown that the physiological and pharmacological manipulation reproductive states with morphine to rats in late pregnancy, by themselves, are capable of altering the maternal ability, affecting the development of the offspring, and can modulate the expression of genes encoding the opioid receptors in regions implicated in the control of CM, are unknown but the results of this opioid-treated rats in the early stages of pregnancy, aim of this work as well as the physical and neurobehavioral parameters of the offspring and molecular biology of opioid receptors in different brain regions both in the offspring as mothers. The results showed that morphine treatment in the first two thirds of pregnancy of rats changed some parameters of the CM as the recovery of the puppies, and changed some of the physical parameters such as weight gain and the development of sex organs and neurobehavioral development in both offspring as well as the patterns of gene expression and protein products in mothers and their offspring in the striatum, hypothalamus and PAG. It follows therefore that treatment with morphine during pregnancy in rats can alter the physiological status of mothers with direct implications in offspring.

Die schmerzstillende Wirkung von Opiaten wird über Opioidrezeptoren im zentralen und peripheren Nervensystem vermittelt. Die Schmerzlinderung kann jedoch mit sehr starken Nebenwirkungen einhergehen, die das Patientenwohlbefinden beeinträchtigen. Dies legt die Bedeutung von neuen Opioidanalgetika nahe, die ihre schmerzstillende Wirkung ausschließlich über Opioidrezeptoren im PNS entfalten, ohne unerwünschte zentrale Nebenwirkungen zu induzieren. Die orale Gabe von Medikamenten minimiert Unannehmlichkeiten für den Patienten, jedoch müssen die Substanzen die intestinale Barriere passieren können, um in die Blutzirkulation eintreten zu können. Die intestinale Permeabilität von zwei peripher wirksamen Opiaten (AS006 und Loperamid) wurde in Ussing-Kammer Experimenten untersucht. Um die Darmepithelpermeabilität für beide Opiate zu erhöhen, wurde der Absorptionsverstärker Chitosan verwendet. Chitosan bewirkte nach 30 Minuten bei HT29/B6 und Caco-2 Zelllinien eine Abnahme des epithelialen Widerstands in vitro. Die Permeabilität für AS006 war bei beiden Zelllinien erhöht, für Loperamid nur bei HT29/B6, jedoch nicht bei Caco-2 Zellmonolayern. Verhaltensexperimente zur Messung des antinozizeptiven Effektes von oral appliziertem Loperamid auf Entzündungsschmerz wurden an Ratten durchgeführt. Die orale Gabe von Loperamid induzierte eine Dosis-abhängige antinozizeptive Wirkung in der entzündeten Hinterpfote. Bei oraler Gabe von Loperamid in Kombination mit Chitosan wurde keine signifikante Verstärkung des maximalen antinozizeptiven Effekts von Loperamid beobachtet. Zusammenfassend ist Chitosan ein geeigneter Absorptionsverstärker für intestinale Permeabilitätsstudien von peripher wirksamen Opioidanalgetika in vitro. Die in vitro Ergebnisse haben gezeigt, dass der Effekt von Chitosan auf Loperamid möglicherweise schwächer ist als auf AS006. Dementsprechend fiel die Wirkung des Absorptionsverstärkers auf Loperamid-induzierte Analgesie im Verhaltensversuch eher gering aus. / Analgesic effects of opioids are mediated by opioid receptors that are widely distributed in the central and peripheral nervous systems (CNS and PNS, respectively). Although opioids are the most powerful analgesics, severe side effects restrict their use and affect patient convalescence. This suggests an advantage of new analgesic opioids which selectively bind to opioid receptors in the PNS. After oral administration however, peripherally restricted opioids first have to cross the intestinal epithelial barrier before absorption into the circulation and distribution to opioid receptors in peripheral tissues. Here, the transport across intestinal epithelia of two opioid ligands (AS006 and loperamide) that selectively activate peripheral opioid receptors without entering the CNS were investigated. To increase the intestinal passage of these drugs, the absorption enhancer chitosan was used. Chitosan significantly decreased the transepithelial resistance of HT29/B6 and Caco-2 cell monolayers after 30 min in vitro. The permeability values for AS006 increased from < 0.3 × 10-6 cm/s up to 10 × 10-6 cm/s in the presence of chitosan. In contrast, HT29/B6 monolayers showed moderate loperamide permeability in the presence of chitosan, and chitosan had no effect on the permeability of loperamide using Caco-2 monolayers. Oral administration of loperamide induced a dose-depended elevation of paw pressure thresholds in inflamed paws that lasted for 60 min. Oral administration of loperamide combined with chitosan slightly but nonsignificantly enhanced the antinociceptive effect of loperamide. In conclusion, chitosan is a suitable absorption enhancer for in vitro intestinal permeability studies. Future in vivo experiments might investigate different formulations and application schedules, and further address the effects of chitosan on the antinociceptive efficacy of hydrophilic opioids.

