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Introduction: The endocannabinoid system has been implicated in the neurobiology of opioid use disorder. While the CB1 receptor antagonist rimonabant has been shown to block some of the behavioral effects of opioids, studies suggest that the treatment environment (i.e., receiving treatment in the drug-associated environment, and/or novelty) can influence its effects. In the present study, we investigated the role of the treatment environment in the effects of rimonabant on the expression of morphine-induced behavioral sensitization. Methods: Adult female Swiss mice were submitted to a behavioral sensitization protocol, during which they received morphine (20 mg/kg, i.p.) in the open-field apparatus, and were subsequently treated with vehicle or rimonabant (1 or 10 mg/kg, i.p.) either in the open-field, in the home-cage or in an activity box (novel environment). The expression of conditioned locomotion (increased locomotor activity in the open-field apparatus in the absence of morphine) and of morphine-induced behavioral sensitization (increased locomotor activity in animals sensitized to morphine) was evaluated during asubsequent saline and morphine challenge, respectively. Results: Animals treated with morphine expressed behavioral sensitization, showing a significant increase in locomotor activity over time. Animals sensitized to morphine and treated with vehicle in the home-cage expressed conditioned locomotion, an effect that was blocked by home-cage treatment with rimonabant. During a saline challenge, only animals sensitized to morphine and treated with saline in the home-cage expressed morphine-induced conditioned locomotion. All morphine-treated animals that received saline during the treatment phase (control groups) expressed behavioral sensitization during the morphine challenge. Treatment with rimonabant in the open-field and in the activity box, but not in the home-cage, blocked the expression of morphine-induced behavioral sensitization. Discussion: Our findings suggest that CB1 receptor antagonism can modulate conditioned responses to morphine even when administered in the home-cage. However, exposure to the drug-associated environment or to a novel environment is necessary for the expression of rimonabant's effects on morphine-induced behavioral sensitization during a morphine challenge., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Marinho, Oliveira-Lima, Reis, Santos-Baldaia, Wuo-Silva, Hollais, Yokoyama, Frussa-Filho and Berro.)

Background: Evidence suggests that aripiprazole, a partial dopamine D2 and serotonin 5-HT1A receptor agonist and 5-HT2A receptor antagonist, show significant efficacy in reducing alcohol use. We have previously demonstrated that treatment with aripiprazole blocked the reinstatement of cocaine-induced behavioral sensitization in a context-dependent manner, suggesting that the treatment environment may modulate the therapeutic effects of aripiprazole. The present study aimed to evaluate the effects of treatment with aripiprazole on ethanol-induced behavioral sensitization and conditioned place preference in female mice, and the role of the treatment environment in those effects., Methods: Adult female mice were either sensitized with ethanol injections in the open-field apparatus, or conditioned with ethanol in the conditioned place preference (CPP) apparatus. Animals were then treated with vehicle or 0.1 mg/kg aripiprazole paired to the test environment (open-field or CPP apparatus) or not (home-cage treatments) for 4 alternate days, and the subsequent expression of behavioral sensitization or CPP to ethanol was evaluated during or following an ethanol re-exposure, respectively., Results: Repeated treatment with aripiprazole attenuated the expression of ethanol-induced behavioral sensitization regardless of the treatment environment. Treatment with aripiprazole was only effective at preventing the reinstatement of ethanol-induced CPP when paired with the ethanol-associated environment, but not when administered in the home-cage., Conclusions: The present findings corroborate previous studies suggesting the effectiveness of aripiprazole for the treatment of alcohol use disorder. Our results also point to an important role of the treatment environment in the therapeutic effects of aripiprazole in rodent models of ethanol abuse., Competing Interests: Declaration of Competing Interest No conflict declared., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.

