Cannabidiol Treatment Shows Therapeutic Efficacy in a Rodent Model of Social Transfer of Pain in Pair-Housed Male Mice.

Introduction: Prosocial behavior refers to sharing emotions and sensations such as pain. Accumulated data indicate that cannabidiol (CBD), a nonpsychotomimetic component of the Cannabis sativa plant, attenuates hyperalgesia, anxiety, and anhedonic-like behavior. Nevertheless, the role of CBD in the social transfer of pain has never been evaluated. In this study, we investigated the effects of acute systemic administration of CBD in mice that cohabited with a conspecific animal suffering from chronic constriction injury. Furthermore, we assessed whether repeated CBD treatment decreases hypernociception, anxiety-like behavior, and anhedonic-like responses in mice undergoing chronic constriction injury and whether this attenuation would be socially transferred to the partner. Materials and Methods: Male Swiss mice were Housed in pairs for 28 days. On the 14th day of living together, animals were then divided into two groups: cagemate nerve constriction (CNC), in which one animal of each partner was subjected to sciatic nerve constriction; and cagemate sham (CS), subjected to the same surgical procedure but without suffering nerve constriction. In Experiments 1, 2, and 3 on day 28 of living together, the cagemates (CNC and CS) animals received a single systemic injection (intraperitoneally) of vehicle or CBD (0.3, 1, 10, or 30 mg/kg). After 30 min, the cagemates were subjected to the elevated plusmaze followed by exposure to the writhing and sucrose splash tests. For chronic treatment (Exp. 4), sham and chronic constriction injury animals received a repeated systemic injection (subcutaneous) of vehicle or CBD (10 mg/kg) for 14 days after the sciatic nerve constriction procedure. On days 28 and 29 sham and chronic constriction injury animals and their cagemates were behaviorally tested. Results and Conclusion: Acute CBD administration attenuated anxiety-like behavior, pain hypersensitivity, and anhedonic-like behavior in cagemates that cohabited with a pair in chronic pain. In addition, repeated CBD treatment reversed the anxiety-like behavior induced by chronic pain and enhanced the mechanical withdrawal thresholds in Von Frey filaments and the grooming time in the sucrose splash test. Moreover, repeated CBD treatment effects were socially transferred to the chronic constriction injury cagemates.

The Reversal of Empathy-Induced Hypernociception in Male Mice by Intra-Amygdala Administration of Midazolam and Cannabidiol Depends on 5-HT3 Receptors.

Introduction: Empathy is a fundamental prosocial behavior. It has been defined as perception, awareness, and understanding of others' emotional states, including painful processes. Mice living in pairs with conspecific chronic suffering from constriction injury exhibit pain hypersensitivity mediated by the amygdaloid complex. Nevertheless, the underlying mechanisms in the amygdala responsible for this response remain to be determined. This study investigated if the anxiolytic benzodiazepine midazolam (MDZ) and cannabidiol (CBD), a phytocannabinoid with multiple molecular targets, would attenuate this behavioral change. We also investigated if serotonergic and γ-aminobutyric acid (GABA)ergic mechanisms in the amygdala are involved in this effect. Materials and Methods: Male Swiss mice were housed in pairs for 28 days. The pairs were divided into two groups on the 14th day: cagemate nerve constriction and cagemate sham. On the 24th day, cagemates underwent a stereotaxic surgery and, on the 28th day, were evaluated on the writhing test. Results: The results showed that living with chronic pain leads to hypernociception in the cagemate and increases the expression of 5-HT3 receptor (5-HT3R) and glutamic acid decarboxylase 67 within the amygdala. MDZ (3.0 and 30 nmol) and CBD (30 and 60 nmol) attenuated the hypernociceptive behavior. The 5-HT3R antagonist ondansetron (0.3 nmol) prevented the antinociceptive effects of MDZ and CBD. Conclusion: These findings indicate that 5-HT3R and GABAergic mechanisms within the amygdala are involved in the pain hypersensitivity induced by the empathy for pain model. They also suggest that MDZ and CBD could be a new potential therapy to alleviate emotional pain disorders.