Background Heroin dependence is associated with increased risk of the transmission of blood-borne viral (BBV) infections such as HIV, as a result of unsafe injecting practices. Opioid Substitution Treatment (OST) Programmes including Methadone Maintenance Treatment (MMT) programmes are a recommended way of addressing heroin dependence with the dual aims of reducing both heroin use and associated harms. However, OST programmes, particularly in prison settings, are often unavailable, in spite of large numbers of prisoners with heroin dependence and the high risk of HIV transmission in the prison setting. Little is currently known about the delivery of OST programmes within prison settings. A systematic literature review conducted within this study revealed that there are only a small number of studies from middle and lower-income countries and the perspectives of the range of stakeholders are often underrepresented. Aim and setting of this study This aim of this study was to understand the role of Methadone Maintenance Treatment (MMT) programmes within the context of HIV prevention programmes and to identify barriers and facilitators that influence the implementation, routine delivery and sustainability of methadone programmes in Indonesian prisons. Study design Three prison settings were selected as part of a qualitative case study. These comprised: a narcotics prison that provided methadone, a general prison that provided methadone, and a general prison, where there was no methadone programme. This allowed the exploration of multiple perspectives of prisoners and the diverse range of staff involved in the implementation of programmes. Interview and observational data were supplemented by data from medical case notes. Qualitative data underwent thematic analysis, with the help of framework analysis for data management. Principal findings This study found that there were many misconceptions about methadone programmes. HIV infection was not recognised as a problem and prison staff, healthcare staff and prisoners alike lacked understanding of the roles of methadone programmes. Prisoners participating in programmes were often stigmatised, while many prisoners believed methadone withdrawal was dangerous and could lead to death. These factors all contributed to low level participation, observed in both prisons with methadone programmes. Lack of confidentiality and associated stigmatisation as well as inappropriate assessment criteria also contributed to this, as did a lack of support systems. A reduction in international funding and a shift in national drug policy priorities away from the provision of methadone to drug-free Therapeutic Community (TC) programmes, together with a failure to embed methadone programmes within the daily prison routine currently pose challenges to effective implementation, delivery and programme sustainability. Conclusion Educating policy makers and practitioners could improve understanding of the roles of methadone programmes and increase support for programme delivery within prisons. It is therefore recommended that Indonesian government and prison policy focuses on ensuring effective delivery and sustainability of methadone programmes for people with heroin dependence in the prison setting.