Opioid addiction is a growing public health problem, being currently considered an epidemic in the United States. Investigating the behavioral effects of opioids and the factors influencing their development becomes of major importance. In animals, the effects of drugs of abuse can be assessed using the behavioral sensitization model, which shares similar neuronal substrates with drug craving in humans. Importantly, novelty plays a critical role on the development of behavioral sensitization. The aim of the present study was to investigate the influence of a new environment on both the induction and expression phases of morphine (Mor)-induced behavioral sensitization in the two-injection protocol. Mice were initially treated with saline, 15 or 30 mg/kg Mor (induction phase), and subsequently challenged 7 days later with 15 mg/Kg Mor (expression phase). Locomotor frequency was evaluated during behavioral sessions, performed as follow: induction session on a novel environment and expression on a familiar open-filed apparatus; induction session on animals' home-cage (familiar environment) and expression session on an unknown open-filed apparatus; both sessions on novel environments; and both sessions on familiar contexts. Mor-induced behavioral sensitization was only observed when animals were exclusively exposed to novelty during the induction phase, not being observed when both the induction and expression sessions were performed on similar (novel or familiar) environments. Our results suggest that the development of behavioral sensitization to Mor depends on the exposure to novelty during the induction phase and absence of novelty during the expression phase, indicating a complex relationship between novelty and Mor-induced behavioral effects., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Sleep deprivation (SD) and amphetamine use are commonly associated conditions. SD shares similar neurobiological effects with psychostimulants, playing an important role in drug addiction, especially through conditioning manipulations. The aim of the present study was to investigate the effects of SD on the development of amphetamine-induced conditioned place preference (CPP) in a protocol with a reduced number of conditioning sessions. Male adult Wistar rats were submitted to 4 conditioning sessions (2 sessions/day) in the CPP apparatus, half with saline (non-drug-paired compartment) and half with 2 mg/kg amphetamine (drug-paired compartment) after control (home-cage maintained) or SD (6 h gentle handling method) conditions. Control animals did not express a preference for the amphetamine-paired compartment, showing that 2 conditioning sessions with the drug were not sufficient to establish CPP. On the other hand, animals submitted to SD during the conditioning sessions expressed a preference for the amphetamine-paired compartment, which was maintained across the entire test session. SD precipitated the development of CPP to amphetamine, showing that lack of sleep can contribute to the establishment of a conditioning between the drug effect and environmental cues., (Copyright © 2018 Elsevier B.V. All rights reserved.)

CB1 receptor antagonists have been shown to prevent acute and long-term behavioral effects of cocaine. Here we evaluate the effectiveness of the CB1 receptor antagonist rimonabant to modify sensitized responses to cocaine. Mice were treated with saline or cocaine injections in a 15-day intermittent sensitization treatment and subsequently treated with either vehicle, 1 or 10mg/kg rimonabant in the drug-associated environment for 8 consecutive days. Animals were then challenged with saline and cocaine in the open-field apparatus on subsequent days to evaluate the expression of conditioned and sensitized effects to cocaine. c-Fos protein expression was evaluated in the nucleus accumbens (NAcc), ventral tegmental area (VTA), basolateral amygdala (BLA), medial prefrontal cortex (mPFC) and caudate-putamen (CPu) after the last (cocaine) challenge. Previous treatment with 10mg/kg rimonabant blocked the expression of conditioned hyperlocomotion and behavioral sensitization to cocaine, but not acute cocaine-induced hyperlocomotion. These behavioral effects were accompanied by significant changes in c-Fos expression in the brain reward system. Chronic cocaine sensitization blunted a subsequent acute cocaine-induced increase in c-Fos protein in the NAcc, effect that was reversed by previous treatment with rimonabant. Treatment with 10mg/kg rimonabant also attenuated the significant increase in c-Fos expression in the CPu, mPFC and BLA induced by previous chronic sensitization with cocaine. Our findings add to the evidence that drugs targeting CB1 receptors are good candidates for the treatment of cocaine abuse and provide further insights into the mechanisms underlying endocannabinoid signaling within the brain reward system in the context of cocaine abuse., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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.

