Raphael Wuo-Silva

Addictive potential of modafinil and cross-sensitization with cocaine: a pre-clinical study.

Repeated or even a single exposure to drugs of abuse can lead to 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. Male mice were used to investigate the ability of modafinil to induce locomotor sensitization after repeated or single administration in mice. Bidirectional cross‐sensitization with cocaine and modafinil‐induced conditioned place preference were also evaluated. Both repeated and single exposure to moderate and high doses of modafinil produced a pronounced locomotor sensitization that cross‐sensitized in a bidirectional way with cocaine. Remarkably, when cocaine and modafinil were repeatedly administered sequentially, their behavioral sensitization was additive. Supporting these behavioral sensitization data, modafinil produced a pronounced conditioned place preference in the mouse. Taken together, the present findings provide pre‐clinical 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.

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 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.

Environmental novelty and illumination modify ethanol-induced open-field behavioral effects in mice.

Both spontaneous and drug-induced animal behaviors can be modified by exposure to novel stimuli or different levels of environmental illumination. However, research into how these factors specifically impact ethanol (ETH)-induced behavioral effects is currently lacking. We aimed to investigate the effects of these two factors, considered separately or in conjunction, on ETH-induced acute hyperlocomotor effect and its sensitization in adult male Swiss mice. Mice were placed in a novel or familiar open-field under normal light (200 lx) or low light (9 lx) immediately after receiving an ip injection of either 1.8 g/kg ETH or saline (SAL). After 7 days, all animals received an ip challenge injection of 1.8 g/kg ETH, and were placed in the open-field under the same light conditions described above. Novelty increased central locomotion and decreased grooming, while low light increased grooming. Acute ETH administration increased both total and peripheral locomotion and these effects were potentiated by low light. Both low light and novelty were able to facilitate ETH-induced locomotor sensitization, which was detected by the central locomotion parameter. However, there was no synergism between the effects of these two modulating factors on ETH-induced behavioral sensitization. We conclude that both the acute behavioral effects of ETH and behavioral sensitization induced by previous administration of this drug can be critically modified by environmental factors. In addition, our study stresses the importance of using different behavioral parameters to evaluate the interaction between environmental factors and ETH effects.

Effects of ayahuasca on the development of ethanol-induced behavioral sensitization and on a post-sensitization treatment in mice.

BACKGROUND Hallucinogenic drugs were used to treat alcoholic patients in the past, and recent developments in the study of hallucinogens led to a renewal of interest regarding the application of these drugs in the treatment of addiction. In this scenario, accumulating evidence suggests that the hallucinogenic brew ayahuasca (Aya) may have therapeutic effects on substance abuse problems. METHODS We investigated the effects of Aya on spontaneous locomotor activity and ethanol(Eth)-induced hyperlocomotion and subsequent locomotor sensitization by a two-injection protocol. Additionally, we tested the effect of Aya on an 8-day counter-sensitization protocol to modify sensitized responses induced by a repeated treatment with Eth (1.8g/kg) for 8 alternate days. RESULTS Aya showed high sensitivity in preventing the development of Eth-induced behavioral sensitization, attenuating it at all doses (30, 100, 200, 300 or 500 mg/kg) without modifying spontaneous locomotor activity. At the highest doses (300 and 500 mg/kg), Aya also showed selectivity to both acute and sensitized Eth responses. Finally, a counter-sensitization strategy with 100 or 300 mg/kg of Aya for 8 consecutive days after the establishment of Eth-induced behavioral sensitization was effective in blocking its subsequent expression on an Eth challenge. CONCLUSIONS We demonstrated that Aya not only inhibits early behaviors associated with the initiation and development of Eth addiction, but also showed effectiveness in reversing long-term drug effects expression, inhibiting the reinstatement of Eth-induced behavioral sensitization when administered in the Eth-associated environment.

Selective action of an atypical neuroleptic on the mechanisms related to the development of cocaine addiction: a pre-clinical behavioural study

An increased function in the mesolimbic dopaminergic system has been extensively associated with the rewarding effects of both natural stimuli and drugs of abuse. Thus, dopamine receptor blockers, such as neuroleptic drugs, can be proposed as candidates for potential therapeutic approaches to treat drug dependence. Notwithstanding, this therapeutic potential of neuroleptics critically depends on a selective action on the specific mechanisms related to the development of addiction. We compared the effects of different doses of haloperidol, ziprasidone and aripiprazole (first-, second- and third-generation neuroleptics, respectively) on spontaneous locomotor activity of mice in a novel environment, hyperlocomotion induced by acute cocaine administration and cocaine-induced locomotor sensitization by a two-injection protocol. Whereas high doses of haloperidol abolished the three behavioural paradigms without selectivity, low doses of ziprasidone selectively abolished the development of the behavioural sensitization phenomenon. Finally, low doses of aripiprazole inhibited acute cocaine-induced hyperlocomotion and behavioural sensitization without modifying spontaneous locomotor activity. Thus, aripiprazole at lower doses was the most selective antipsychotic drug concerning the inhibition of the development of behavioural sensitization to cocaine. Because locomotor sensitization in rodents has been proposed to share plastic mechanisms with drug addiction in humans, our data provide relevant suggestions to the clinical practice.

