Biomedical subjects

J Miñarro

Publications and source records attributed to J Miñarro.

At least 19 recordsLinked to original sources

PubMed2006

Social stress is as effective as physical stress in reinstating morphine-induced place preference in mice.

RATIONALE: Relapse to drug-seeking in abstinent heroin addicts and reinstatement in experimental animals are observed when exposed to drug-associated stimuli or cues, the drug itself, and stressful events. It has been shown that footshock-induced stress increases the rewarding effects of opiates, delays extinction, and induces the reinstatement of drug-seeking. However, the effects of social stress on the reinstatement of opiate-seeking after extinction has not been studied. OBJECTIVES: The role of physical (restraint and tail pinch) and social (social defeat) stressors on the reinstatement of morphine-induced conditioned place preference (CPP) was evaluated. METHODS: Adult male OF1 mice were conditioned with 10, 20, or 40 mg/kg of morphine or saline. Only morphine-conditioned animals acquired CPP. All mice underwent extinction sessions until the CPP was extinguished. Then, the effects of physical or social stress on the reinstatement of CPP were evaluated. Morphine- and saline-conditioned animals were exposed to the respective stressor or control stress condition immediately or 15 min before reinstatement tests. In experiment 1, animals underwent restraint for 15 min. In experiment 2, animals were exposed to tail pinch or placed in a cage without any manipulation for 15 min. In experiment 3, animals performed an agonistic encounter with an isolated or anosmic mouse or were placed in a cage without any social contact or manipulation. RESULTS: Restraint, tail pinch, and social defeat in an agonistic encounter with an isolated mouse produce the reinstatement of CPP in morphine-conditioned animals. CONCLUSIONS: These data demonstrate that social stress is as effective as physical stress in reinstating morphine-seeking.

Agonistic Behavior↗

PubMed2005

Long-lasting rewarding effects of morphine induced by drug primings.

To evaluate the persistence of the rewarding effects of morphine, the acquisition, maintenance, extinction and reinstatement of a conditioned place preference (CPP) was assessed in OF1 mice. In Experiment 1, the persistence of morphine-induced CPP was evaluated weekly. Mice showed CPP after four sessions of conditioning with 5, 10, 20 and 40 mg/kg of morphine, which lasted 0, 1, 2 and 4 weeks, respectively. In Experiment 2, after four sessions of conditioning with 40 mg/kg of morphine, the effects of four schedules of extinction differing in the time interval (2, 4, 6 or 8 weeks) between sessions were evaluated. CPP was no longer evident after 8 weeks for the groups examined each 2 or 8 weeks and after 12 weeks for the groups examined each 4 and 6 weeks. After extinction, the reinstating effects of a priming dose of 20 mg/kg of morphine were demonstrated. This procedure of extinction/reinstatement was repeated with a decreasing priming dose of morphine (10, 5, 2.5 and 1.25 mg/kg) until a noneffective dose was found. These results show that morphine-induced CPP is very persistent over time, suggesting that drug exposure induces long-lasting changes in the brain, which supports the idea that drug addiction must be considered as a chronic, lifelong disorder.

Analgesics, Opioid↗

PubMed2005

Prenatal cocaine exposure alters spontaneous and cocaine-induced motor and social behaviors.

The abuse of cocaine in pregnant women could affect emotional behaviors in their descendents. The aim of this work was to evaluate the effects of prenatal cocaine exposure on spontaneous and cocaine-induced motor and social behaviors in mice. Three kinds of prenatal treatment were used: non-treated animals; mice treated daily with physiological saline during the last week of pregnancy; and finally, those treated with cocaine (25 mg/kg) during the same period. Behavioral studies took place on adult males, which were housed in two different conditions: grouped (non-aggressive), or isolated (aggressive). Cocaine-pretreated animals exhibited slight differences in spontaneous motor activity, but alterations in their social relationship with conspecifics were presented, with decreases in isolated but increases in grouped mice. The cocaine challenge increased aggression specifically in grouped prenatally cocaine-treated mice, but increases in motor activity or avoidance and flee behavior were presented in those animals pretreated with either saline or cocaine. Isolated saline-or cocaine-treated animals exhibited greater concentrations of DA and DOPAC than those grouped. A decrease in 5-HIAA concentrations was presented in pretreated animals, irrespective of their housing conditions. In conclusion, cocaine administration during pregnancy induces long lasting effects on the offspring, for both behavioral abnormalities and cocaine response, which last to adult life.

