Behavioral effects of morphine and methadone in rhesus monkeys

Pharmacology Biochemistry and Behavior, 1996

The relationship between drug concentration and choice. PHARMACOL BIOCHEM BEHAV 54(3) [547][548][549][550][551][552][553][554] 1996.-The relative reinforcing effects of orally delivered methadone were studied in five male rhesus monkeys. Drug deliveries were available under either a fixed-ratio (FR) or a fixed-interval (FI) schedule. Three concentrations of methadone, low (0.05 mg/ml), intermediate (0.2 mg/ml), and high (0.8 mg/ml) were delivered in 0.65 ml volumes. In the first experiment, monkeys were presented with a choice paradigm. Under independent FR schedules responding led to a delivery of either a methadone solution or the water vehicle. For each concentration, deliveries of a methadone solution maintained higher response rates than did deliveries of water. In the second experiment, methadone concentrations were tested in pairs in the following sequence: high vs. low, high vs. intermediate, intermediate vs. low, high vs. intermediate (retest), and high vs. low (retest). The retest of the last two pairs was designed to counterbalance the test sequence, so that order effects, if they existed, could be detected. Regardless of the schedule, the higher concentration of the methadone pair maintained a greater response rate than did the lower concentration. The present results are consistent with the generalization based on other studies that over a broad range of concentrations and across pharmacological classes, reinforcement schedules, and routes of administration, reinforcing effects increase with increases in drug concentration. Drug self-administration Methadone Opioids Drug addiction Reinforcement magnitude Drug reinforcement Choice Dose Relative reinforcement Fixed-ratio schedules Choice procedures Oral route Rhesus monkeys IN DRUG self-administration studies with simple reinforcement schedules response rate is usually an inverted U-shaped (or bitonic) function of dose . This response-rate function has been interpreted several ways. The ascending part of the curve often has been ascribed to increases in reinforcing effects with increases in dose, while the descending portion has been attributed to motor impairment, satiation, aversive effects, and/or decreases in reinforcing effects (15). If decreases in response rate do reflect decreases in reinforcing effectiveness, then the dose that maintains the highest rate of responding, that is, the dose at the peak of the inverted U-shaped function should be the most reinforcing dose, and rate of responding would be a universal measure of the magnitude of reinforcing effects. However, this interpretation has not been' supported by studies with rhesus monkeys (13,14,17,18, 21,22,37). These studies were conducted with psychomotor stimulants and barbiturates as reinforcers, and indicate that, at least with these drugs, the dose that maintains the highest rate is usually not the most reinforcing dose.

Psychopharmacology, 1964

A fixed interval-fixed ratio chain of behavior was maintained for periods as long as 6 months by intravenously administered morphine. The morphine reinforced FI-FR chain was found to be a sensitive and reliable index of motivational changes induced by drug deprivation, nalorphine antagonism and pretreatment with morphine. Profound behavioral disruption occurred in both shock avoidance and food reinforced ratio behavior under conditions of drug deprivation. The behavioral disruption of the food reinforced and shock avoidance behaviors was ameliorated by a single self-administration of morphine. Substitution of saline for the morphine solution produced a transitory placebo effect characterized by an immediate return of the food and avoidance behaviors to their pre-deprivation baseline conditions, but followed by progressive disruption as time without the drug increased.

