Sex differences in behavioral traits related with high sensitivity to the reinforcing effects of cocaine

Cocaine is the most prevalent illegal stimulant drug in Europe among the adult population. Its abuse is characterized by a faster substance abuse disorder (SUD) development than other drugs, with high vulnerability to relapse. However, there does not exist an effective treatment for cocaine dependence. Sex differences have been reported in psychological disorders including SUD. For this reason, it is essential to identify risk factors that predict susceptibility or resilience to cocaine addiction for the development of effective prevention strategies considering sex differences. In the present study, the main objective was to determine more sensitive phenotypes to the conditioned reinforcin…

Sex differences of anxiety disorders: Possible psychobiological causes

Los trastornos de ansiedad son, en la actualidad, enfermedades psiquiátricas muy frecuentes e incapacitantes. Las mujeres en edad reproductiva son más vulnerables a desarrollar trastornos de ansiedad, aproximadamente entre 2 a 3 veces más que los hombres. Ser hombre o mujer no sólo puede influir en la prevalencia de los trastornos mentales, sino también en la manifestación y expresión de los síntomas, la voluntad para solicitar asistencia médica o psicológica, el curso de la enfermedad, incluso en la respuesta al tratamiento. Cada vez hay pruebas más sólidas de que existen diferencias entre ambos sexos respecto a la anatomía cerebral, la neuroquímica y los patrones de activación y respuesta…

El modulador alostérico negativo de los mGluR5, MPEP, potencia la reinstauración de la preferencia condicionada inducida con priming de cocaína

Cocaine addiction is a chronic disorder with high relapse rates; therefore, understanding the neuronal mechanisms underlying drug-seeking during relapse is a priority to develop targeted pharmacotherapy. The metabotropic glutamate receptor 5 (mGluR5) seems to be involved in the reinstatement induced by cocaine-associated cues. The main objective of the study was to evaluate the efficacy of MPEP, a negative allosteric modulator of mGluR5, in attenuating or potentiating the reinstatement induced by priming doses of cocaine in the CPP paradigm, ultimately to further knowledge regarding the role of the mGluR5 in relapse into cocaine abuse. OF1 mice (48 female and 48 male) were conditioned in th…

Are the effects of the antidepressants amitriptyline, maprotiline, and fluoxetine on inhibitory avoidance state-dependent?

Abstract State-dependent learning (SDL) is a phenomenon in which the retrieval of newly acquired information is possible if the subject is in the same physiological state as during the encoding phase. SDL makes it possible to separate the effects of drugs per se on learning from the effects due to changes in drug state during the task. The present work was designed to investigate whether the antidepressants amitriptyline (30 mg/kg), maprotiline (25 mg/kg), and fluoxetine (15 mg/kg) produce SDL of the inhibitory avoidance conditioning in male and female CD1 mice. In three separate experiments, independent groups were used for each pharmacological treatment and for each sex using a 2 × 2 expe…

Chronic administration of fluoxetine impairs inhibitory avoidance in male but not female mice

The effects of chronic administration of fluoxetine (20 mg/kg/day i.p.) on a one-trial step-through inhibitory avoidance task were investigated in male and female CD1 mice. In Experiment 1, treatment was administered for 21 days before the training session, whereas in Experiment 2, other subjects were subjected to the same treatment starting 24 h after the training session. The comparison of test versus training latencies showed memory deterioration with pre-training administration of fluoxetine (Experiment 1), which affected males but not females. Sex differences in this task were also observed in Experiment 1, with females showing a better performance. Sex differences were evident in cont…

The novelty-seeking phenotype modulates the long-lasting effects of adolescent MDMA exposure.