Embora existam muitos estudos clínicos avaliando analgésicos e o controle da dor em cães, poucos são realizados em animais com dor do câncer e submetidos a procedimento cirúrgico para ressecção da neoplasia como a maxilectomia e mandibulectomia. Este estudo clínico foi realizado de forma prospectiva, comparativa, aleatória e de maneira simples cego com o propósito de avaliar a eficácia analgésica de diferentes tratamentos no período pós-operatório em cães submetidos à maxilectomia ou mandibulectomia. Foram utilizados no estudo 42 cães com neoplasia oral. Todos os animais foram prémedicados com acepromazina (0,05mg/kg) associado à meperidina (2mg/kg) por via intramuscular e a anestesia foi induzida com propofol por via iv na dose suficiente realizar a intubação (2.3-6.5mg/kg). O isoflurano foi utilizado para a manutenção da anestesia. Trinta minutos antes do fim do procedimento cirúrgico, os cães foram distribuídos aleatoriamente em um dos 5 diferentes grupos para analgesia pósoperatória: tramadol 2mg/kg (Tra), codeína 2mg/kg (Co), cetoprofeno 2mg/kg (Ce), tramadol 2mg/kg associado ao cetoprofeno 2mg/kg (TraCe) ou codeína 2mg/kg associado ao cetoprofeno 2mg/kg (CoCe), por via subcutânea. A freqüência cardíaca (FC) e respiratória (FR), pressão arterial sistólica (PAS), pressão arterial diastólica (PAD) e pressão arterial média (PAM), glicose sanguínea, cortisol e interleucina-6 (IL- 6) e grau de sedação foram verificados até 24 horas, e grau de analgesia foi verificado por até 120 horas do início da administração do analgésico, ou seja, os respectivos tratamentos foram mantidos por 5 dias da seguinte forma: tramadol ou codeína a cada 8 horas e cetoprofeno a cada 24 horas por via oral (MBL, M1, M2, M3, M4, M5, M24, M48, M72, M96 e M120). O resgate analgésico foi realizado nos animais que apresentaram escore de dor 4 em qualquer momento do estudo (dipirona 25mg/kg e morfina 0,1mg/kg). A análise estatística foi realizada por meio do Kruskal-Wallis, Friedman para mensurações repetidas, ANOVA e teste 2. Os gráficos em boxplot ou diagrama em caixas representam a distribuição dos dados. Os valores com p<0,05 foram considerados significantes. Não houve diferença entre os grupos de tratamento com relação ao peso, tempo de cirurgia, tempo para extubação, FC, FR, PAS, PAD e PAM, cortisol e IL-6 séricos, e escore de dor pela escala de análise descritiva. A concentração da glicose sanguínea aumentou de forma significante com relação aos valores basais no grupo Tra (M5= 96±14), Co (M1= 120±66 e M3=96±21), Ce (M5= 105±22) e CoCe (M3=104±16). Aumento do escore de dor foi observado no M2 do grupo Tra em relação a MBL e M1 a M5 do grupo Co em relação a M120 (p<0,05), contudo a média do escore não foi maior que 2,7. Baixo grau de sedação ainda foi observado no grupo CoCe no M24 (0,1±0,4 p<0,001) com relação ao M1. O número de resgate foi baixo, totalizando 19 administrações. No grupo Ce houve maior necessidade de resgate analgésico. Com base nos resultados obtidos, pôde-se concluir que os grupos de tratamento analgésico promoveram controle da dor pós-operatória de boa qualidade na maioria dos cães do estudo e com baixa incidência de efeitos adversos, podendo ser indicados no controle da dor em procedimentos de maxilectomia e mandibulectomia. / Although there are many clinical studies evaluating analgesics and pain control in dogs, very few were carried out in animals with cancer pain, and submitted to oncologic surgery with tumor resections such as maxillectomy and mandibulectomy. This clinical, prospective, randomized, simple blinded study was performed with the purpose of evaluating analgesic efficacy of different treatments in the postoperative period in dogs submitted to maxillectomy or mandibulectomy. Forty-two client-owned dogs with oral tumor were used in the study. Dogs were premedicated with acepromazine (0.05mg kg-1) and meperidine (2mg kg-1) by the intramuscular route and anesthesia was induced with intravenous propofol in a dose sufficient to allow intubation (2.3-6.5mg-1). Isoflurane was used for maintenance of anesthesia. Thirty minutes prior to the end of surgery, dogs were randomly allocated in one of 5 different groups for postoperative analgesia: tramadol 2mg kg-1 (Tra), codeine 2mg kg-1 (Co), ketoprofen 2mg kg-1 (Ke), tramadol 2mg kg-1 + ketoprofen 2mg kg-1 (TraKe) or codeine 2mg kg-1 + ketoprofen 2mg kg-1 (CoKe), subcutaneously. Heart (HR) and respiratory (RR) rates, systolic (SBP), median (MBP) and diastolic (DBP) blood pressures, blood glucose, serum cortisol and interleukin-6 (IL-6) and degree of sedation were recorded for 24 hours, and degree of analgesia were evaluated until 120 hours of the start of analgesic administration (MBL, M1, M2, M3, M4, M5, M24, M48, M72, M96 and M120), being that treatments were maintained for 5 days as follows: codeine or tramadol every 8 hours and the ketoprofen every 24 hours orally. Analgesic rescue was delivered to animals with pain scores equal or superior to 4 at any time of the study (dypirone 25mg -1 and morphine 0,1mg-1). Statistical analyses were performed by means of the Kruskal-Wallis, Friedmann for repeated measures, ANOVA and 2 tests. Graphics boxplot or box diagrams represents dates of distribution. Values of p<0.05 were considered significant. There were no differences between groups related to weight, surgical time, extubation time, HR, RR, SBP, MBP, DBP, serum cortisol and IL-6, and pain score by Descriptive Scale (DS). Blood glucose concentrations were significantly increased in relation to baseline, in groups Tra (M5= 96±14), Co (M1= 120±66 e M3=96±21), Ke (M5= 105±22) and CoKe (M3=104±16). Increase of pain score was observed in M2 of group Tra in relation to baseline, and M1 to M5 of group Co in relation to M120 (p<0,05), however the average score was not higher than 2.7. Low level of sedation was also observed in group CoKe in M24 (0.1 ± 0.4 - p <0.001) compared to M1.. The number of rescue was low, totaling 19 administrations. Ke group required more analgesic rescue. So, it can be conclude that treatment analgesic groups promoted a good quality pain control of postoperative in most of the dogs in the study and with low incidence of side effects, could be indicated in the control of the pain in procedures of maxillectomy and mandibulectomy.

