Participation of Dopamine D1 and D2 Receptors in the Rapid-Onset Behavioral Sensitization to Modafinil

Studies on the abuse potential of modafinil, a psychostimulant-like drug used to treat narcolepsy, are still controversial. While some studies claim no potential for abuse, increasing evidence suggests that modafinil induces abuse-related effects, including rapid-onset behavioral sensitization (i.e., a type of sensitization that develops within hours from the drug priming administration). The rapid-onset sensitization paradigm is a valuable tool to study the neuroplastic changes that occur quickly after drug administration, and shares neuroadaptations with drug abuse in humans. However, the mechanisms involved in the rapid-onset behavioral sensitization induced by modafinil are uncertain. Our aim was to investigate the possible involvement of dopamine D1 and D2 receptors on acute modafinil-induced hyperlocomotion and on the induction and expression of rapid-onset behavioral sensitization induced by modafinil in male Swiss mice. Treatment with the D1 receptor antagonist SCH 23390 or the D2 receptor antagonist sulpiride attenuated the acute modafinil-induced hyperlocomotion in a dose-dependent manner. Pretreatment with either antagonist before the priming injection of modafinil prevented the development of sensitization in response to a modafinil challenge 4 h later. However, only SCH 23390 decreased the expression of modafinil-induced rapid-onset behavioral sensitization. Taken together, the present findings provide evidence of the participation of D1 and D2 receptors on the development of rapid-onset behavioral sensitization to modafinil, and point to a prominent role of D1 receptors on the expression of this phenomenon

Modafinil induces rapid-onset behavioral sensitization and cross-sensitization with cocaine in mice: implications for the addictive potential of modafinil

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)There is substantial controversy about the addictive potential of modafinil, a wake promoting drug used to treat narcolepsy, proposed as pharmacotherapy for cocaine abuse, and used indiscriminately by healthy individuals due to its positive effects on arousal and cognition. The rapid-onset type of behavioral sensitization (i.e., a type of sensitization that develops within a few hours from the drug priming administration) has been emerged as a valuable tool to study binge-like patterns of drug abuse and the neuroplastic changes that occur quickly after drug administration that ultimately lead to drug abuse. Our aim was to investigate the possible development of rapid-onset behavioral sensitization to modafinil and bidirectional rapid-onset cross sensitization with cocaine in male Swiss mice. A priming injection of a high dose of modafinil (64 mg/kg) induced rapid-onset behavioral sensitization to challenge injections of modafinil at the doses of 16, 32, and 64 mg/kg, administered 4 h later. Furthermore, rapid-onset cross-sensitization was developed between modafinil and cocaine (64 mg/kg modafinil and 20 mg/kg cocaine), in a bidirectional way. These results were not due to residual levels of modafinil as the behavioral effects of the priming injection of modafinil were no longer present and modafinil plasma concentration was reduced at 4 h post-administration. Taken together, the present findings provide preclinical evidence that modafinil can be reinforcing per se and can enhance the reinforcing effects of stimulants like cocaine within hours after administration.There is substantial controversy about the addictive potential of modafinil, a wake promoting drug used to treat narcolepsy, proposed as pharmacotherapy for cocaine abuse, and used indiscriminately by healthy individuals due to its positive effects on aro7FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOCAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIORFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)2014/24277-4sem informaçãosem informaçã

Addictive potencial of modafinil and cross-sensitization with cocaine: a preclinical study

Repeated or even a single exposure to all addictive drugs causes persistent locomotor sensitization, which is the result of an abundance of neuroplastic changes occurring within the circuitry involved in motivational behavior and is thought to play a key role in certain aspects of drug addiction. There is substantial controversy about the addictive potential of modafinil, a wake-promoting drug used to treat narcolepsy that is increasingly being used as a cognitive enhancer and has been proposed as a pharmacotherapy for cocaine dependence. We investigated the ability of modafinil to induce locomotor sensitization after repeated or single administration in mice. Bi-directional crosssensitization with cocaine and modafinil-induced conditioned place preference were also evaluated. Both repeated and single exposure to modafinil produced a pronounced locomotor sensitization that cross-sensitized in a bi-directional way with cocaine. Remarkably, when cocaine and modafinil were repeatedly administered sequentially, their behavioral sensitization was additive. In addition, similar to the clinical situation in which the abuse potential of modafinil seems to be higher in female subjects, modafinil-induced locomotor sensitization had a higher magnitude in female mice. Supporting these behavioral sensitization data, modafinil produced a pronounced conditioned place preference in the mouse. Taken together, the present findings provide preclinical evidence for the addictive potential of modafinil. Our data also strongly suggest that similar neural substrates are involved in the psychomotor/rewarding effects of modafinil and cocaine.Há grande controvérsia sobre o potencial de abuso do modafinil, uma droga que promove alerta e que tem sido utilizada no tratamento da narcolepsia e para aumentar a cognição, tendo sido utilizada também na farmacoterapia da dependência por cocaína. Na presente tese, nós investigamos a capacidade do modafinil em induzir sensibilização locomotora após tratamento repetido ou uma injeção única em camundongos. Avaliamos também a possibilidade do desenvolvimento de sensibilização cruzada bidirecional entre modafinil e a cocaína e a capacidade do modafinil em induzir preferência condicionada por lugar. Tanto a administração repetida como uma injeção única de modafinil promoveram sensibilização locomotora robusta e sensibilização cruzada bidirecional entre modafinil e cocaína. Ainda, quando cocaína e modafinil foram administrados repetidamente e sequencialmente, a sensibilização locomotora foi de maior magnitude. Além disso, similar a situação clinica em que o potencial de abuso do modafinil parece ser maior em mulheres, a sensibilização locomotora induzida por modafinil foi de magnitude maior em camundongos fêmeas. Corroborando os dados da sensibilização comportamental, o modafinil induziu também preferência condicionada por lugar robusta. Tomados em conjunto, os presentes achados fornecem evidencias pré-clinicas do potencial de abuso do modafinil. Nossos dados também sugerem que os sistemas neuronais envolvidos nos efeitos psicomotores/recompensadores do modafinil e da cocaína são semelhantes.TEDEBV UNIFESP: Teses e dissertaçõe