Exposure to drugs such as ethanol or cocaine during adolescence induces alterations in the central nervous system that are modulated by the novelty-seeking trait. Our aim was to evaluate the influence of this trait on the long-term effects of MDMA administration during adolescence on spontaneous behavior and conditioned rewarding effects in adulthood. Adolescent mice were classified as high or low novelty seekers (HNS or LNS) according to the hole-board test and received either MDMA (0, 10 or 20mg/kg PND 33-42) or saline. Three weeks later, having entered adulthood (PND>68), one set of mice performed the elevated plus maze and social interaction tests, while another set performed the condit…

CB1 Cannabinoid Receptors and Aggression

Abstract The relation between the use of cannabis and violent behavior is controversial, partly owing to the complexity of the concept of aggression and variability among the studies performed. The primary psychoactive compound of cannabis, Δ9-tetrahydrocannabinol, acts on G-protein-coupled receptors such as the cannabinoid type 1 (CB1) receptor, the most important of the endocannabinoid system. Although historically suspected of instigating aggressive behaviors, the findings of research about cannabis use in humans are mixed. While cannabis intoxication seems to reduce the likelihood of violence, mounting evidence associates withdrawal with an increase in aggression. Acute or chronic canna…

Influence of trait anxiety on the effects of acute stress on learning and retention of the passive avoidance task in male and female mice

The influence of anxiety on the effects of acute stress for the acquisition and retention of passive avoidance conditioned task was evaluated in male and female mice. Animals were categorized as high-, medium-, and low-anxiety according to their performance in the elevated plus-maze test. Subsequently, half of the mice in each group were exposed to an acute stressor and assayed in an aversive conditioning test two days later. Exposure to restraint stress before inhibitory avoidance conditioning had a differential impact on the conditioned response of males and females according to their trait anxiety. The acute stressor significantly altered the conditioned response of mice with a high-anxi…

Adolescent Exposure to the Synthetic Cannabinoid WIN 55212-2 Modifies Cocaine Withdrawal Symptoms in Adult Mice

Chronic cannabinoid consumption is an increasingly common behavior among teenagers and has been shown to cause long-lasting neurobehavioral alterations. Besides, it has been demonstrated that cocaine addiction in adulthood is highly correlated with cannabis abuse during adolescence. Cocaine consumption and subsequent abstinence from it can cause psychiatric symptoms, such as psychosis, cognitive impairment, anxiety, and depression. The aim of the present research was to study the consequences of adolescent exposure to cannabis on the psychiatric-like effects promoted by cocaine withdrawal in adult mice. We pre-treated juvenile mice with the cannabinoid CB1 receptor agonist WIN 55212-2 (WIN)…

Prepulse Inhibition of the Startle Reflex as a Predictor of Vulnerability to Develop Locomotor Sensitization to Cocaine

Prepulse inhibition (PPI) of the startle reflex is a measure of sensory-motor synchronization. A deficit in PPI has been observed in psychiatric patients, especially those with schizophrenia and vulnerable subjects, since the neural bases of this disorder are also involved in the regulation of PPI. Recently, we have reported that baseline PPI levels in mice can predict their sensitivity to the conditioned reinforcing effects of cocaine in the conditioned place preference (CPP) paradigm. Mice with a low PPI presented a lower sensitivity to the conditioned rewarding effects of cocaine; however, once they acquired conditioned preference with a higher dose of the drug, a more persistent associa…

High novelty-seeking predicts greater sensitivity to the conditioned rewarding effects of cocaine

Novelty-seeking in rodents, defined as enhanced specific exploration of novel situations, is considered to predict the response of animals to drugs of abuse and, thus, identify "drug-vulnerable" individuals. The main objective of this work was to determine the capacity of two animal models-the novel object recognition task and the novel environment test-for evaluating to what extent novelty-seeking can predict greater sensitivity to the rewarding properties of cocaine in young adult (PND 56) and adolescent (PND 35) OF1 mice of both sexes. Conditioned place preference, a useful tool for evaluating the sensitivity of individuals to the incentive properties of addictive drugs, was induced with…

Piracetam counteracts the effects of amitriptyline on inhibitory avoidance in CD1 mice.

