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

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

Distinctive Neuroanatomic Regions Involved in Cocaine-Induced Behavioral Sensitization in Mice

The present study aimed to characterize the phenomenon of behavioral sensitization to cocaine and to identify neuroanatomical structures involved in the induction and expression phases of this phenomenon. For this, in experiment 1 (induction phase), mice were treated with saline or cocaine every second day for 15 days (conditioning period), in the open-field or in their home-cages. In experiment 2 (expression phase), the same protocol was followed, except that after the conditioning period the animals were not manipulated for 10 days, and after this interval, animals were challenged with cocaine. Neuroanatomical structures involved in the induction and expression phases were identified by stereological quantification of c-Fos staining in the dorsomedial prefrontal cortex (dmPFC), nucleus accumbens core (NAc core and shell (NAc shell), basolateral amygdala (BLA), and ventral tegmental area (VTA). Neuroanatomical analysis indicated that in the induction phase, cocaine-conditioned animals had higher expression of c-Fos in the dmPFC, NAc core, BLA, and VTA, whereas in the expression phase, almost all areas had higher expression except for the VTA. Therefore, environmental context plays a major role in the induction and expression of behavioral sensitization, although not all structures that compose the mesolimbic system contribute to this phenomenon

Distinctive neuroanatomic regions involved in cocaine-induced behavioral sensitization in mice.

The present study aimed to characterize the phenomenon of behavioral sensitization to cocaine and to identify neuroanatomical structures involved in the induction and expression phases of this phenomenon. For this, in experiment 1 (induction phase), mice were treated with saline or cocaine every second day for 15 days (conditioning period), in the open-field or in their home-cages. In experiment 2 (expression phase), the same protocol was followed, except that after the conditioning period the animals were not manipulated for 10 days, and after this interval, animals were challenged with cocaine. Neuroanatomical structures involved in the induction and expression phases were identified by stereological quantification of c-Fos staining in the dorsomedial prefrontal cortex (dmPFC), nucleus accumbens core (NAc core and shell (NAc shell), basolateral amygdala (BLA), and ventral tegmental area (VTA). Neuroanatomical analysis indicated that in the induction phase, cocaine-conditioned animals had higher expression of c-Fos in the dmPFC, NAc core, BLA, and VTA, whereas in the expression phase, almost all areas had higher expression except for the VTA. Therefore, environmental context plays a major role in the induction and expression of behavioral sensitization, although not all structures that compose the mesolimbic system contribute to this phenomenon

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