Maria de los Angeles

@uv.es

Neurobehavioural Mechanisms and Endophenotypes of Addictive Behavior Research Unit, Department of Psychobiology, University of Valencia
Doctor Junior

Maria de los Angeles


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https://researchid.co/maria.a

RESEARCH, TEACHING, or OTHER INTERESTS

Psychology, Experimental and Cognitive Psychology
15

Scopus Publications

Scopus Publications

  • Ketamine attenuates the effects of intermittent social defeat on anxiety, social interaction and cocaine-induced conditioned place preference in male mice
    M.A. Martínez-Caballero, M.P. García-Pardo, C. Calpe-López, M.C Arenas, C Manzanedo, M.A. Aguilar
    Physiology and Behavior, 2026
    Mice exposed to intermittent social defeat (ISD) stress in late adolescence exhibit short-term anxiety- and depression-like behaviours and demonstrate greater sensitivity to the rewarding effects of cocaine in adulthood. Furthermore, the development of depression-like symptoms predicts subsequent enhanced vulnerability to cocaine reward. The aim of this study was to investigate whether ketamine, a non-competitive glutamate N-methyl-D-aspartate (NMDA) receptor antagonist with antidepressant properties, could prevent the short-term effects of ISD on anxiety- and depression-like behaviours and the long-term effects of ISD on the cocaine-induced conditioned place preference. Four groups of late adolescent C57BL/6 male mice were used. One non-stressed group (control) and three ISD-exposed groups treated with ketamine (0, 10 or 30 mg/kg). After the last defeat episode, the mice were tested in the elevated plus maze, social interaction, splash and tail suspension tests. Three weeks later, the mice were conditioned with cocaine (1 mg/kg). Stressed mice showed anxiety, displayed a deficit in social interaction, spent less time immobile in the tail suspension test and developed a cocaine place preference. Ketamine attenuated ISD-induced anxiety, social avoidance and cocaine reward potentiation. These results support the usefulness of ketamine in preventing some effects of social stress.
  • Behaviour of female mice defeated in an inter-female aggression protocol predicts resilience to cocaine-induced conditioned place preference
    María Ángeles Martínez-Caballero, Claudia Calpe-López, María Pilar García-Pardo, María Carmen Arenas, Carmen Manzanedo, María Asunción Aguilar
    Pharmacology Biochemistry and Behavior, 2026
    Several studies have demonstrated that exposure to different protocols of social defeat induces anxiety- and depression-like symptoms in male and female mice. Moreover, male mice exposed to an intermittent social defeat (ISD) show increased vulnerability to the rewarding effects of cocaine, although several behavioural traits have been found to confer resilience against this effect. However, the effects of ISD on the vulnerability to drugs of abuse in female mice have not been studied. Thus, our aim was to evaluate the short-term behavioural effects of ISD and its long-term influence on the rewarding effects of cocaine in female mice. Intruder female mice were exposed to an ISD protocol and performed the elevated plus maze, hole-board, social interaction, splash, object recognition and tail suspension tests 24 or 48 h after the last episode of defeat. Three weeks later, female mice underwent the conditioned place preference procedure with cocaine. ISD exposure induced a slight anxiogenic effect, decreased novelty-seeking behaviour and enhanced sensitivity to the conditioned rewarding effects of cocaine. However, defeated female mice characterized by an active coping response during episodes of defeat and an avoidance of potential dangers in unknown environments did not develop cocaine preference. Our results show that defeat in an inter-female aggression protocol is a useful way to study the long-term consequences of social stress on cocaine reward and the behavioural traits associated with resilience. • Defeat in inter-female aggression encounters induced a slight anxiolytic effect. • Defeat in inter-female aggression encounters decreased novelty-seeking behaviour. • Defeat in inter-female aggression encounters enhanced sensitivity to cocaine reward. • Lower submission during episodes of defeat predicted resilience to cocaine reward. • Anxiety-like behaviour after defeat episodes predicted resilience to cocaine reward.