The purpose of the present work was to study the effects of amitriptyline on animal cognition in relation to some characteristics of its therapeutic effects. The modulation of acute and chronic effects of amitriptyline on inhibitory avoidance in male and female mice by piracetam was investigated. In Experiment 1, mice were subjected to the training phase of inhibitory avoidance conditioning 60 min after acute piracetam (100 mg/kg) or physiological saline administration. Immediately after the behavioural task, they received a single injection of the tricyclic antidepressant amitriptyline (30 mg/kg) or physiological saline. Twenty-four hours later, subjects were tested for avoidance. In Exper…

Diferencias entre hombres y mujeres en los trastornos de ansiedad: una aproximación psicobiológica

Los trastornos de ansiedad son, en la actualidad, enfermedades psiquiátricas muy frecuentes e incapacitantes. Las mujeres en edad reproductiva son más vulnerables a desarrollar trastornos de ansiedad, aproximadamente entre 2 a 3 veces más que los hombres. Ser hombre o mujer no sólo puede influir en la prevalencia de los trastornos mentales, sino también en la manifestación y expresión de los síntomas, la voluntad para solicitar asistencia médica o psicológica, el curso de la enfermedad, incluso en la respuesta al tratamiento. Cada vez hay pruebas más sólidas de que existen diferencias entre ambos sexos respecto a la anatomía cerebral, la neuroquímica y los patrones de activación y respuesta…

Prepulse Inhibition and Vulnerability to Cocaine Addiction

Effects of acute amitriptyline administration on memory, anxiety and activity in male and female mice

The effects of acute administration of amitriptyline on memory consolidation in male and female CD1 mice were investigated. Three doses of this tricyclic antidepressant (7.5, 15 and 30 mg/kg) were administered immediately after inhibitory avoidance training. Forty-five minutes after injection, subjects explored the elevated plus-maze for five minutes. Subjects were tested for avoidance twenty-four hours later. Amitriptyline impaired inhibitory avoidance consolidation at doses 7.5, 15 and 30 mg/kg in males, and at doses 7.5 and 30 mg/kg in females. In the elevated plus-maze, amitriptyline had no effect on anxiety (percentage of open arm entries) and induced a dose-dependent impairment of act…

Antidepressant drugs and memory: Insights from animal studies

This is a selective review of the literature concerning the effects of antidepressant drugs on animal memory, which was performed with the aid of the PubMed database. Monoamine oxidase inhibitors tend to either have no effect on memory or result in its improvement. Studies with cyclic antidepressants have reported no effect or, more often, memory impairments. Pre-training administration of selective serotonin reuptake inhibitors (SSRIs) has been shown to have either no effect on memory or undermine it (with some isolated exceptions, in which improvements have been recorded), while post-training administration of SSRIs has been demonstrated to improve memory or have no effect. A small group …

Gender differences in dual diagnoses associated with cannabis use: A review

Gender differences in psychiatric disorders and drug use are well known. Cannabis is the most widely used illegal drug among young people. In recent years, its use has been related to the development of psychiatric pathologies; however, few studies have incorporated the gender perspective as of yet. The present work analyses the literature to determine the existence of gender differences in the development of psychotic, depressive and anxious symptoms associated with cannabis use. First, we describe cannabis misuse and its consequences, paying special attention to adolescent subjects. Second, the main gender differences in psychiatric disorders, such as psychosis, depression, anxiety and ca…

Diferencias entre hombres y mujeres en los trastornos de ansiedad: una aproximación psicobiológica

Los trastornos de ansiedad son, en la actualidad, enfermedades psiquiátricas muy frecuentes e incapacitantes. Las mujeres en edad reproductiva son más vulnerables a desarrollar trastornos de ansiedad, aproximadamente entre 2 a 3 veces más que los hombres. Ser hombre o mujer no sólo puede influir en la prevalencia de los trastornos mentales, sino también en la manifestación y expresión de los síntomas, la voluntad para solicitar asistencia médica o psicológica, el curso de la enfermedad, incluso en la respuesta al tratamiento. Cada vez hay pruebas más sólidas de que existen diferencias entre ambos sexos respecto a la anatomía cerebral, la neuroquímica y los patrones de activación y respuesta…