A estimulação opioidérgica decorrente do tratamento com morfina em fêmeas reprodutoras gera efeitos moleculares e comportamentais tardios diferenciados de acordo com o estado fisiológico no momento do tratamento. Trabalhos prévios têm demonstrado um importante papel da substância cinzenta periaquedutal (PAG) neste fenômeno. Assim, investigou-se a expressão dos receptores opióides centrais, por meio de estudos da atividade dos seus genes e da presença dos respectivos produtos protéicos. Possíveis modulações decorrentes do uso agudo e crônico de agonistas dos receptores de opióides na PAG durante os períodos de gestação ou lactação no comportamento maternal em ratas também foram investigadas. Os resultados mostraram que a expressão dos receptores opióides na PAG em fêmeas é modulada tanto pelo estado fisiológico como por desafios farmacológicos com possíveis implicações para o comportamento maternal. / Morphine-induced opioidergic stimulation leads to tardive molecular and behavioral changes in female rats. Previous works have demonstrated a role for the periaqueductal grey (PAG) on opioid-mediated behavioral selection during lactation. This study was designed to investigate the maternal behavior and the physiological and pharmacological modulation of the expression of opioid receptors. The results showed that PAG opioid gene expression is modulated both by physiological status and pharmacological treatments. These data may have implications for maternal behavior.

O consumo de drogas e álcool constitui cada vez mais um problema social e de saúde pública, pelas consequências negativas que provocam no desenvolvimento emocional e físico dos indivíduos. Existem poucas referências na literatura avaliando o uso destas substâncias por portadores de doença falciforme (DF). Estes pacientes apresentam crises álgicas severas, recorrentes, frequentemente controladas por opióides. O comprometimento da qualidade de vida predispõe a ocorrência de transtornos psiquiátricos não-psicóticos, como depressão por exemplo, tornando o grupo vulnerável ao uso abusivo de substâncias. Objetivos: avaliar o consumo de álcool e drogas em pacientes portadores de DF acompanhados pelo Centro de Referência de Doença Falciforme (CRAF) do Hospital de Clínicas de Porto Alegre (HCPA), estimar o percentual de pacientes em tratamento da doença falciforme que fazem uso abusivo de álcool e drogas, e colaborar com o estudo que avaliará a efetividade de um centro de referência multidisciplinar para esta população. Métodos: estudo transversal, de uma amostra de conveniência, com 139 pacientes portadores de DF acompanhados no CRAF do HCPA. Resultados: a prevalência do uso abusivo foi de 1,5% para o álcool e 3,0% para o tabaco, e não se identificou o uso abusivo de outras substâncias, inclusive opióides. O padrão para o uso de substâncias não foi influenciado pela exposição ou por transtornos psiquiátricos não-psicóticos. Conclusão: São necessários mais estudos para reforçar estes achados, mas demonstra-se a segurança do uso de analgésicos opióides para o manejo das crises dolorosas apresentadas pelos portadores de DF. / Drug abuse is increasingly becoming a social and public health problem, because of the negative consequences that such abuse causes on the emotional and physical development of individuals. There are few references in the literature evaluating the use of these substances by individuals with sickle cell disease (SCD). These patients have severe and recurrent pain crises, frequently needing opioids drugs to control it. The compromised quality of life can predispose this population to the occurrence of non-psychotic psychiatric disorders such as depression, making them vulnerable to substance abuse. Objectives: To evaluate the level of consumption of alcohol and drugs in patients with SCD followed by Sickle Cell Disease Reference Center (CRAF) at Hospital de Clínicas de Porto Alegre; to estimate the percentage of patients in treatment of SCD who abuse alcohol and drugs, and to collaborate with the study evaluating the effectiveness of the CRAF. Methods: cross-sectional study of a convenience sample of 139 patients with SCD treated at CRAF. Results: the prevalence of abusive use of the studied population was 1.5% for alcohol and 3.0% for tobacco, and no abusive use of any other substance, including opioids, was identified. It was verified that the pattern for substance use was not influenced by exposure to substances or the presence of non-psychotic psychiatric disorders. Conclusion: More studies are needed to reinforce these findings, but they suggested that the use of opioid analgesics for the management of SCD painful crises is safe and do not induces substance abuse.