  • Cannabidiol prevents social avoidance, potentiation of cocaine reward and gene expression alterations induced by exposure to intermittent social defeat in mice
    Maria Ángeles Martínez-Caballero, Daniela Navarro, Claudia Calpe-López, Abraham B. Torregrosa, Maria Pilar García-Pardo, Jorge Manzanares, Maria Asunción Aguilar
    Neuropharmacology, 2025
    Exposure to intermittent social defeat (ISD), a model of social stress, increased anxiety- and depression-like behaviors and enhanced sensitivity of mice to the rewarding effects of cocaine. In this study, we evaluated the role of cannabidiol on these behavioral effects of ISD and ISD-induced alterations in targets of the serotonin, endocannabinoid and hypothalamus-pituitary-adrenal (HPA) systems. Male mice were treated with cannabidiol (30 or 60 mg/kg) and exposed to four episodes of social defeat on PND 47, 50, 53 and 56. Control mice were not exposed to stress. In experiment 1, on PND 57-58, mice were tested in several behavioral tests and, three weeks later, underwent a cocaine-induced conditioned place preference. In experiment 2, the gene expression of the serotonin transporter in the dorsal raphe, corticotrophin-releasing factor in the paraventricular nucleus, proopiomelanocortin in the arcuate nucleus and the glucocorticoid and cannabinoid receptors in the hippocampus were evaluated after the last episode of defeat. CBD reversed the social interaction deficit and the potentiation of cocaine preference, but not anxiety-like effects induced by ISD. In addition, except for the glucocorticoid receptor, ISD reduced gene expression, and this effect was reversed by cannabidiol. Our results indicated the involvement of serotonin, HPA and endocannabinoid systems in the effects of social stress. They showed that CBD is a promising therapeutic agent to prevent social avoidance, enhanced vulnerability to cocaine and gene expression alterations in stress-exposed individuals. • Cannabidiol prevents social avoidance induced by intermittent social defeat in mice • Cannabidiol prevents the potentiation of cocaine reward induced by social defeat • Intermittent social defeat reduces 5-HTT, CRF, POMC, CB1R and CB2R gene expression • Intermittent social defeat increases glucocorticoid receptor gene expression • Cannabidiol prevents the reduction in gene expression induced by social defeat
  • Enhanced novelty-seeking after early adolescent exposure to vicarious social defeat predicts the vulnerability of female mice to cocaine reward
    María Ángeles Martínez-Caballero, Claudia Calpe-López, María Pilar García-Pardo, María Carmen Arenas, Jose Enrique de la Rubia Ortí, María Benlloch, Carmen Manzanedo, María Asunción Aguilar
    Pharmacology Biochemistry and Behavior, 2025
    Stressful experiences can have a serious impact on adolescents, as the process of brain maturation, particularly of the prefrontal cortex, takes place during this developmental period. In animal models, male mice exposed to social defeat during early or late adolescence show increased vulnerability to cocaine reward, but this effect has only been studied in late adolescent female mice exposed to Vicarious Intermittent Social Defeat (VISD). The aim of the present study was to investigate the biochemical and behavioural effects of exposure to VISD during early adolescence in female mice. VISD only induced anxiety-like symptoms in the elevated plus maze (EPM) and increased novelty-seeking behaviour in the hole-board test. Furthermore, the behavioural profile of VISD-exposed mice in these tests was associated with their vulnerability or resilience to cocaine reward in adulthood. Female mice that exhibited a higher frequency of entries in the closed arms of the EPM and a lower latency of dips in the hole-board subsequently acquired cocaine-induced conditioned place preference. Thus, exposure of female mice to VISD during early adolescence also induced short-term changes that increased sensitivity to cocaine reward in susceptible individuals.
  • Voluntary wheel running prevented the short-term behavioural effects of vicarious intermittent social defeat in female mice