Journal of the Experimental Analysis of Behavior, 1986

Squirrel monkeys were trained to respond under a multiple fixed-interval, fixed-interval schedule in which the first response after 5 min terminated a visual stimulus in the presence of which electric shocks could occur. During one component of the schedule, correlated with one color of stimulus lights, every 30th response also produced electric shock; responding was suppressed during this component to approximately 10 to 12% of that occurring in the alternate component in which responding was not punished. In contrast to previous research, morphine (0.03 to 1.0 mg/kg) increased punished responding. Unpunished responding, however, was either not affected or decreased at doses of morphine that increased punished responding. Increases in rate of punished responding also occurred when the single-schedule punishment condition was studied alone in these animals. Subsequent experimentation, which systematically analyzed the development of the rate-enhancing effects of morphine on punished responding, involved the study of drug effects in additional monkeys trained initially under a single-schedule punishment condition. The effects of morphine on punished responding were studied before, after, and then during exposure to the multiple schedule that included a component in which responding was not punished. Increases in response rate with morphine did not occur until it was administered during exposure to the multiple schedule that included a component in which responding was not punished. As with the other monkeys, once the rate increases in punished responding occurred under the multiple schedule, thcse effects of morphine persisted, even when the multiple schedule was removed. These findings indicate that the behavioral effects of a drug can depend on the combined influencc of that drug and the specific circumstances under which it is studied. Neither the behavioral experience alone nor exposure to the drug was sufficient to alter morphine's effects. Once this drug-behavior interaction occurs, however, the behavioral effects of that drug can be changed substantially.

Drug and Alcohol Dependence, 1999

The effects of the opioid antagonist naloxone were studied with three monkeys under a mutually exclusive fixed-interval 15 s (FI 15 s) schedule of reinforcement. Under this schedule, at the end of each interval, the monkey could obtain one liquid delivery from either the spout that delivered methadone (0.8 mg/ml) or the spout that delivered vehicle (deionized water). Naloxone doses from 0.0125 to 0.2 mg/kg (IM daily 10 min prior to the session) were studied in an ascending then descending order. In the ascending series, low naloxone doses produced increases of methadone deliveries in the first hour of the session for three monkeys and increases over the entire 3-h session for two of the three monkeys. At higher doses naloxone decreased methadone deliveries in all three monkeys. Naloxone's effects were usually greater during the descending dose series than during the ascending series. These findings suggest that a history of naloxone injections is one determinant of response to the drug. Vehicle maintained responding was generally low and not changed by naloxone in a systematic way. The time course of methadone deliveries showed that naloxone's effects were greatest in the first hour of the session and were a direct function of dose. These experiments demonstrate that oral methadone reinforced behavior is sensitive to naloxone pretreatment and that the effects of naloxone are a direct function of dose.

Pharmacology Biochemistry and Behavior, 1989

Twelve pigeons were initially trained under either a fixed-ratio (FR) 50 or differential-reinforcement-of-low-rate (DRL) 10-sec schedule of food presentation. After 50 sessions of exposure to the foregoing schedules all pigeons key pecked under a fixed-interval (FI) 90-sec schedule. Key-peck rates differed as a function of schedule history, with FR-history subjects responding at significantly higher rates under the FI schedule than DRL-history subjects. To better compare methadone's rate-altering effects on baseline response rates, 8 naive pigeons were trained from the outset to key peck under an FI 90-sec schedule and were subsequently divided into 2 groups based on overall response rates (groups FI-H and FI-L). After at least 40 sessions under the FI schedule methadone dose-response curves were determined at doses of 0.6, 1.2 and 2.4 mg/kg. Low and intermediate methadone doses did not effect key-peck rates by pigeons with an FR history compared to significant rate decreases by pigeons having comparable rates but without a history of responding under an FR schedule (group FI-H). No differential effects following methadone were observed in low-rate subjects (DRL history and FI-L). When methadone (9.0 and 12.0 mg/kg/day) was administered chronically, response rates of all subjects were initially suppressed, with FI control subjects showing more complete recovery of drug-free baselines than either FR- or DRL-history groups. Naloxone (1.0 mg/kg) reversed methadone's rate-decreasing effects, although these actions were significantly less in subjects with prior experience under DRL schedules. Following completion of the chronic phase, and when subjects had been drug free for at least 14 sessions, the methadone dose-response curve was redetermined. The differential effects of methadone associated with reinforcement history were no longer evident, suggesting that a drug history can interact with a schedule history. These experiments add to the growing body of evidence indicating that prior experience can influence the behavioral actions of drugs independent of control rate of responding. Moreover, the data reveal that the influence of reinforcement schedule history depends on whether drugs are administered acutely or chronically.

