Baclofen prevents morphine rewarding effects and associated biochemical alterations in male and female mice.

Previous studies from our laboratory have shown sex differences in the behavioral, molecular, and neurochemical manifestations of morphine withdrawal and they were related to an increased sensitivity to morphine effects in males. In addition, we observed an interaction between the GABAergic and opioid systems that could also be sex-dependent. Baclofen, a GABAB receptor agonist, prevented the somatic expression and the molecular and neurochemical changes induced by morphine withdrawal syndrome in mice. On the contrary, little is known about baclofen effects in the rewarding properties of morphine in male and female mice. The present study aimed to explore the effect of baclofen (1, 2 and 3 mg/kg, i.p.) pretreatment in the rewarding effects induced by morphine (7 mg/kg, s.c.) and its effect on c-Fos and brain-derived neurotrophic factor (BDNF) expression induced by the rewarding properties of morphine in prepubertal male and female mice. Baclofen (2 mg/kg) pretreatment prevented the rewarding effects of morphine only in male mice, while baclofen (3 mg/kg) reduced these effects in both sexes. Moreover, the rewarding effects of morphine were associated with a decrease of BDNF and c-Fos expression cingulate cortex, nucleus accumbens shell, cornu ammonis 1 (CA1), and cornu ammonis 3 (CA3) areas of the hippocampus only in male mice. In addition, baclofen pretreatment prevented these changes in BDNF, but not in c-Fos expression. In conclusion, our results show that GABAB receptors have a regulatory role in the rewarding effects of morphine that could be of interest for a potential future therapeutic application in opioid use disorders.

Estrés de pandemia por COVID-19 y el conflicto trabajo-familia y familia-trabajo en Buenos Aires, Argentina / Pandemic stress due to COVID-19 and the work-family and family-work conflict in Buenos Aires, Argentina

Resumen La pandemia ha generado un nuevo entorno que establece determinadas exigencias o demandas de actuación a las personas, potenciales estresores que pueden desencadenar el proceso de estrés, al que se le podría denominar Estrés de Pandemia (EDP). A este contexto, se sumaron los cambios en la jornada laboral que derivaron en mayor interferencia entre la familia y el trabajo. De esta manera, se volvió relevante generar conocimiento sobre la temática durante este contexto particular. El objetivo del presente estudio fue determinar la asociación entre el (EDP) y el Conflicto Trabajo-Familia (CTF) y Familia-Trabajo (CFT). Además, se indagaron diferencias de grupos según factores laborales como la modalidad de trabajo y la tenencia o no de niños a cargo, entre otros. Se utilizó el Inventario SISCO de EDP (Macías, 2020), la escala de CTF y CFT (Netemeyer et al., 1996) y un cuestionario ad-hoc. Los participantes fueron 637 adultos (M.edad = 38.14, DS = 13.05, femenino = 487). Se encontraron asociaciones positivas entre las variables CFT y CTF y ambas se asociaron de manera positiva con el EDP. Quienes trabajaron de manera virtual evidenciaron mayor CFT y quienes lo hicieron, tanto virtual como presencialmente fueron los que más puntuaron en CTF. Finalmente, quienes tenían niños a cargo tuvieron mayor CFT y CTF. En conclusión, el estrés en torno al COVID-19 se vincula con mayor interferencia y conflictos entre el ámbito laboral y el familiar.