Dose Dependency of Sex Differences in the Effects of Repeated Haloperidol Administration in Avoidance Conditioning in Mice

Sex differences in the effects of haloperidol in active avoidance conditioning in mice have previously been found in various studies carried out in our laboratory. Males were more affected than females by the disruptive effects of this neuroleptic. The work described here broadens the study of these sex differences to higher doses of haloperidol (0.1 and 0.2 mg/kg) using a repeated administration schedule (5 days). The results did not show sex differences in the deteriorating effects of this dopamine antagonist in the escape-avoidance response, but a tendency in the number of nonresponses was observed in the same direction as former results: male animals were more sensitive than females to …

Prepulse inhibition can predict the motivational effects of cocaine in female mice exposed to maternal separation

The prepulse inhibition (PPI) of the startle response can identify the rodents that are more sensitive to the effects of cocaine. Mice with a lower PPI presented a higher vulnerability to the effects of cocaine and a higher susceptibility to developing a substance use disorder (SUD). Maternal separation with early weaning (MSEW) is a relevant animal model to induce motivational alterations throughout life. Nevertheless, only a few studies on females exist, even though they are more vulnerable to stress- and cocaine-related problems. Hence, the aim of the present study was to evaluate the ability of PPI to identify females with a greater vulnerability to the long-term consequences of early s…

Gender differences in escape-avoidance behavior of mice after haloperidol administration.

Gender differences in the disruptive effects of haloperidol on some reinforced behaviors have been observed in different species. However, the inhibitory action of haloperidol on the acquisition and performance of escape-avoidance behavior has only been investigated in male subjects. The present experiment was designed to investigate possible gender differences in the effects of haloperidol on the initial phase of an escape-avoidance learning task. Male and female mice of the OF1 strain were given a single training session in a shuttle-box. Thirty minutes prior to the behavioral test, mice were injected IP with haloperidol (0.25 mg/kg) or physiological saline (10 ml/kg). Latencies of escape…

Acute effects of fluoxetine on inhibitory avoidance consolidation in male and female OF1 mice

The effects of acute administration of fluoxetine on memory consolidation using an inhibitory avoidance task were investigated in male and female OF1 mice. Several doses of this antidepressant (5, 10, and 20 mg/kg) were intraperitoneally administered immediately after the training session. The test session was carried out four days later and response latencies were measured in both sessions. The results showed that the highest dose of fluoxetine significantly increased response latencies of inhibitory avoidance compared with the lowest dose and the control group. Sex differences in this task were observed, females showing a better performance. But the drug's effects were not sexually dimorp…

Capacity of novelty-induced locomotor activity and the hole-board test to predict sensitivity to the conditioned rewarding effects of cocaine

Novelty-seeking in rodents, defined as enhanced specific exploration of novel situations, is considered to predict the response of animals to drugs of abuse and, thus, allow "drug-vulnerable" individuals to be identified. The main objective of this study was to assess the predictive ability of two well-known paradigms of the novelty-seeking trait - novelty-induced locomotor activity (which distinguishes High- and Low-Responder mice, depending on their motor activity) and the hole-board test (which determines High- and Low-Novelty Seeker mice depending on the number of head dips they perform) - to identify subjects that would subsequently be more sensitive to the conditioned rewarding effect…

Influence of the Novelty-Seeking Endophenotype on the Rewarding Effects of Psychostimulant Drugs in Animal Models

Novelty seeking (NS), defined as a tendency to pursue novel and intense emotional sensations and experiences, is one of the most relevant individual factors predicting drug use among humans. High novelty seeking (HNS) individuals present an increased risk of drug use compared to low novelty seekers. The NS endophenotype may explain some of the differences observed among individuals exposed to drugs of abuse in adolescence. However, there is little research about the particular response of adolescents to drugs of abuse in function of this endophenotype, and the data that do exist are inconclusive. The present work reviews the literature regarding the influence of NS on psychostimulant reward…