    María Ángeles Martínez-Caballero, Claudia Calpe-López, María Pilar García-Pardo, María Carmen Arenas, Carmen Manzanedo, María Asunción Aguilar
    Psychopharmacology, 2025
    In a previous study, we observed that a Vicarious Intermittent Social Defeat (VISD) protocol induced anxiety- and depression-like symptoms in late adolescent female mice, and in some of them, enhanced sensitivity to cocaine reward in adulthood. Exposure to voluntary physical activity has been shown to mitigate the effects of different stress protocols in both male and female mice. Therefore, the aim of this study was to evaluate the efficacy of a voluntary wheel running (VWR) procedure in preventing the effects of the VISD in female mice. Four groups of female mice were used; (1) mice without exercise (control) nor stress (only exploration of an empty cage) (CONTROL + EXPL); (2) mice without exercise and exposed to VISD on PND 47, 50, 53 and 56 (CONTROL + VISD), (3) mice exposed to VWR (1 h, 3 days/week, from PND 21 to PND 46) without stress (VWR + EXPL); (4) mice exposed to both VWR and VISD (VWR + VISD). On PND 57–58, all female mice performed the Elevated Plus Maze, Hole-Board, Social Interaction, Splash and Object Recognition tests. Three weeks later, all female mice underwent a place conditioning procedure with cocaine. VWR exposure attenuated the VISD-induced reduction in the percentage of time spent in the open arms of the elevated plus maze and prevented the effects of the VISD in the hole-board, splash and object recognition tests. In addition, VWR facilitated the acquisition of the cocaine-induced conditioned place preference. Therefore, access to exercise during adolescence induced protective effects against the short-term negative consequences of social stress in female mice.
  • Sex differences in stress-modulated cocaine vulnerability: female rodents are more sensitive to the effects of stress exposure at different developmental stages
    María Ángeles Martínez-Caballero, Claudia Calpe-López, Maria Pilar García-Pardo, M. Carmen Arenas, Carmen Manzanedo, María A. Aguilar
    Frontiers in Behavioral Neuroscience, 2025
    Introduction Stressful life events can trigger the initiation of cocaine use, facilitate the transition to a cocaine-use disorder (CUD), and precipitate relapse. Evidence suggests that women progress more rapidly to a CUD than men. Thus, the influence of stressful life events on CUD development may differ by sex, contributing to the enhanced vulnerability seen among females. In this work, we provide a comprehensive (non-systematic) review of clinical and preclinical studies comparing the effects of cocaine and its modulation by stress in both sexes. Methods We performed a search of the PubMed database (1986–2025) in which we combined the keywords “cocaine” and “stress” with “sex differences” or “female rat” or “female mice” or “women.” We then read the abstracts of the search results to select potentially relevant studies, which we read in full to determine if they fulfilled our criteria and to extract the relevant information. Results Sex is often overlooked as a biological variable in preclinical and clinical research. The results of clinical studies indicate the existence of sex differences in the response to stress among individuals with CUD. Preclinical studies strongly suggest that female rodents are more vulnerable to developing addiction-like features than male rodents, particularly in the self-administration paradigm. Furthermore, exposure to stress appears to amplify the effects of cocaine, especially in females. Discussion There is growing evidence that women and female rodents are more vulnerable to the behavioral and neurochemical changes that characterize cocaine addiction. The influence of sex should be considered in research and in the selection of strategies for preventing and treating CUD, including those targeting stress reduction.
  • Inhibition of Nitric Oxide Synthesis Prevents the Effects of Intermittent Social Defeat on Cocaine-Induced Conditioned Place Preference in Male Mice
    María Ángeles Martínez-Caballero, María Pilar García-Pardo, Claudia Calpe-López, María Carmen Arenas, Carmen Manzanedo, María Asuncion Aguilar