Abstract Pandemic Stress can be defined as a psychological state produced by an adaptation process where the individual values ​​the environment demands, determined by the pandemic, as overflowing with their resources to carry them out effectively (Macías, 2020). The change in routine carries the possibility of an increase in relation to work-family conflict. Family conflict involves two directions: work can interfere with the family (family work conflict or FWC) and the family can interfere with work (work family conflict, or WFC) (Bellavia y Frone, 2005) because of the incompatibility of responsibilities in the workplace and family (Greenhaus y Beutell, 1985). Added to this context are changes in the working day and, since there are no studies that analyze the relationships between SP and family and work conflict, it becomes relevant to generate knowledge on this issue during this context that humanity is going through. In this way, the aim was to establish the association between Pandemic Stress (PS), Work-Family Conflict (WFC) and Family-Work Conflict (FWC). In addition, the possible existence of group differences was analyzed according to work factors such as work modality, and the possession or not of dependent children. SISCO Pandemic Stress Inventory (Macías, 2020), the Work-Family Conflict and Family-Work Conflict scale (Netemeyer et al., 1996) and an ad-hoc questionnaire were used. The participants were 637 adults (M.age = 38.14, SD = 13.05, female = 487). Positive associations were found between the variables WFC and FWC, and both were positively associated with PS. Those who worked virtually showed higher FWC and those who did it both virtually and in person, were the ones who scored the most in WFC, realizing the difficulty in balancing family and work demands. This could be due to the difficulty for parents who worked outside the home, since they had to organize alternative solutions to take care of their children, which is hampered by the closure of establishments, difficulty in mobilizing and preventive and mandatory isolation of social networks that, in another context, contribute to the care of children. It is of great relevance to consider that the majority of those surveyed have been women, being the most likely to report that the excessive amount of housework made it difficult for them to combine work and family (Blasko, 2020). Finally, those who had children had higher WFC and FWC. In this sense, Gutierrez et al. (2020) explain that in households the unpaid workload and care has increased, which falls unequally on women, a fact that further limits their availability of time to develop productive and / or work activities. Following Park et al. (2020), being young, being female, and being a caregiver increase the risk of exposure to stressors and a greater level of stress. In conclusion, the lawsuits surrounding COVID-19 interfere in conflicts between the workplace and the family. This shows the importance of carrying out evidence-based interventions aimed at mitigating the effects of SP due to COVID-19 and reducing WFC and FWC. In this sense, the present research provides an advance in the understanding of interference between home and work, as well as the impact of the pandemic in both spheres of daily life.

GABAB receptors modulate morphine antinociception: Pharmacological and genetic approaches.

Previous studies in our laboratory showed an interaction between the GABAergic and opioid systems involved in the analgesic effect of baclofen (BAC). Furthermore, it is known that sex differences exist regarding various pharmacological responses of morphine (MOR) and they are related to an increased sensitivity to MOR effects in males. The aims of the present study were to evaluate the possible involvement of the GABAB receptors in the antinociceptive responses induced by MOR (1, 3 and 9 mg/kg, s.c.) administration using both pharmacological (BAC 2 mg/kg, i.p.; and 2-OH-saclofen, SAC 0.3 mg/kg, intra cisterna magna) and genetic approaches (GABAB1 knockout mice; GABAB1 KO) in mice of both sexes. In addition, we explored the alterations in c-Fos expression of different brain areas involved in the antinociceptive effect of MOR using both approaches. The pharmacological approach showed a higher dose-dependent antinociceptive effect of MOR in male mice compared to female mice. BAC and SAC pretreatment potentiated and attenuated the antinociceptive effect of MOR, respectively, in both sexes. The genetic approach revealed a dose-dependent antinociceptive effect of MOR in the wild type mice, but not in the GABAB1 KO mice and no sex differences were observed. Additionally, BAC and SAC pretreatment and the lack of GABAB1 subunit of the GABAB receptor prevented the changes observed in c-Fos expression in the cingulate cortex and nucleus accumbens of male mice. Our results suggest that the GABAB receptors are involved in the MOR antinociceptive effect of both male and female mice.

Nicotine-induced molecular alterations are modulated by GABAB receptor activity.

It has been demonstrated that GABAB receptors modulate nicotine (NIC) reward effect; nevertheless, the mechanism implicated is not well known. In this regard, we evaluated the involvement of GABAB receptors on the behavioral, neurochemical, biochemical and molecular alterations associated with the rewarding effects induced by NIC in mice, from a pharmacological and genetic approach. NIC-induced rewarding properties (0.5 mg/kg, subcutaneously, sc) were evaluated by conditioned place preference (CPP) paradigm. CPP has three phases: preconditioning, conditioning and postconditioning. GABAB receptor antagonist 2-hydroxysaclofen (0.25, 0.5 and 1 mg/kg; intraperitoneally, ip) or the GABAB receptor agonist baclofen (3 mg/kg; ip) was injected before NIC during the conditioning phase. GABAB1 knockout (GABAB1 KO) mice received NIC during the conditioning phase. Vehicle and wild-type controls were employed. Neurochemical (dopamine, serotonin and their metabolites), biochemical (nicotinic receptor α4ß2, α4ß2nAChRs) and molecular (c-Fos) alterations induced by NIC were analyzed after the postconditioning phase by high-performance liquid chromatography (HPLC), receptor-ligand binding assays and immunohistochemistry, respectively, in nucleus accumbens (Acb), prefrontal cortex (PFC) and ventral tegmental area (VTA). NIC induced rewarding effects in the CPP paradigm and increased dopamine levels in Acb and PFC, α4ß2nAChRs density in VTA and c-Fos expression in Acb shell (AcbSh), VTA and PFC. We showed that behavioral, neurochemical, biochemical and molecular alterations induced by NIC were prevented by baclofen. However, in 2-hydroxysaclofen pretreated and GABAB1 KO mice, these alterations were potentiated, suggesting that GABAB receptor activity is necessary to control alterations induced by NIC-induced rewarding effects. Therefore, the present findings provided important contributions to the mechanisms implicated in NIC-induced rewarding effects.