The purpose of the present study was to determine whether physical exercise (PE) has a protective effect in an experimental animal model of sleep-related movement disorder (A11 dopaminergic nuclei lesions with 6-OHDA). Rats were divided into four groups (Control PE-CTRL/PE, SHAM/PE, A11 lesion/NPE, A11 lesion/PE). Two experiments were performed: (1) the rats underwent PE before (2 weeks) and after (4 weeks) the A11 lesion; and (2) the rats underwent PE only after (4 weeks) the A11 lesion. Electrode insertion surgery was performed and sleep analyses were conducted over a period of 24h (baseline and after PE) and analyzed in 6 blocks of 4h. The results demonstrated that the A11 lesion produced an increased percentage of wakefulness in the final block of the dark period (3-7am) and a significant enhancement of the number of limb movements (LM) throughout the day. Four weeks of PE was important for reducing the number of LMs in the A11 lesion group in the rats that performed PE before and after the A11 lesion. However, in the analysis of the protective effect of PE on LM, the results showed that the number of LMs was lower at baseline in the group that had performed 2 weeks of PE prior to the A11 lesion than in the group that had not previously performed PE. In conclusion, these findings consistently demonstrate that non-pharmacological manipulations had a beneficial effect on the symptoms of sleep-related movement disorder., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Prenatal environmental adversities may affect brain development and are associated with increased risk for schizophrenia, an illness with 50% comorbidity with addiction. Maternal immune activation by poly-inosinic-citidilic acid (Poly(I:C)) exposure can promote behavioral alterations consistent with schizophrenia symptoms in rodents., Objectives: Considering the vulnerability to addiction in patients with schizophrenia, we evaluated the interactions between prenatal Poly(I:C) administration and addiction in two animal models (behavioral sensitization and conditioned place preference - CPP) in mice repeatedly treated with amphetamine (AMP). Additionally, stereotyped behavior and cross-sensitization with cocaine (COC) were also investigated., Methods: Swiss male mice offspring were submitted to prenatal administration of 5mg/kg Poly(I:C) in the 9(th) day of pregnancy. At the age of 90days, mice were treated with 2.5mg/kg AMP for 9days to evaluate behavioral sensitization or stereotyped behavior. Cross-sensitization with 10mg/kg COC was evaluated 24h after the last treatment day. For AMP-induced CPP evaluation, mice were treated during 8 consecutive days., Results: Prenatal Poly(I:C) administration potentiated both AMP-induced behavioral sensitization and CPP. Furthermore, Poly(I:C) increased cross-sensitization with COC., Conclusions: Prenatal administration of Poly(I:C) is able to potentiate vulnerability to addiction in two animal models, without however modulating stereotyped behavior., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Although the cognitive-enhancing abilities after modafinil have been demonstrated, its effects on memory consolidation remain overlooked. We investigated the effects of repeated modafinil administration on consolidation of a discriminative avoidance task., Methods: Mice were trained in the plus-maze discriminative avoidance task. After training, mice received intraperitonial modafinil (doses of 32, 64 or 128 mg/kg). Animals were treated for more 9 consecutive days; 30 min after the last injection, testing was performed. In addition, the effects of 32 mg/kg modafinil on consolidation at different time points were examined., Results: The smaller dose of modafinil (32 mg/kg) impaired memory consolidation, without modifying anxiety or locomotion. Still, modafinil post-training administration at 1 or 2 h impaired memory persistence., Conclusions: Modafinil impaired memory consolidation in a dose- and time-dependent fashion.

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 10mg/kg) on spontaneous locomotor activity in the open-field, hyperlocomotion induced by acute administration of ethanol (1.8g/kg), morphine (20mg/kg) or cocaine (10mg/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 1mg/kg potentiated the central hyperlocomotion induced by acute morphine injection, it was effective in attenuating 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., (Copyright © 2014 Elsevier Inc. All rights reserved.)