Curcumin-Loaded Mesoporous Silica Nanoparticles Dispersed in Thermo-Responsive Hydrogel as Potential Alzheimer Disease Therapy.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive and behavioral impairment. Curcumin-loaded mesoporous silica nanoparticles (MSN-CCM) can overcome the drawbacks related to the free curcumin (CCM) clinical application, such as water insolubility and low bioavailability, besides acting over the main causes associated to AD. A thermo-responsive hydrogel is an interesting approach for facilitating the administration of the nanosystem via a nasal route, as well as for overcoming mucociliary clearance mechanisms. In light of this, MSN-CCM were dispersed in the hydrogel and evaluated through in vitro and in vivo assays. The MSNs and MSN-CCM were successfully characterized by physicochemical analysis and a high value of the CCM encapsulation efficiency (EE%, 87.70 ± 0.05) was achieved. The designed thermo-responsive hydrogel (HG) was characterized by rheology, texture profile analysis, and ex vivo mucoadhesion, showing excellent mechanical and mucoadhesive properties. Ex vivo permeation studies of MSN-CCM and HG@MSN-CCM showed high permeation values (12.46 ± 1.08 and 28.40 ± 1.88 µg cm-2 of CCM, respectively) in porcine nasal mucosa. In vivo studies performed in a streptozotocin-induced AD model confirmed that HG@MSN-CCM reverted the cognitive deficit in mice, acting as a potential formulation in the treatment of AD.

Dorsal hippocampus plays a causal role in context-induced reinstatement of alcohol-seeking in rats.

Drug addiction is a chronic mental disorder characterized by frequent relapses. Contextual cues associated with drug use to play a critical causal role in drug-seeking behavior. The hippocampus has been implicated in encoding drug associative memories. Here we examine whether the dorsal hippocampus mediates context-induced reinstatement of alcohol-seeking. Male Long-Evans rats were trained to self-administer alcohol in Context A. Alcohol self-administration was extinguished in a distinct context (Context B). On the test day, animals were re-exposed to the alcohol Context A or the extinction Context B. Next, to assess a causal role for the dorsal hippocampus in context-induced alcohol-seeking, on the test day, we injected cobalt chloride (CoCl2; a nonselective synapse inhibitor) or vehicle into the dorsal hippocampus, and 15 min later, rats were tested by re-exposing them to the drug-associated context. The re-exposure to the alcohol-associated Context A reinstated alcohol seeking and increased Fos-positive cells in the dorsal hippocampus neurons (CA1, CA3, and Dentate Gyrus). Pharmacological inactivation with cobalt chloride of the dorsal hippocampus attenuated the reinstatement of alcohol-seeking. Our data suggest that the dorsal hippocampus may be involved in context-induced alcohol-seeking behavior.

Functional inactivation of the orbitofrontal cortex disrupts context-induced reinstatement of alcohol seeking in rats.

BACKGROUND: The high rate of relapse to drug use remains a central challenge to treating drug addiction. In human and rat models of addiction, environmental stimuli in contexts associated with previous drug use can provoke a relapse of drug seeking. Pre-clinical studies have used the ABA renewal procedure to study context-induced reinstatement of drug seeking. In the current study, we studied the role of the orbitofrontal cortex (OFC) in context-induced reinstatement to alcohol. METHODS: We trained male and female rats to self-administer alcohol in context A, extinguished drug-reinforced responding in a distinct context B, and assessed context-induced reinstatement in context A or B (control group). Next, we determined the effect of context-induced renewal of alcohol-seeking behavior on the expression of Fos (a neuronal activity marker) in the OFC. Finally, we determined the effect of reversible inactivation by GABAa and GABAb receptor agonists (i.e., muscimol and baclofen, respectively) in the OFC. RESULTS AND CONCLUSIONS: There were no differences between male and female rats in context-induced reinstatement of alcohol-seeking behavior. Re-exposure to Context A, but not Context B, reinstated alcohol-seeking behavior and increased expression of the neural activity marker Fos in the OFC. Reversible inactivation of the OFC with muscimol and baclofen attenuated context-induced reinstatement. Our data indicated that the OFC mediates context-induced reinstatement of alcohol-seeking behavior.