Baclofen prevents the elevated plus maze behavior and BDNF expression during naloxone precipitated morphine withdrawal in male and female mice.

In previous studies we have shown that baclofen, a selective GABAB receptor agonist, prevents the somatic expression and reestablishes the dopamine and µ-opioid receptors levels, modified during naloxone-precipitated morphine withdrawal syndrome in male and female mice. There are no previous reports regarding sex differences in the elevated plus maze (EPM) and the expression of BDNF in morphine-withdrawn mice. The present study analyses the behavioral and biochemical variations during morphine withdrawal in mice of both sexes, and whether these variations are prevented with baclofen. Swiss-Webster albino prepubertal mice received morphine (2 mg/kg, i.p.) twice daily, for 9 consecutive days. On the 10th day, one group of morphine-treated mice received naloxone (opioid receptor antagonist; 6 mg/kg, i.p.) 1 h after the last dose of morphine to precipitate withdrawal. A second group received baclofen (2 mg/kg, i.p.) before naloxone administration. The EPM behavior was measured during 15 min after naloxone injection. The expression of BDNF-positive cells was determined by immunohistochemistry. Withdrawn male mice showed a higher percentage of time spent and number of entries to the open arms compared to withdrawn female mice. Baclofen prevented this behavior in both sexes. BDNF expression decreased in the AcbC, BNST, CeC, and CA3 of the hippocampus while increased in the BLA of morphine withdrawn male. Baclofen pretreatment prevented the BDNF expression observed in morphine withdrawn male mice in all the brain areas studied except in the CeC. Baclofen prevention of the EPM behavior associated to morphine withdrawal could be partially related to changes in BDNF expression.

Lack of GABAB receptors modifies behavioural and biochemical alterations induced by precipitated nicotine withdrawal.

The nicotine (NIC) withdrawal syndrome is considered to be a major cause of the high relapse rate among individuals undergoing smoking cessation. The aim of the present study was to evaluate a possible role of GABAB receptors in NIC withdrawal, by comparing GABAB1 knockout mice and their wild-type littermates. We analysed the time course of the global withdrawal score, the anxiety-like effects, monoamine concentrations, the brain-derived neurotrophic factor (BDNF) expression, the corticosterone plasmatic levels and [(3)H]epibatidine binding sites during NIC withdrawal precipitated by mecamylamine, a nicotinic receptor antagonist (MEC). In NIC withdrawn wild-type mice, we observed a global withdrawal score, an anxiety-like effect in the elevated plus maze, a decrease of the striatal dopamine and 3,4-dihydroxyphenylacetic acid concentrations, an increase of corticosterone plasma levels, a reduction of BDNF expression in several brain areas and an increase of [(3)H]epibatidine binding sites in specific brain regions. Interestingly, the effects found in NIC withdrawn wild-type mice were absent in GABAB1 knockout mice, suggesting that GABAB1 subunit of the GABAB receptor is involved in the regulation of the behavioural and biochemical alterations induced by NIC withdrawal in mice. These results reveal an interaction between the GABAB receptors and the neurochemical systems through which NIC exerts its long-term effects.

Involvement of GABAB receptors in biochemical alterations induced by anxiety-related responses to nicotine in mice: genetic and pharmacological approaches.