Caracterização experimental da sensibilização comportamental imediata ao modafinil em camundongos

Há grande controvérsia sobre o potencial de abuso do modafinil, uma droga aprovada para o tratamento da narcolepsia, estudada como possível agente terapêutico para o tratamento da dependência por cocaína, e utilizada de modo indiscriminado por indivíduos saudáveis devido aos seus efeitos benéficos sobre o alerta e a cognição. Uma forma de se estudar as alterações neuroplásticas que ocorrem rapidamente após a administração de drogas e que levam, consequentemente ao abuso destas, é por meio do modelo animal de sensibilização comportamental imediata, previamente caracterizado para a anfetamina em roedores. Nesse modelo, uma injeção de anfetamina em uma dose baixa foi capaz de eliciar comportamentos estereotipados e hiperlocomoção vigorosos quando administrada a roedores que haviam recebido uma única injeção de anfetamina apenas algumas horas antes. Sendo assim, essa Tese teve como objetivos: 1) validar e caracterizar comportamentalmente o fenômeno de sensibilização imediata ao modafinil em camundongos, 2) verificar a participação de receptores dopaminérgicos D1 e D2 no desenvolvimento da sensibilização imediata ao modafinil, 3) verificar o possível desenvolvimento de sensibilização comportamental imediata cruzada entre modafinil e cocaína e 4) verificar possíveis alterações na neurogênese hipocampal após a sensibilização imediata ao modafinil e a sensibilização imediata cruzada entre o modafinil e a cocaína. Como resultados, verificamos que o efeito estimulante locomotor da injeção indutora de modafinil cessou 150 minutos após a sua administração e que uma injeção indutora de modafinil na dose de 64 mg/kg induziu sensibilização comportamental imediata a injeções desafio de modafinil nas doses de 16 mg/kg, 32 mg/kg e 64 mg/kg, administradas 4 horas após a injeção indutora. Verificamos ainda que o antagonista D1 SCH 23390, mas não o antagonista D2 sulpiride, atenuou o efeito estimulante locomotor induzido pelo modafinil. No entanto, ambos os antagonistas dopaminérgicos inibiram a sensibilização comportamental imediata ao modafinil. Ainda, a sensibilização imediata também ocorreu de maneira cruzada e bidirecional entre o modafinil e a cocaína Por fim, a sensibilização imediata ao modafinil e a sensibilização imediata cruzada entre modafinil e cocaína não alteraram a neurogênese, avaliada pela quantificação de neurônios DCX+ no hipocampo. Tomados em conjunto, os presentes achados fornecem evidências pré-clínicas do potencial de abuso do modafinil, mostrando que essa droga é capaz de promover neuroadaptações praticamente imediatas, que envolvem a participação dos receptores dopaminérgicos D1 e D2, e que estão intimamente relacionadas aos mecanismos subjacentes à dependência de cocaína.Dados abertos - Sucupira - Teses e dissertações (2013 a 2016

Modafinil Induces Rapid-Onset Behavioral Sensitization and Cross-Sensitization with Cocaine in Mice: Implications for the Addictive Potential of Modafinil