Inactivation of the Prelimbic Cortex Impairs the Context-Induced Reinstatement of Ethanol Seeking.

Evidence indicates that drug relapse in humans is often provoked by exposure to the self-administered drug-associated context. An animal model called "ABA renewal procedure" has been used to study the context-induced relapse to drug seeking. Here, we reported a new and feasible training procedure for the ABA renewal method to explore the role of the prelimbic cortex in context-induced relapse to ethanol seeking. By using a saccharin fading technique, we trained rats to self-administer ethanol (10%). The drug delivery was paired with a discrete tone-light cue. Lever pressing was subsequently extinguished in a non-drug-associated context in the presence of the discrete cue. Rats were subsequently tested for reinstatement in contexts A or B, under extinction conditions. Ethanol-associated context induced the reinstatement of ethanol seeking and increased the expression of Fos in the prelimbic cortex. The rate of neural activation in the prelimbic cortex was 3.4% in the extinction context B and 7.7% in the drug-associated context A, as evidenced by double-labeling of Fos and the neuron-specific protein NeuN. The reversible inactivation of the neural activity in the prelimbic cortex with gamma-Aminobutyric acid (GABA) receptor agonists (muscimol + baclofen) attenuated the context-induced reinstatement of ethanol self-administration. These results demonstrated that the neuronal activation of the prelimbic cortex is involved in the context-induced reinstatement of ethanol seeking.

Stress-Induced Locomotor Sensitization to Amphetamine in Adult, but not in Adolescent Rats, Is Associated with Increased Expression of ΔFosB in the Nucleus Accumbens.

While clinical and pre-clinical evidence suggests that adolescence is a risk period for the development of addiction, the underlying neural mechanisms are largely unknown. Stress during adolescence has a huge influence on drug addiction. However, little is known about the mechanisms related to the interaction among stress, adolescence and addiction. Studies point to ΔFosB as a possible target for this phenomenon. In the present study, adolescent and adult rats (postnatal day 28 and 60, respectively) were restrained for 2 h once a day for 7 days. Three days after their last exposure to stress, the animals were challenged with saline or amphetamine (1.0 mg/kg i.p.) and amphetamine-induced locomotion was recorded. Immediately after the behavioral tests, rats were decapitated and the nucleus accumbens was dissected to measure ΔFosB protein levels. We found that repeated restraint stress increased amphetamine-induced locomotion in both the adult and adolescent rats. Furthermore, in adult rats, stress-induced locomotor sensitization was associated with increased expression of ΔFosB in the nucleus accumbens. Our data suggest that ΔFosB may be involved in some of the neuronal plasticity changes associated with stress induced-cross sensitization with amphetamine in adult rats.

Effects of chronic stress and alendronate therapy on the osseointegration of titanium implants.

PURPOSES: The purposes of this study were to evaluate the influence of chronic stress (CS) on implant osseointegration and also to analyze whether alendronate (ALN) therapy could prevent these eventual stress-negative effects. MATERIALS AND METHODS: Adult male Holtzmann rats were assigned to one of the four experimental groups: AL (ALN; 1 mg/kg/week; n = 12), ALS (ALN + CS; 1 mg/kg/week; n = 12), CTL (sterile physiological saline; n = 12), or CTLS (sterile physiological saline + CS; n = 12). After 58 days of drug therapy, the ALS and CTLS groups were exposed to CS, and 2 days later all animals underwent tibial implant installation. The animals were euthanized 28 days following the operative surgical procedure. RESULTS: It was observed that the CTLS group presented an impairment of bone metabolism represented by lowest levels of bone-specific alkaline phosphatase and bone area fraction occupancy values. Furthermore, these animals presented a higher proportion of empty osteocytic lacunae. In contrast, the ALN therapy showed increased osseointegration and torque value parameters, regardless of stress exposition. CONCLUSIONS: Analysis of the data presented suggests that CS partially impairs the osseointegration of tibial implants and that ALN therapy is able to prevent these negative effects.