Previous studies from our laboratory showed that anxiety-related responses induced by nicotine (NIC), measured by the elevated plus maze, were abolished by 2-OH-saclofen (GABAB receptor antagonist) (1 mg/kg; ip) or the lack of GABAB receptors (GABAB1 knockout mice). Based on these behavioral data, the aims of the present study were: 1) to evaluate the possible neurochemical changes (dopamine, DA, serotonin, 5-HT, 3,4-dihydroxyphenylacetic acid, DOPAC, 5-hydroxyindoleacetic acid, 5-HIAA and noradrenaline, NA) and the c-Fos expression induced by the anxiolytic (0.05 mg/kg) or anxiogenic (0.8 mg/kg) doses of NIC in the dorsal raphe (DRN) and lateral septal (LSN) nucleus; 2) to study the possible involvement of GABAB receptors on the neurochemical alterations and c-Fos expression induced by NIC (0.05 and 0.8 mg/kg), using both pharmacological (2-OH-saclofen) and genetic (mice GABAB1 knockout) approaches. The results revealed that in wild-type mice, NIC (0.05 mg/kg) increased the concentration of 5-HT and 5-HIAA (p < 0.05) in the DRN, and NIC (0.8 mg/kg) increased the levels of 5-HT (p < 0.01) and NA (p < 0.05) in the LSN. Additionally, 2-OH-saclofen pretreatment (1 mg/kg, ip) or the lack of GABAB receptors abolished these neurochemical changes induced by NIC (p < 0.01, p < 0.05, respectively). On the other hand, NIC 0.05 and 0.8 mg/kg increased (p < 0.01) the c-Fos expression in the DRN and LSN respectively, in wild-type mice. In addition, 2-OH-saclofen pretreatment (1 mg/kg, ip) or the lack of GABAB receptors prevented the c-Fos alterations induced by NIC (p < 0.01). In summary, both approaches show that GABAB receptors would participate in the modulation of anxiolytic- and anxiogenic-like responses induced by NIC, suggesting the potential therapeutic target of these receptors for the tobacco addiction treatment.

Baclofen did not modify sexually dimorphic c-Fos expression during morphine withdrawal syndrome.

In previous studies, we have reported sex-related differences during morphine withdrawal. We have also shown that the GABA(B) agonist baclofen (BAC) was able to prevent the morphine withdrawal syndrome in male as well as in female mice. Considering that early gene expression is induced by drugs of abuse, we evaluated the expression of c-Fos in several brain areas, in mice of either sex during naloxone (NAL)-precipitated withdrawal, and after pretreatment with BAC. Swiss-Webster prepubertal mice were rendered dependent by i.p. injection of morphine (2 mg/kg), twice daily for 9 days. On the 10th day, dependent mice were divided into two groups: the withdrawal group received NAL (6 mg/kg, i.p.) after the last dose of morphine, while the prevention group received BAC (2 mg/kg, i.p.) before NAL. Thirty minutes after NAL, animals were sacrificed by transcardial perfusion. Brains were removed and slices were obtained to perform immunohistochemical studies. Our results show a significant decrease in c-Fos expression in hippocampal dentate gyrus, CA3, and CA1 areas of morphine withdrawn males, vs. their control group. Conversely, in females, the number of c-Fos positive nuclei was not modified in any of the areas studied. BAC pretreatment had no effect on the decreased c-Fos expression in morphine withdrawn males. The sexual dimorphism observed here confirms the greater sensitivity of males over females in their response to morphine. The preventive action of BAC on the expression of morphine withdrawal would not be related to an effect on c-Fos expression.

Ethanol facilitates consummatory extinction.

Rats given access to an empty sipper tube after having obtained 32% sucrose in the same situation undergo extinction of consummatory behavior (cE). Ethanol (0.75 and 1g/kg, i.p.) accelerated cE when administered before the second extinction session. The effect was not attributable to increased activity or state-dependent reduction in consummatory behavior. These data are discussed in the context of research on the effects of ethanol on behavioral assays involving incentive downshifts.

Diferencias individuales en adicciones: perfiles psicosociales asociados al consumo de cocaína / Individual differences in addictions: associated psychosocial profiles to cocaine use

En las últimas décadas se ha encontrado evidencia acerca de la existencia de dos perfiles claramente distinguibles en los pacientes alcohólicos. Estos perfiles incluyen diferencias que van desde la edad de comienzo, gravedad y estilo de consumo, hasta características diferenciales de personalidad. Diferentes grupos de investigación han denominado a dichos patrones como Tipo I y II, o Tipo A y B. En los últimos años se ha intentado probar si dichos hallazgos son generalizables a otras adicciones. En el presente trabajo se hará una revisión de esas investigaciones, centrando el análisis en aquellas que han sido realizadas con personas adictas a la cocaína, con resultados positivos hasta el momento.