Pharmacology, biochemistry, and behavior, 1983

Rats were given the opportunity to take one of five concentrations of saccharin solutions. Intake across concentrations generated a preference-aversion curve. Morphine, 2 mg/kg, increased intake of saccharin solutions when rats were 12-hr water deprived or were not deprived. These effects with morphine are opposite to those of naloxone and strengthen the idea that there is opioid involvement in incentive motivation.

Journal of Pharmacology and Experimental Therapeutics

Opioid abuse remains a serious public health challenge, despite the availability of medications that are effective in some patients (naltrexone, buprenorphine, and methadone). This study explored the potential of a pseudoirreversible mu-opioid receptor antagonist [methocinnamox (MCAM)] as a treatment for opioid abuse by examining its capacity to attenuate the reinforcing effects of mu-opioid receptor agonists in rhesus monkeys. In one experiment, monkeys responded for heroin (n 5 5) or cocaine (n 5 4) under a fixed-ratio schedule. Another group (n 5 3) worked under a choice procedure with one alternative delivering food and the other alternative delivering the mu-opioid receptor agonist remifentanil. A third group (n 5 4) responded for food and physiologic parameters were measured via telemetry. The effects of MCAM were determined in all experiments and, in some cases, were compared with those of naltrexone. When given immediately before sessions, naltrexone dosedependently decreased responding for heroin and decreased choice of remifentanil while increasing choice of food, with responding returning to baseline levels 1 day after naltrexone injection. MCAM also decreased responding for heroin and decreased choice of remifentanil while increasing choice of food; however, opioid-maintained responding remained decreased for several days after treatment. Doses of MCAM that significantly decreased opioid-maintained responding did not decrease responding for cocaine or food. MCAM did not impact heart rate, blood pressure, body temperature, or activity at doses that decreased opioid self-administration. Because MCAM selectively attenuates opioid self-administration for prolonged periods, this novel drug could be a safe and effective alternative to currently available treatments for opioid abuse.

Psychopharmacology, 2011

Rationale-Delta-opioid agonists enhance the antinociceptive efficacy of methadone and other mu-opioid agonists. However, relatively little is known about the degree to which delta agonists might enhance the abuse-related effects of mu agonists.