Animals↗

PubMed2005

NMDA glutamate but not dopamine antagonists blocks drug-induced reinstatement of morphine place preference.

The effects of dopaminergic and glutamatergic antagonists on the drug-induced reinstatement of a previously extinguished morphine conditioned place preference (CPP) in mice were evaluated. Following extinction of a place preference induced by morphine (40 mg/kg), a non-contingent injection of the dopaminergic antagonists SCH 23390 (0.125, 0.5 mg/kg), raclopride (0.3, 1.2 mg/kg), haloperidol (0.1, 0.2 mg/kg) and the dopamine (DA) release inhibitor CGS 10746B (1, 10 mg/kg) or glutamatergic NMDA antagonists memantine (10, 20, 40 mg/kg) and MK-801 (0.1, 0.2, 0.3 mg/kg) alone or with 10 mg/kg morphine was given. Neither the dopaminergic nor the glutamatergic antagonists alone reinstated the place preference. Dopamine antagonists failed to block the morphine-induced reinstatement of place preference while memantine and MK-801 blocked it with intermediate and high doses. These results suggest that drug-induced reinstatement of place preference may be largely independent of dopamine and more closely related to glutamatergic neurotransmission.

Analgesics, Opioid↗

PubMed2005

Cross-reinstatement by cocaine and amphetamine of morphine-induced place preference in mice.

The cross-reinstatement by psychostimulants of a conditioned place preference (CPP) induced by morphine was evaluated in mice. In Experiment 1, we examined the effects of a single dose of cocaine and amphetamine on a previously extinguished morphine CPP. After acquisition of CPP induced by morphine (40 mg/kg), animals underwent daily extinction sessions of 15 min duration until the CPP was extinguished. Subsequently, animals received a non-contingent injection of cocaine (25 mg/kg) or amphetamine (4 mg/kg), which produced the reinstatement of the extinguished morphine-induced CPP. In Experiment 2, we evaluated the reinstating effects of several priming doses of cocaine (Experiment 2A) or amphetamine (Experiment 2B). As in the first experiment, after conditioning with morphine (40 mg/kg), mice underwent daily 15 min extinction sessions. When the preference was no longer evident, we tested the effects of cocaine (0, 6.25, 12.5, 25 and 50 mg/kg) and amphetamine (0, 0.5, 1, 2 and 4 mg/kg) on the reinstatement of CPP. Doses from 12.5 mg/kg of cocaine upward and doses from 1 mg/kg of amphetamine upward effectively reinstated CPP. Our results demonstrate cross-reinstatement with psychostimulants and opiates, suggesting that in abstinent individuals, drug exposure can produce craving for the previously abused drug and relapse.

Amphetamine↗

PubMed2004

Social behavioural profile of cocaine in isolated and grouped male mice.

Studies concerning the relationship between cocaine and aggression in humans as well as in animals have discrepant outcomes. Increases, decreases, or no changes, have been reported after single or chronic cocaine administration in animal models. To clarify, at least in part, the complex behavioural actions of cocaine, the present study evaluated cocaine effects on social behaviours of mice exposed to different situations (isolated or group housed) using confrontations between two male mice in a neutral area. Different doses of cocaine (6, 25 and 50 mg/kg) were administered in a single or binge pattern (three doses in 24 h) and the behavioural test was performed 20 min after the last injection. No increases in aggression were observed in any situation tested. Instead, cocaine at the two higher doses employed (either in single or binge administration), decreased aggressive behaviours in isolated mice, with no changes being observed in grouped animals. In both types of animals, cocaine increased defensive elements (avoidance/flee) and abolishes social contacts. In conclusion, cocaine presents an anti-aggressive action and may be interpreted as having an anxiogenic-like effect.

Aggression↗

PubMed2003

Memantine presents different effects from MK-801 in motivational and physical signs of morphine withdrawal.

Adaptive changes in neural systems due to chronic opiate exposure are related to the neural plasticity phenomenon, NMDA receptors being implicated in these processes, e.g. tolerance, dependence or withdrawal. In this work, we investigated the effect of two non-competitive NMDA antagonists, memantine and MK-801, in motivational (Conditioned Place Aversion paradigm, CPA) and physical aspects of morphine withdrawal. After the induction of morphine dependence, animals in which the CPA was studied, received memantine (5 and 10 mg/kg) or MK-801 (0.3-0.006 mg/kg) either during the acquisition (conditioning) or expression (test) phase of this procedure. Both drugs were capable of inhibiting conditioned aversion when administered in any phase. In a second experiment, the effects of these drugs were evaluated in the intensity of the physical signs of withdrawal, only memantine administration being efficient. In addition to these studies, the intensity of morphine dependence was investigated under the blockade of NMDA receptors, i.e. morphine was co-administered with memantine or MK-801. These animals did not develop CPA and present less intensity in the physical signs of morphine withdrawal. Our results support the idea that NMDA receptors are involved in the behavioural changes and therefore in the neural adaptations produced by repeated morphine administration.