The purpose of this study is to explore professional drug addiction care workers’ attitudes towards harm reduction interventions. The data collection was conducted through digital survey mailed to mangers and staff. In total 73 individuals choose to answer the survey. The biopsychosocial perspective and stigmatization theory were used to theoretically reflect on the results. Most respondents reported positive attitudes towards maintenance treatment, needle exchange programs and overdose prevention with naloxone. The result also shows that the majority of respondents’ have a negative attitude towards injection rooms and decriminalization of drugs for personal use. Moreover, staff with higher education reported more positive attitudes towards maintenance treatment, needle exchange, injection rooms and decriminalization of drugs for personal use. In conclusion, it is important to recognize and spread new developments and evidence-based research regarding harm reduction and decriminalization of narcotics drugs. Based on the respondents’ negative attitudes towards implement injection rooms and decriminalize drugs for personal use, but also the improvement of staffs’ attitudes that present study found it is supposed that neglecting prohibition and showing zero tolerance towards personal use will probably disappear in the future even in Sweden.

Uma nutrição maternal rica em lipídios pode causar prejuízos no desenvolvimento e na vida adulta dos descendentes, como elevado risco de desenvolver alterações metabólicas e obesidade, e também parece alterar a sinalização central por opióides. Porém, estudos realizados a fim de investigar a influência da dieta hiperlipídica (HF) materna sobre o comportamento materno e o desenvolvimento da prole não são conclusivos. Este trabalho investigou a influência da dieta HF sobre a interação mãe-filhote, em duas gerações, e os efeitos imediatos e tardios sobre a prole, relacionando-os ao sistema opióide. As mães HF apresentaram prejuízos na ejeção do leite e maior expressão dos receptores opióides no hipotálamo. No geral, os descendentes HF apresentaram elevados níveis de colesterol, baixa leptina plasmática, maior expressão de peptídeos relacionados à ingestão alimentar, e menor peso. Portanto, o consumo materno de dieta HF causou alterações metabólicas, comportamentais e na expressão gênica na mãe e nos descendentes, mesmo que esses animais não tenham se tornado obesos. / A maternal nutrition high in fat may impair offspring development and adulthood, increasing the risk to develop metabolic alterations and obesity, and may modify the opioids central signaling. However, studies investigating maternal high fat (HF) diet influences on maternal behavior and offspring development are inconclusive. This study aimed to evaluate the influences of a diet high in fat on mother-pup interaction, in two generations, and its early and late effects in the offspring, connecting them to the opioid system. HF dams show decreased milk ejections and higher expression of opioid receptors in the hypothalamus. Overall, HF offspring had higher cholesterol levels, less serum leptin, higher expression of peptides related to food intake, and were lighter. Therefore, maternal intake of HF diet promoted metabolic, behavioral and gene expression alterations in the mother and her offspring, even though these animals did not become obese.

No description available.