There is substantial controversy about the addictive potential of modafinil, a wake promoting drug used to treat narcolepsy, proposed as pharmacotherapy for cocaine abuse, and used indiscriminately by healthy individuals due to its positive effects on arousal and cognition. The rapid-onset type of behavioral sensitization (i.e., a type of sensitization that develops within a few hours from the drug priming administration) has been emerged as a valuable tool to study binge-like patterns of drug abuse and the neuroplastic changes that occur quickly after drug administration that ultimately lead to drug abuse. Our aim was to investigate the possible development of rapid-onset behavioral sensitization to modafinil and bidirectional rapid-onset cross sensitization with cocaine in male Swiss mice. A priming injection of a high dose of modafinil (64 mg/kg) induced rapid-onset behavioral sensitization to challenge injections of modafinil at the doses of 16, 32, and 64 mg/kg, administered 4 h later. Furthermore, rapid-onset cross-sensitization was developed between modafinil and cocaine (64 mg/kg modafinil and 20 mg/kg cocaine), in a bidirectional way. These results were not due to residual levels of modafinil as the behavioral effects of the priming injection of modafinil were no longer present and modafinil plasma concentration was reduced at 4 h post-administration. Taken together, the present findings provide preclinical evidence that modafinil can be reinforcing per se and can enhance the reinforcing effects of stimulants like cocaine within hours after administration.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundo de Auxílio aos Docentes e Alunos (FADA)Associação Fundo de Incentivo à Psicofarmacologia (AFIP)Univ Fed Sao Paulo, Dept Physiol, Lab Neurophysiol, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Pharmacol, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Psychobiol, Sao Paulo, BrazilUniv Estadual Campinas, Fac Pharmaceut Sci, Campinas, SP, BrazilLaboratory of Neurophysiology, Department of Physiology, Universidade Federal de São Paulo, São Paulo, BrazilDepartment of Pharmacology, Universidade Federal de São Paulo, São Paulo, BrazilDepartment of Psychobiology, Universidade Federal de São Paulo, São Paulo, BrazilFAPESP: 2014/24277-4Web of Scienc

The effects of paradoxical sleep deprivation on amphetamine-induced behavioral sensitization in adult and adolescent mice

Drug-induced behavioral sensitization (BS), paradoxical sleep deprivation (PSD) and adolescence in rodents are associated with changes in the mesolimbic dopaminergic system. We compared the effects of PSD on amphetamine-induced BS in adult and adolescent mice. Adult (90 days old) and adolescent (45 days old) Swiss mice were subjected to PSD for 48 h. Immediately after PSD, mice received saline or 2.0 mg/kg amphetamine intraperitoneally (i.p.), and their locomotion was quantified in activity chambers. Seven days later, all the animals were challenged with 2.0 mg/kg amphetamine i.p., and their locomotion was quantified again. Acute amphetamine enhanced locomotion in both adult and adolescent mice, but BS was observed only in adolescent mice. Immediately after its termination, PSD decreased locomotion of both saline- and amphetamine-treated adolescent mice. Seven days later, previous PSD potentiated both the acute stimulatory effect of amphetamine and its sensitization in adolescent mice. in adult animals, previous PSD revealed BS. Our data suggest that adolescent mice are more vulnerable to both the immediate and long-term effects of PSD on amphetamine-induced locomotion. Because drug-induced BS in rodents shares neuroplastic changes with drug craving in humans, our findings also suggest that both adolescence and PSD could facilitate craving-related mechanisms in amphetamine abuse. (C) 2014 Elsevier Ireland Ltd. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo, Dept Pharmacol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, BR-04024002 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pharmacol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, BR-04024002 São Paulo, BrazilFAPESP: 05/54956-1FAPESP: 301742/2010-3FAPESP: 98/143030-3Web of Scienc

Antinociceptive Activity of the Skin Secretion of Phyllomedusa rohdei (Amphibia, Anura)

Pain is a distressful experience that can have a major impact on an individual’s quality of life. The need for new and better analgesics has been further intensified in light of the current opioid epidemic. Substances obtained from amphibians have been shown to contain bioactive peptides that exert analgesic effects. The genus Phyllomedusa represents an important source of peptides and bioactive components. The aim of this study was to investigate the antinociceptive effects of the skin secretion of Phyllomedusa rohdei in rodent models of pain. The crude skin extract of P. rohdei was tested in different pain models: acetic acid-induced writhing test (mice), formalin test (rats), Von Frey electronic test for hypernociception induced by PGE2 (rats), and hot plate test (mice). Motor-impairing effects were tested using the rota-rod test. The results showed that the skin extract of P. rohdei exerted antinociceptive effects in all pain models tested. Particularly, the highest dose tested of the skin extract decreased acetic acid-induced writhing by 93%, completely blocked formalin-induced nociception both during the acute and inflammatory phases of the test, PGE2-induced hypernociception by 73% and increased latency to paw withdrawal in the hot plate test by 300%. The effects observed in the hot plate test were reversed by pretreatment with selective µ and κ, but not δ, opioid receptor antagonists, indicating a mechanism of action dependent on µ and κ opioid receptors. The results were not influenced by sedative effects. Further studies remain necessary to reveal the specific compounds involved in the antinociceptive effects of P. rohdei skin extract as a new therapeutic tool in pain management