Animals↗

PubMed2003

GHB differentially affects morphine actions on motor activity and social behaviours in male mice.

There are several reports suggesting that gamma-hydroxybutyric acid (GHB) influences the endogenous opioid system. The present study aimed to investigate the effects of GHB on motor and social activities and to examine its influence on morphine's actions on these behaviours. In a first experiment, several doses of GHB were studied but only the highest (200 and 400 mg/kg) produced a decrease in spontaneous motor activity measured in an actimeter cage. When hyperactivity induced by injecting 50 mg/kg of morphine was evaluated, all the GHB doses efficiently counteracted this morphine action. Using the paradigm of isolation-induced aggression, administration of 200 mg/kg of GHB significantly decreased threat and attack without impairing motor activity and, in addition, increased time spent in social contact. GHB increased morphine's suppression of threat or nonsocial exploratory behaviours. In conclusion, the interaction between GHB and the opioid systems was confirmed, with the drug having an additive effect on morphine-affected social behaviours but counteracting morphine-induced increases in motor activity.

Aggression↗

PubMed2003

The dopamine release inhibitor CGS 10746B blocks conditioned physical signs of morphine withdrawal.

Environment previously paired with morphine withdrawal leads to conditioned physical signs of withdrawal, this effect being modulated by additional exposition to morphine administration. In this study, the putative role of dopamine in conditioned withdrawal signs is evaluated by administering the dopamine release inhibitor CGS 10746B prior to suffering two naloxone-induced withdrawals in a distinctive environment associated or not with morphine administration. The results show that dopamine seems to be necessary for the development of conditioned somatic signs of morphine withdrawal, as animals which received CGS 10746B do not present paw tremor or body shakes when they are placed in the environment paired with two previously induced withdrawals. On the other hand, the conditioned decrease in aggression is not affected by the dopamine release inhibitor. Taken together, our results confirm a critical role for dopamine in the processes of conditioning to the aversive physical signs of withdrawal.

Animals↗

PubMed2003

Reinstatement of morphine-induced conditioned place preference in mice by priming injections.

To construct a model of relapse of drug abuse in mice, the induction, we evaluated the extinction and reinstatement of morphine-induced place preference. In Experiment 1, we examined the effects of morphine (0, 2, 3, 5, 10, 20 and 40 mg/kg) in the conditioned place preference (CPP) paradigm. Mice showed CPP with 5, 10, 20 and 40 mg/kg. In Experiment 2, we evaluated the effects of two different extinction procedures. After conditioning with 40 mg/kg of morphine, the mice underwent daily extinction sessions of 60 or 15 min of duration. CPP was extinguished after seven and nine sessions, respectively. In Experiment 3, we tested the reinstating effects of several priming doses of morphine. Mice were conditioned with 40 mg/kg of morphine and underwent the daily 15 min extinction sessions until CPP was no longer evident. Then, the effects of morphine (0, 2, 3, 5, 10, 20, 40 mg/kg, i.p.) were evaluated. CPP was reinstated by doses from 5 mg/kg upward. The results show that morphine priming injections are effective in reactivating opiate-seeking behavior in mice, and thus, the CPP paradigm might be useful to investigate the mechanisms underlying relapse of drug abuse.

Animals↗

PubMed2002

Memantine does not block antiaggressive effects of morphine in mice.

The action of the noncompetitive N-methyl-D-aspartate (NMDA) receptor blocker memantine (5, 10, 20 and 40 mg/kg) was evaluated during social encounters in mice. Although a dose-dependent increase in locomotion was observed, only with the highest dose did it reach statistical significance. Aggressive behavior was decreased with 20 and 40 mg/kg of memantine, social contacts being increased only with 20 mg/kg. Subsequently, the effect of these memantine doses on the antiaggressive actions of morphine (10 mg/kg) was evaluated. None of the doses affected the antiaggressive action of morphine. As memantine administration produced an antiaggressive effect only at doses that affected locomotion, it is unlikely that the glutamatergic system mediates the antiaggressive actions of morphine.

Adaptation, Psychological↗

PubMed2001

Effects of CGS 10746B on hyperactivity and place preference induced by morphine.