Surgiu, pelos anos 40, na Europa, especialmente na França, um movimento de interesse voltado para os antigos escritores cristãos, conhecidos tradicionalmente como "Padres da Igreja", ou "santos Padres", e suas obras. Esse movimento, liderado por Henri de Lubac e Jean Daniélou, deu origem à coleção "Sources Chrétiennes", hoje com mais de 500 títulos, alguns dos quais com várias edições. Com o Concílio Vaticano II, ativou-se em toda a Igreja o desejo e a necessidade de renovação da liturgia, da exegese, da espiritualidade e da teologia a partir das fontes primitivas. Surgiu a necessidade de "voltar às fontes" do cristianismo. No Brasil, em termos de publicação das obras destes autores antigos, pouco se fez. A Paulus Editora procura, agora, preencher esse vazio existente em língua portuguesa. Nunca é tarde ou fora de época para rever as fontes da fé cristã, os fundamentos da doutrina da Igreja, especialmente no sentido de buscar nelas a inspiração atuante, transformadora do presente. Não se propõe uma volta ao passado através da leitura e estudo dos textos primitivos como remédio ao saudosismo. Ao contrário, procura-se oferecer aquilo que constitui as "fontes" do cristianismo para que o leitor as examine, as avalie e colha o essencial, o espírito que as produziu. Cabe ao leitor, portanto, a tarefa do discernimento. Paulus Editora quer, assim, oferecer ao público de língua portuguesa, leigos, clérigos, religiosos, aos estudiosos do cristianismo primevo, uma série de títulos, não exaustiva, cuidadosamente traduzida e preparada, dessa vasta literatura cristã do período patrístico. Para não sobrecarregar o texto e retardar a leitura, procurou-se evitar anotações excessivas, as longas introduções estabelecendo paralelismos de versões diferentes, com referências aos empréstimos da literatura pagã, filosófica, religiosa, jurídica, às infindas controvérsias sobre determinados textos e sua autenticidade. Procurou-se fazer com que o resultado desta pesquisa original se traduzisse numa edição despojada, porém, séria. Cada obra tem uma introdução breve com os dados biográficos essenciais do autor e um comentário sucinto dos aspectos literários e do conteúdo da obra suficientes para uma boa compreensão do texto. O que interessa é colocar o leitor diretamente em contato com o texto. O leitor deverá ter em mente as enormes diferenças de gêneros literários, de estilos em que estas obras foram redigidas: cartas, sermões, comentários bíblicos, paráfrases, exortações, disputas com os heréticos, tratados teológicos vazados em esquemas e categorias filosóficas de tendências diversas, hinos litúrgicos. Tudo isso inclui, necessariamente, uma disparidade de tratamento e de esforço de compreensão a um mesmo tema. As constantes, e por vezes longas, citações bíblicas ou simples transcrições de textos escriturísticos devem-se ao fato de que os Padres escreviam suas reflexões sempre com a Bíblia numa das mãos. Julgamos necessário um esclarecimento a respeito dos termos patrologia, patrística e Padres ou Pais da Igreja. O termo patrologia designa, propriamente, o estudo sobre a vida, as obras e a doutrina dos Padres da Igreja. Ela se interessa mais pela história antiga, incluindo também obras de escritores leigos. Por patrística se entende o estudo da doutrina, das origens dessa doutrina, suas dependências e empréstimos do meio cultural, filosófico, e da evolução do pensamento teológico dos Padres da Igreja. Foi no século XVII que se criou a expressão "teologia patrística" para indicar a doutrina dos Padres da Igreja, distinguindo-a da "teologia bíblica", da "teologia escolástica", da "teologia simbólica" e da "teologia especulativa". Finalmente, "Padre ou Pai da Igreja" se refere a escritor leigo, sacerdote ou bispo, da antiguidade cristã, considerado pela tradição posterior como testemunho particularmente autorizado da fé. Na tentativa de eliminar as ambiguidades em torno desta expressão, os estudiosos convencionaram em receber como "Pai da Igreja" quem tivesse estas qualificações: ortodoxia de doutrina, santidade de vida, aprovação eclesiástica e antiguidade. Mas os próprios conceitos de ortodoxia, santidade e antiguidade são ambíguos. Não se espere encontrar neles doutrinas acabadas, buriladas, irrefutáveis. Tudo estava ainda em ebulição, fermentando. O conceito de ortodoxia é, portanto, bastante largo. O mesmo vale para o conceito de santidade. Para o conceito de antiguidade, podemos admitir, sem prejuízo para a compreensão, a opinião de muitos especialistas que estabelece, para o Ocidente, Igreja latina, o período que, a partir da geração apostólica, se estende até Isidoro de Sevilha (560-636). Para o Oriente, Igreja grega, a antiguidade se estende um pouco mais, até a morte de São João Damasceno (675-749). Os "Pais da Igreja" são, portanto, aqueles que, ao longo dos sete primeiros séculos, foram forjando, construindo e defendendo a fé, a liturgia, a disciplina, os costumes e os dogmas cristãos, decidindo, assim, os rumos da Igreja. Seus textos se tornaram fontes de discussões, de inspirações, de referências obrigatórias ao longo de toda tradição posterior. O valor dessas obras que agora Paulus Editora oferece ao público pode ser avaliado neste texto: "Além de sua importância no ambiente eclesiástico, os Padres da Igreja ocupam lugar proeminente na literatura e, particularmente, na literatura greco-romana. São eles os últimos representantes da Antiguidade, cuja arte literária, não raras vezes, brilha nitidamente em suas obras, tendo influenciado todas as literaturas posteriores. Formados pelos melhores mestres da Antiguidade clássica, põem suas palavras e seus escritos a serviço do pensamento cristão. Se excetuarmos algumas obras retóricas de caráter apologético, oratório ou apuradamente epistolar, os Padres, por certo, não queriam ser, em primeira linha, literatos, mas arautos da doutrina e moral cristãs. A arte adquirida, não obstante, vem a ser para eles meio para alcançar este fim. (…) Há de se lhes aproximar o leitor com o coração aberto, cheio de boa vontade e bem disposto à verdade cristã.

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