Effects of group exposure on single injection-induced behavioral sensitization to drugs of abuse in mice

BACKGROUND Behavioral sensitization in rodents is hypothesized to reflect neuronal adaptations that are related to drug addiction in humans. We evaluated the effects of group exposure on the acute hyperlocomotion and behavioral sensitization induced by four drugs of abuse in C57BL/6 mice: methylenedioxymethamphetamine (MDMA), d-amphetamine, morphine and ethanol. METHODS In the priming session, animals received an ip injection of one of the drugs of abuse and were exposed to an open field either individually or in groups of four. Seven days later, we assessed behavioral sensitization in the challenge session. All animals received an ip injection of the same drug and were exposed to the open field in the same social conditions described for the priming session. Locomotion and social interaction were quantified during each session. RESULTS Acute MDMA, morphine and ethanol, but not d-amphetamine, increased social interaction. However, group exposure only potentiated MDMA-induced hyperlocomotion. After a challenge injection of each drug, there was no sensitization to the facilitating effect of MDMA, morphine or ethanol on social interaction, but locomotion sensitization developed to all drugs of abuse except ethanol. This sensitization was potentiated by group exposure in MDMA-treated animals, attenuated in morphine-treated animals and not modified in d-amphetamine-treated animals. Acute MDMA enhanced body contact and peaceful following, while acute morphine and ethanol increased social sniffing. CONCLUSIONS These results provide preclinical evidence showing that while different drugs of abuse affect different components of social interaction, the neuronal adaptations related to drug dependence can be critically and specifically influenced by group exposure.

Sleep deprivation impairs the extinction of cocaine-induced environmental conditioning in mice.

Persistence of a drug-environment conditioning induced by repeated psychostimulant treatment is thought to play a key role in the addictive cycle. In addition, sleep disorders are a common feature in patients with addictive disorders. Sleep deprivation shares similar neurobiological effects with psychostimulants. Therefore, we investigated whether sleep deprivation would impair the extinction of previously established conditioning between the drug effect and the environmental cues. Four cohorts of male adult mice underwent a behavioral sensitization procedure pairing drug (cocaine at 15 mg/kg, i.p.) or saline with environment (open-field apparatus). The extinction of conditioned locomotion was evaluated after control (home-cage maintained) or sleep deprivation (gentle handling method for 6h) conditions. Sleep deprivation both postponed the initiation and impaired the completeness of extinction of the conditioned locomotion promoted by previous drug-environment conditioning in cocaine-sensitized animals. While the cocaine control group required 5 free-drug sessions of exposure to the open-field apparatus to complete extinction of conditioned locomotion, the cocaine pre-treated group that experienced sleep deprivation before each extinction session still significantly differed from its respective control group on Day 5 of extinction. The possibility that the sleep condition can influence the extinction of a long-lasting association between drug effects and environmental cues can represent new outcomes for clinically relevant phenomena.

Sleep Deprivation Increases Mortality in Female Mice Bearing Ehrlich Ascitic Tumor

Objectives: Sleep deprivation is a growing public health hazard, yet it is still under-recognized. Sleep disorders and disruption of sleep patterns may compromise the immune function and adversely affect host resistance to infectious diseases. This is a particular risk in cancer patients, who report a high frequency of sleep disturbances. The present study investigated the effects of sleep deprivation on the development of Ehrlich ascitic tumors (EAT) in female BALB/c mice. Our study also evaluated whether EAT would induce alterations in sleep pattern. Spleen lymphocyte cell populations and mortality were also quantified. Methods: Female BALB/c mice were intraperitoneally inoculated with EAT cells. Immediately after the inoculation procedure, animals were sleep deprived for 72 h. Ten or 15 days after inoculation, the number of tumoral cells was quantified and the lymphocytic cell population in the spleen was characterized by flow cytometry. In addition, the effect of sleep deprivation on EAT-induced mortality was quantified and the influence of EAT on sleep patterns was determined. Results: Sleep deprivation did not potentiate EAT growth, but it significantly increased mortality. Additionally, both EAT and sleep deprivation decreased frequencies of splenic CD4+, CD8+ and CD19+ cells. With respect to sleep patterns, EAT significantly enhanced paradoxical sleep time. Conclusions: Although sleep deprivation did not potentiate EAT growth, it decreased the survival of female tumor-bearing mice.

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) (6h) 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 min. 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.

Acute total sleep deprivation potentiates cocaine-induced hyperlocomotion in mice.

Sleep deprivation is common place in modern society. Nowadays, people tend to self-impose less sleep in order to achieve professional or social goals. In the social context, late-night parties are frequently associated with higher availability of recreational drugs with abuse potential. Physiologically, all of these drugs induce an increase in dopamine release in the mesolimbic dopaminergic system, which leads to hyperlocomotion in rodents. Sleep deprivation also seems to play an important role in the events related to the neurotransmission of the dopaminergic system by potentiating its behavioral effects. In this scenario, the aim of the present study was to investigate the effects of total sleep deprivation (6h) on the acute cocaine-induced locomotor stimulation in male mice. Animals were sleep deprived or maintained in their home cages and subsequently treated with an acute i.p. injection of 15mg/kg cocaine or saline and observed in the open field. Total sleep deprivation for 6h potentiated the hyperlocomotion induced by acute cocaine administration. In addition, the cocaine sleep deprived group showed a decreased ratio central/total locomotion compared to the cocaine control group, which might be related to an increase in the impulsiveness of mice. Our data indicate that acute periods of sleep loss should be considered risk factors for cocaine abuse.