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

Effects of rimonabant on the development of single dose-induced behavioral sensitization to ethanol, morphine and cocaine in mice

Rationale: the endocannabinoid system has been implicated in the neurobiological mechanism underlying drug addiction, especially the primary rewarding dopamine-dependent processes. Therefore, endocannabinoid receptor antagonists, such as the CB1 cannabinoid antagonist rimonabant, have been proposed as candidates for preventive addiction therapies.Objectives: Investigate the possible involvement of CB1 receptors in the development of behavioral sensitization to ethanol, morphine and cocaine in mice.Methods: We compared the effects of different doses of rimonabant (0.3, 1, 3 and 10 mg/kg) on spontaneous locomotor activity in the open-field, hyperlocomotion induced by acute administration of ethanol (1.8 g/kg), morphine (20 mg/kg) or cocaine (10 mg/kg) and on subsequent drug-induced locomotor sensitization using a two-injection protocol in mice. We also investigated a possible depressive-like effect of an acute rimonabant challenge at the highest dose and its potential anxiogenic property.Results: At the highest dose, rimonabant abolished ethanol-and cocaine-induced hyperlocomotion and behavioral sensitization without modifying spontaneous and central locomotor activity or inducing depressive-like behavior on the forced swim test in mice. the other doses of rimonabant also selectively blocked acute ethanol-induced central hyperlocomotion. Although rimonabant at 0.3 and 1 mg/kg potentiated the central hyperlocomotion induced by acute morphine injection, it was effective inattenuating morphine-induced behavioral sensitization at all doses.Conclusions: Because the neural basis of behavioral sensitization has been proposed to correspond to some components of addiction, our findings indicate that the endocannabinoid system might be involved in ethanol, cocaine and morphine abuse. (C) 2014 Elsevier Inc. All rights reserved.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 Apoio ao Docente e Aluno (FADA)Associacao Fundo de Incentivo a Pesquisa (AFIP)Univ Estadual Santa Cruz UESC, Dept Ciencias Saude, Ilheus, BA, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Fisiol, São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Farmacol, São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Psicobiol, São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Fisiol, São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Farmacol, São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Psicobiol, São Paulo, BrazilWeb of Scienc

Acute total sleep deprivation potentiates amphetamine-induced locomotor-stimulant effects and behavioral sensitization in mice

It has been demonstrated that a prolonged period (48 h) of paradoxical sleep deprivation (PSD) potentiates amphetamine (AMP)-induced behavioral sensitization, an animal model of addiction-related neuroadaptations. in the present study, we examined the effects of an acute short-term deprivation of total sleep (TSD) (6 h) on AMP-induced behavioral sensitization in mice and compared them to the effects of short-term PSD (6 h). Three-month-old male C57BL/6J mice underwent TSD (experiment 1 gentle handling method) or PSD (experiment 2 multiple platforms method) for 6 h. Immediately after the sleep deprivation period, mice were tested in the open field for 10 min under the effects of saline or 2.0 mg/kg AMP. Seven days later, to assess behavioral sensitization, all of the mice received a challenge injection of 2.0 mg/kg AMP and were tested in the open field for 10 mm. Total, peripheral, and central locomotion, and grooming duration were measured. TSD, but not PSD, potentiated the hyperlocomotion induced by an acute injection of AMP and this effect was due to an increased locomotion in the central squares of the apparatus. Similarly, TSD facilitated the development of AMP-induced sensitization, but only in the central locomotion parameter. the data indicate that an acute period of TSD may exacerbate the behavioral effects of AMP in mice. Because sleep architecture is composed of paradoxical and slow wave sleep, and 6-h PSD had no effects on AMP-induced hyperlocomotion or sensitization, our data suggest that the deprivation of slow wave sleep plays a critical role in the mechanisms that underlie the potentiating effects of TSD on both the acute and sensitized addiction-related responses to AMP. (C) 2013 Elsevier Inc. All rights reserved.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 Apoio ao Docente e Aluno (FADA)Associacao Fundo de Incentivo a Pesquisa (AFIP)Universidade Federal de São Paulo, Dept Psychobiol, BR-04024002 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pharmacol, BR-04023062 São Paulo, BrazilFlorida State Univ, Dept Psychol, Tallahassee, FL 32306 USAUniversidade Federal de São Paulo, Dept Psychobiol, BR-04024002 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pharmacol, BR-04023062 São Paulo, BrazilWeb of Scienc