    Pharmaceuticals, 2024
    We have previously observed that mice exposed to social defeat stress are more sensitive to cocaine in the conditioned place preference (CPP) paradigm. In this context, it has been suggested that the nitric oxide (NO) pathway plays a role in the effects of stress. The present study evaluates the role of a neuronal NO synthase (nNOS) inhibitor (7-nitroindazole, 7-NI) in the short- and long-term behavioural effects of intermittent social defeat (ISD). Four groups of mice were employed for the study: a control group and three stressed groups, one treated with vehicle and two treated with 7-NI (7.25 or 12.5 mg/kg). After the last episode of defeat, mice were tested in the elevated plus maze (EPM), social interaction, object recognition and tail suspension tests. Three weeks later, mice were conditioned with cocaine (1 mg/kg). Stressed mice, irrespective of the treatment received, showed anxiety in the EPM, presented a deficit of social interaction and spent less time immobile in the tail suspension test. However, only stressed mice treated with vehicle developed CPP. Thus, although 7-NI did not modify the short-term behavioural effects of ISD, it prevented ISD-induced potentiation of the rewarding properties of cocaine in adulthood. These results support a specific role of nNOS in the effects of social stress on drug reward.
  • Behavioural traits related with resilience or vulnerability to the development of cocaine-induced conditioned place preference after exposure of female mice to vicarious social defeat
    Maria Ángeles Martínez-Caballero, Claudia Calpe-López, Maria Pilar García-Pardo, Maria Carmen Arenas, Jose Enrique de la Rubia Ortí, Raquel Bayona-Babiloni, Maria Asunción Aguilar
    Progress in Neuro Psychopharmacology and Biological Psychiatry, 2024
    Exposure to stress induced by intermittent repeated social defeat (IRSD) increases vulnerability to the development of cocaine-induced conditioned place preference (CPP) among male mice; however, some defeated mice are resilient to these effects of stress. In the present study we evaluated the effects of vicarious IRSD (VIRSD) in female mice and explored behavioural traits that are potentially predictive of resilience. C57BL/6 female mice (n = 28) were exposed to VIRSD, which consisted of the animals witnessing a short experience of social defeat by a male mouse on postnatal day (PND) 47, 50, 53 and 56. The control group (n = 10) was not exposed to stress. Blood samples were collected on PND 47 and 56 for corticosterone and interleukin-6 determinations. On PND 57-58, female mice performed several behavioural tests (elevated plus maze, hole-board, object recognition, social interaction, TST and splash tests). Three weeks later, the effects of cocaine (1.5 mg/kg) on the CPP paradigm were assessed. VIRSD decreased corticosterone levels (on PND 56), increased interleukin-6 levels, enhanced novelty-seeking, improved recognition memory and induced anxiety- and depression-like symptoms. Control and VIRSD female mice did not acquire CPP, although some stressed individuals with certain behavioural traits - including a high novelty-seeking profile or the development of depression-like behaviour in the splash test shortly after VIRSD - acquired cocaine CPP. Our results confirm that some behavioural traits of female mice are associated with vulnerability or resilience to the long-term effects of social stress on cocaine reward, as previously observed in males.
  • Resilience to the short- and long-term behavioral effects of intermittent repeated social defeat in adolescent male mice
    Claudia Calpe-López, Maria Ángeles Martínez-Caballero, Maria Pilar García-Pardo, Maria A Aguilar
    Pharmacology Biochemistry and Behavior, 2023