Stress induces behavioral sensitization, increases nicotine-seeking behavior and leads to a decrease of CREB in the nucleus accumbens.

Experimental evidence shows that exposure to stress engenders behavioral sensitization and increases drug-seeking and leads to intense drug taking. However the molecular mechanisms involved in these processes is not well known yet. The present experiments examined the effects of exposure to variable stress on nicotine-induced locomotor activation, cAMP-response element-binding protein (CREB) and extracellular signal-regulated kinase (ERK) activity and nicotine intravenous self-administration in rats. Male Wistar rats were exposed to variable stress that consisted of the exposure to different stressors twice a day in random order for 10 days. During this period the control group was left undisturbed except for cage cleaning. Ten days after the last stress episode, rats were challenged with either saline or nicotine (0.4 mg/kgs.c.) and the locomotor activity was recorded for 20 min. Immediately after behavioral recordings rats were sacrificed and their brains were removed to posterior western blotting analysis of CREB, phosphoCREB, ERK and phosphoERK in the nucleus accumbens. An independent set of control and stressed animals were subjected to an intravenous nicotine self-administration protocol. The break point during a progressive ratio schedule and nicotine intake patterns during a 24-hour binge was analyzed. Repeated variable stress caused a sensitized motor response to a single challenge of nicotine and decreased CREB in the nucleus accumbens. Furthermore, in the self-administration experiments previous stress exposure caused an increase in the break point and nicotine intake.

Ontogênese, estresse e dependência de substâncias psicoativas / Ortogenesis, stress and psychoactive substances addiction

O estudo da dependência de substâncias psicoativas apresentou grandes avanços conceituais nas últimas décadas. A evolução dos conceitos foi paralela às evidências científicas que têm revelado os aspectos comportamentais e os mecanismos neurais envolvidos nesse fenômeno. Contudo, um grande desafio que permanece na pesquisa sobre a dependência de substâncias psicoativas é a identificação de quais fatores são responsáveis pela transição do uso controlado para o uso compulsivo. Está demonstrado que muitas variáveis interagem para influenciar a probabilidade de que qualquer indivíduo inicie o uso abusivo de substâncias psicoativas ou se torne dependente. Nos últimos anos, o estresse tem sido destacado como um fator importante na iniciação, manutenção e recaída da utilização de substâncias psicoativas. Neste trabalho analisamos os conceitos e teorias da farmacodependência e as principais evidências comportamentais pré-clínicas que demonstram a relação entre estresse e a vulnerabilidade ao abuso e dependência de psicoestimulantes.

The investigation of the mechanisms of drug abuse and addiction showed great advances in the last decades. New concepts emerged from the scientific evidences on behavioral and neural aspects of this phenomenon. However, the biggest challenge for the future is the identification of which risk factors are implicated in the transition from controlled to compulsive drug use. Stress has been pointed as an important factor related to initiation, maintenance and relapse to drug use. In the present paper we discuss the concepts and theories of drug addiction, and the main behavioral pre-clinical evidences showing the relationship between stress and psychostimulant addiction.

Fos-like immunoreactivity in central nervous system of mice simultaneously exposed to the elevated plus-maze and nociception

It has been demonstrated that mice exhibit antinociception when they are exposed to the elevated plus-maze (EPM), an animal model of anxiety. To investigate which brain structures are activated during EPM exposure, the present study assessed the immunohistochemical staining for Fos-like immunoreactivity (Fos-LI) in mice intraperitoneally injected with saline or 0,6 por cente acetic acid (which produces nociception) and cofined in the open arm (threatening situation) or enclosed arm (Control) of the EPM. The following strutuctures were investigated: magnus, dorsal and median raphe nuclei (MR, DR and MnR), periaqueductal gray matter (PAG), dorsal and ventral hippocampus (DH and VH), amygdala (AMY), hypothalamus (HYP) and superior and inferior colliculi (SC and IC)...