Substance use disorders are serious health concerns in the United States. Furthermore, the National Survey on Drug Use and Health reports a continuous increase in substance use disorders in the United States during the last 10 years. However, there are not many effective pharmacotherapeutics available for substance use disorders. The current dissertation is focused on research aimed at discovering pharmacotherapeutics for substance use disorders. First part of dissertation focused on discovering methamphetamine (METH) use disorder therapeutics targeting specific mechanism of METH action on dopaminergic neurons. The second part of dissertation focused on opioids and cocaine use disorder therapeutics targeting rewarding pathway commonly activated by opioids and cocaine. With respect to METH, it induces release of dopamine (DA) in neuronal terminals by interacting with the vesicular monoamine transporter-2 (VMAT2) and DA transporter (DAT). VMAT2 inhibitors have been found by our research group to decrease METH-evoked DA release, METH-induced hyperlocomotion, and METH self-administration in rats. However, these VMAT2 inhibitors lacked selectivity and tolerance developed to these pharmacologic effects after repeated administration, thereby limiting their potential as pharmacotherapeutics for METH use disorders. In the current study, analogs from a novel scaffold were found to selectively inhibit VMAT2 and were evaluated using neurochemical and behavioral pharmacological approaches. R- and S-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine (GZ-11610 and GZ-11608, respectively) exhibited 94- to 3450-fold selectivity for VMAT2 over human-ether-a-go-go (hERG) channel, DAT, serotonin transporter, and nicotinic acetylcholine receptors. GZ-11608 competitively and concentration-dependently inhibited METH-evoked DA release via VMAT2. Also, GZ-11610 (56-300 mg/kg, oral) and GZ-11608 (300 mg/kg, oral; 10-30 mg/kg, s.c.) reduced METH-induced hyperlocomotor activity in METH-sensitized rats. Furthermore, GZ-11608 (1-30 mg/kg, s.c.) inhibited METH self-administration, cue- and METH-induced reinstatement in a dose-dependent manner, and 30 mg/kg (s.c.), 10 mg/kg (s.c.), and 17 mg/kg (s.c.) produced significant effect, respectively. Importantly, the GZ-11608-induced decrease in METH self-administration was not surmounted by increasing the amount of METH available. GZ-11608 did not substitute for METH and did not serve as a reinforcer in rats self-administering METH and drug naïve rats, respectively. Thus, these VMAT2 inhibitors incorporating a new scaffold are novel leads for new pharmacotherapeutics to treat METH use disorders. Substances with high abuse potential including opioids and cocaine elevate extracellular DA concentration in the nucleus accumbens, and this mechanism has long been considered to underly substance-induced reward. DA in the nucleus accumbens originates from DA neuron cell bodies located in the ventral tegmental area in the midbrain. Interestingly, M5 muscarinic acetylcholine receptors (mAChRs) are proteins that are highly expressed on ventral tegmental area DA neurons. Also, studies investigating M5 mAChRs knockout mice showed reduced responding for cocaine in cocaine self-administration and decreased time spent in cocaine-paired and morphine-paired place preference studies. Pharmacological inhibition of M5 mAChRs function via microinfusing mAChR antagonists exhibiting no selectivity among M1-M5 mAChRs subtypes into the ventral tegmental area where expression of M5 mAChRs are dominant, reduced morphine-induced hyperlocomotion and cocaine seeking behaviors in rats. These studies support therapeutic potential of M5 mAChRs selectivity antagonists in opioids and cocaine use disorders. Thus, in the current study, affinity of a series of pethidine and quinuclidinyl N-phenylcarbamate analogs for M5 mAChRs was evaluated using in vitro and ex vivo neuropharmacological assays. Among the pethidine analogs, compound 6a showed the highest binding affinity at M5 (Ki = 0.38 µM), but also high affinity at M1 and M3 mAChRs (0.67 and 0.37 µM, respectively). Among the quinuclidinyl N-phenylcarbamate analogs, compound 13c exhibited the highest affinity at M5 (Ki = 1.8 nM), but also high affinity at M1, M2, M3 and M4 mAChRs (Ki = 1.6, 13, 2.6, 2.2 nM, respectively). Also, 13c acted as an agonist of mAChRs on oxotremorine-induced DA release from rat striatal slices. In addition, compound 13b was found exhibiting the highest selectivity (17-fold) at M3 over M2 mAChRs, suggesting potential of 13b as a chronic obstructive pulmonary disease therapeutics. Taken together, these novel analogs serve as leads for further discovery of subtype-selective M5 mAChR antagonists that may have potential as therapeutics for substance use disorders, as well as for chronic obstructive pulmonary disease.