    BACKGROUND: Exposure to intermittent repeated social defeat (IRSD) increases the sensitivity of mice to the rewarding effects of cocaine in the conditioned place preference (CPP) paradigm. Some animals are resilient to this effect of IRSD, though research exploring this inconsistency in adolescent mice is scarce. Thus, our aim was to characterize the behavioral profile of mice exposed to IRSD during early adolescence and to explore a potential association with resilience to the short- and long-term effects of IRSD. METHODS: Thirty-six male C57BL/6 mice were exposed to IRSD during early adolescence (PND 27, 30, 33 and 36), while another 10 male mice did not undergo stress (controls). Defeated mice and controls then carried out the following battery of behavioral tests; the Elevated Plus Maze, Hole-Board and Social Interaction Test on PND 37, and the Tail Suspension and Splash tests on PND 38. Three weeks later, all the mice were submitted to the CPP paradigm with a low dose of cocaine (1.5 mg/kg). RESULTS: IRSD during early adolescence induced depressive-like behavior in the Social Interaction and Splash tests and increased the rewarding effects of cocaine. Mice with low levels of submissive behavior during episodes of defeat were resilient to the short- and long-term effects of IRSD. In addition, resilience to the short-term effects of IRSD on social interaction and grooming behavior predicted resilience to the long-term effects of IRSD on cocaine reward. CONCLUSION: Our findings help to characterize the nature of resilience to the effects of social stress during adolescence.
  • Intermittent voluntary wheel running promotes resilience to the negative consequences of repeated social defeat in mice
    C. Calpe-López, M.A. Martínez-Caballero, M.P. García-Pardo, M.A. Aguilar
    Physiology and Behavior, 2022
    A novel approach to reduce the incidence of substance use disorders is to promote resilience to stress using environmental resources such as physical exercise. In the present study we test the hypothesis that Voluntary Wheel Running (VWR) during adolescence blocks the negative consequences of stress induced by intermittent repeated social defeat (IRSD). Four groups of adolescent male C57BL/6 mice were employed in the experiment; two groups were exposed to VWR (1 h, 3 days/week) from postnatal day (PND) 21 until the first social defeat (PND 47), while the remaining two groups did not have access to activity wheels (controls). On PND 47, 50, 53 and 56 mice, who had performed VWR, were exposed to an episode of social defeat by a resident aggressive mouse (VWR+IRSD group) or allowed to explore an empty cage (VWR+EXPL group). The same procedure was performed with control mice that had not undergone VWR (CONTROL+IRSD and CONTROL+EXPL groups). On PND 57, all the mice performed the Elevated Plus Maze (EPM), Hole-Board, Social Interaction, Tail Suspension and Splash tests. After an interval of 3 weeks, all mice underwent a conditioned place preference (CPP) procedure with 1 mg/kg of cocaine. Exposure to VWR prevented the negative consequences of social stress in the EPM, splash test and CPP, since the VWR+IRSD group did not display anxiety- or depression-like effects or the potentiation of cocaine reward observed in the Control+IRSD group. Our results support the idea that physical exercise promotes resilience to stress and represents an excellent target in drug abuse prevention.
  • Brief Maternal Separation Inoculates Against the Effects of Social Stress on Depression-Like Behavior and Cocaine Reward in Mice
    C. Calpe-López, M. A. Martínez-Caballero, M. P. García-Pardo, M. A. Aguilar
    Frontiers in Pharmacology, 2022
  • Modulation of Effects of Alcohol, Cannabinoids, and Psychostimulants by Novelty-Seeking Trait
    Claudia Calpe-López, M. Ángeles Martínez-Caballero, María Pilar García-Pardo, María A. Aguilar
    Neuromethods, 2022
  • The Biology of Nitric Oxide Signaling and MDMA 108
    M. Pilar García-Pardo, Claudia Calpe-López, M. Ángeles Martínez-Caballero, María A. Aguilar
    Handbook of Substance Misuse and Addictions from Biology to Public Health, 2022
  • Influence of Social Defeat Stress on the Rewarding Effects of Drugs of Abuse
    María Pilar García-Pardo, José Enrique De la Rubia-Ortí, Claudia Calpe-López, M. Ángeles Martínez-Caballero, María A. Aguilar
    Neuromethods, 2022
  • Behavioral Traits Associated With Resilience to the Effects of Repeated Social Defeat on Cocaine-Induced Conditioned Place Preference in Mice
    Claudia Calpe-López, Maria Pilar García-Pardo, Maria Angeles Martínez-Caballero, Alejandra Santos-Ortíz, Maria Asunción Aguilar
    Frontiers in Behavioral Neuroscience, 2020