Envolvimento do sistema dopaminérgico na sensibilização comportamental ao femproporex / The envolvement of the dopamine system in the behavioral sensitazion to fenproporex (FEN)

No presente trabalho foram estudados os efeitos da administração repetida de femproporex (FEM) sobre a atividade motora em ratos. O grupo tratado com FEM (5,0 mg/kg, i.p., dose única, 7 dias consecutivos) mostrou aumento gradual da atividade motora, indicando a ocorrência de sensibilização comportamental. O grupo que recebeu haloperidol concomitantemente com FEM preveniu o desenvolvimento da sensibilização ao FEM. No 10º dia (teste), todos os animais receberam uma dose-desafio de FEM. O grupo que recebeu administração repetida de FEM mostrou aumento significativo da atividade locomotora avaliada em campo aberto, confirmando a ocorrência de sensibilização. Esses resultados indicam que a administração repetida de FEM desenvolveu sensibilização comportamental e o sistema dopaminérgico pode estar envolvido no mecanismo deste fenômeno.

Effects of acute and chronic administration of benzydamine on the stimulatory effects of ethanol in mice

Acute and chronic effects of benzydamine (BEZ) and its interactions with ethanol (EtOH) were examined on open field locomotion. Male Swiss mice were injected intraperitoneally (i.p.) with 15, 30 or 60 mg kg of BEZ alone or in combination with EtOH (2.0 mg/k, i.p.). Pretreatment with BEZ (60 mg/kg) produced a significant decrease in EtOH-induced behavioral stimulation. Chronic administration of BEZ (15mg/kg/day for 21 days) intensified locomotor response induced by EtOH, suggesting the development of behavioral sensitization. The results show that BEZ can interact with EtOH suggesting that alcohol drinkers should be educated about risks of BEZ toxicity.

Participacao do sistema dopaminergico nas propriedades reforcadoras de psicostimulantes

O presente artigo comenta alguns aspectos sobre a participacao do sistema dopaminergico mesocorticolimbico nas propriedades reforcadoras das drogas psicostimulantes. Alem disso, enfatiza o envolvimento dos receptores dopaminergicfos D1 e D2 no efeito reforcador destas drogas e suas interacoes com os receptores opiodergicos e glutamatergicos. O grau de ativacao desses sistemas pode estar relacionado, ate certo ponto, ao potencial de dependencia de psicostimulantes de outras drogas de abuso.

Consideraçöes sobre a avaliaçäo da farmacodependência em modelos experimentais e clínicos / On the evaluation of drug dependence in experimental and clinical models

O presente artigo comenta alguns aspectos da farmacodependência, tais como a dependência física e psíquica e a tolerância. Destaca-se a importância dos modelos experimentais e clínicos que säo usados para avaliaçäo do potencial de dependência a fármacos. Além disso, enfatiza a atuaçäo dessas substâncias como reforçadores positivos que atuariam no sistema central de recompensa, que tem um de seus componentes no sistema dopaminérgico mesocorticolímbico. Assim, o efeito reforçador seria a causa primária do desenvolvimento da farmacodependência.

Modelos experimentais que avaliam os mecanismos de recompensa e dependencia de drogas

Os sistemas de recompensa sao os substratos neurais do comportamento de aproximacao a um determinado objetivo. As recompensas naturais (alimento), as drogas de abuso e o reforco cerebral ativam tais sistemas, dos quais participam substratos dopaminergicos e opioides. O grau de ativacao destes sistemas pode estar relacionado, ate certo ponto, ao potencial de abuso da droga.

Padroës de uso de psicoestimulantes e energizantes por universitários: análise do período 1983-1988 / Psychostimulants and energizers pattern of use by university student: 1983-1988 period analysis

Foi aplicado um questionário, para avaliar os padröes de uso de alguns medicamentos psicoativos, com ênfase aos psicoestimulatnes e energizantes, em uma amostra de estudantes da área de biomédica da Universidade de Säo Paulo. Os principais medicamentos selecionados mais utilizados foram Nootropil, Valium e glicose. A automedicaçäo e o modo de utilizaçäo sem prescriçäo caracterizaram o uso de alguns medicamentos. Os dados, quando comparados com o período de 1976-1981, mostraram que o uso de energizantes aumentou de 37% para 39%, enquanto que a utilizaçäo dos psicoestimulantes ou anorexígenos e dos ansiolíticos diminuiu, respectivamente, de 20% para 13% e de 22,5 para 13%

Padroes de uso de psicoestimulantes e energizantes por universitarios: analise do periodo 1983-1988

Foi aplicado um questionario, para avaliar os padroes de uso de alguns medicamentos psicoativos, com enfase aos psicoestimulantes e energizantes, em uma amostra de estudantes da area biomedica da Universidade de Sao Paulo. Os principais medicamentos selecionados mais utilizados foram Nootropil, Valium e glicose. A automedicacao e o modo de utilizacao sem prescricao caracterizaram o uso de alguns medicamentos. Os dados, quando comparados com o periodo de 1976-1981, mostraram que o uso de energizantes aumentou de 37 por cento para 39 por cento, enquanto que a utilizacao dos psicoestimulantes ou anorexigenos e dos ansioliticos diminuiu, respectivamente, de 20 por cento para 13 por cento e de 22,5 para 13 por cento.

Trabalho em turno: consumo de medicamentos, bebidas alcoólicas e tabaco por operários de Cubatäo - SP / Shift work: consumption of drugs, alcohol and tobacco by workers of Cubatäo - SP

Foi aplicado um questionário sobre o consumo de medicamentos, bebidas alcoólicas e tabaco em operários pertencentes a regime de turnos de trabalho, residentes no Município de Cubatäo-SP. Os ansiolíticos e os antiácidos foram os medicamentos mais utilizados pelos trabalhadores do turno alternante em relaçäo ao turno administrativo (diurno), segundo as queixas (perturbaçäo do sono, irritaçäo nervosa e distúrbios gastrintestinais). Destacam-se também os analgésicos e os anti-hipertensivos para ambos os turnos. O consumo de bebidas alcoólicas pode ser considerado elevado na populaçäo operária e foi observada significativa diferença de consumo de álcool nos fins de semana entre os trabalhadores do turno administrativo e os do alternante. Este fato reflete maior prejuízo nas atividades de lazer dos operários do turno alternante. O tabagismo é predominante em ambos os turnos de trabalho, pois cerca de 50% da populaçäo em geral tem o hábito de fumar. Os dados do presente estudo foram abordados sob o ponto de vista epidemiológico, procurando-se relacionar os distúrbios decorrentes de fatores de risco, como o trabalho em turnos, com o consumo de medicamentos, bebidas alcoólicas e tabaco por operários de Cubatäo-SP

Alteraçöes na atividade do sistema dopaminérgico estriatal durante e após a administraçäo prolongada de fencanfamina e anfetamina / Changes in the activity of striatal dopaminergic system during and after long-term administration of fencamfamine and amphetamine

As alteraçöes na atividade do sistema dopaminérgico estriatal durante e após a administraçäo prolongada de fencanfamina (FCF) e anfetamina (ANF) foram estudadas em ratos machos. Durante o tratamento com FCF foi observado aumento gradual no comportamento de cheirar e uma tendência em diminuir o levantar estereotipado. Näo foram observadas alteraçöes significativas no comportamento de locomoçäo dos animais tratados com FCF e ANF. Após 72 horas da retirada dos fármacos, a administraçäo prolongada de ANF e FCF alterou os efeitos neuroquímicos da apomorfina (APO) reduzindo os níveis do ácido dihidroxifenilacético (DOPAC) no corpo estriado, quando comparado ao grupo tratado com salina + APO. Essas alteraçöes podem ser responsáveis pela eventual tolerância ou sensibilizaçäo da estereotipia induzida por esses fármacos