The effects of CGS 10746B, a dopamine release inhibitor, on spontaneous locomotor activity, morphine-induced hyperactivity, acquisition of conditioned place paradigm and morphine-induced conditioned place preference (CPP) was evaluated in male mice. In experiment 1, animals treated with CGS 10746B (0.5, 1, 2, 4, 8, 16, 24 and 32 mg/kg), morphine (40 mg/kg) or morphine (40 mg/kg) plus CGS 10746B (0.5, 1, 2, 4, 8, 16, 24 and 32 mg/kg) were placed in an actimeter during a period of 90 min. In experiment 2, animals treated with CGS 10746B (0.5, 1, 3 and 10 mg/kg), morphine (40 mg/kg) or morphine (40 mg/kg) plus CGS 10746B (0.5, 1, 3 and 10 mg/kg) were conditioned following a procedure unbiased in terms of initial spontaneous preference. In experiment 1, it was found that a decrease in spontaneous locomotor activity was produced between 0 and 45 min after administration of 24 and 32 mg/kg of CGS 10746B. In contrast, morphine induced hyperactivity between 45 and 90 min after administration. CGS 10746B reduced morphine-induced hyperactivity with doses of 2 mg/kg and higher. In experiment 2, CGS 10746B did not produce any effect on place conditioning but blocked morphine-induced CPP with doses from 1 mg/kg upwards. Our results confirm that an intact dopamine neurotransmission is critical for the manifestation of the motor and place preference conditioning effects of morphine.

Animals↗

PubMed2001

Effects of dopamine antagonists with different receptor blockade profiles on morphine-induced place preference in male mice.

The effects of dopamine (DA) antagonists with different selectivity for the DA receptors (SCH 23390, 0.5, 0.25, 0.125 mg/kg; haloperidol, 0.2, 0.1 mg/kg; raclopride, 1.2, 0.6, 0.3 mg/kg; risperidone, 0.4, 0.2, 0.1 mg/kg; U-99194A maleate, 40, 20 mg/kg; clozapine, 2.5, 1.25, 0.625 mg/kg) on the acquisition of place conditioning and morphine-induced conditioned place preference (CPP) were explored in male mice. Morphine (40 mg/kg) produced CPP while SCH 23390, haloperidol and clozapine (highest dose) and risperidone (lowest dose) produced conditioned place aversion (CPA). Raclopride and U-99194A maleate did not produce CPP or CPA. Morphine-induced CPP was reversed by the administration of SCH 23390 and risperidone (all doses), haloperidol (highest dose) and raclopride and clozapine (intermediate and lowest doses). U-99194A maleate did not reverse morphine-induced CPP. These results suggest that the conditioned rewarding effects of morphine are mediated by the different subtypes of DA receptors.

Animals↗

PubMed2001

Development of tolerance to the antiaggressive effects of morphine.

Many reports have demonstrated that there is a development of tolerance to many effects produced by morphine. This study was conducted with the aim of determining whether the antiaggressive actions of morphine develop tolerance after chronic administration. Acute morphine administration produced antiaggressive effects which disappeared after chronic (7 days) treatment in isolated mice. An increase in non-social exploration was observed, representing morphine-induced hyperactivity, after acute treatment, which was not present after chronic administration. In conclusion, there is a development of tolerance to the antiaggressive and motor effects of morphine.

Aggression↗

PubMed2000

Chronic moderate hyperammonemia impairs active and passive avoidance behavior and conditional discrimination learning in rats.

The cerebral dysfunction associated with hepatic encephalopathy is generally considered to have hyperammonemia as one of its main causes. Hyperammonemia impairs the neuronal glutamate-nitric oxide-cyclic GMP pathway and the induction of NMDA receptor-dependent long-term potentiation in the hippocampus. We studied the performance of pre/neonatally and postnatally exposed rats to hyperammonemia on active avoidance, passive avoidance, and conditional discrimination tasks. Pre/neonatal hyperammonemia slowed learning of active avoidance behaviors and impaired memory for the passive avoidance task while postnatal hyperammonemia impaired learning on the conditional discrimination task. Hyperammonemia thus may produce cognitive disturbances that relate to the effects of ammonia on the neuronal glutamate-nitric oxide-cyclic GMP pathway.

Acetates↗

PubMed2000

Lack of specific effects of selective D(1) and D(2) dopamine antagonists vs. risperidone on morphine-induced hyperactivity.

In the present study, three different dopamine antagonists were challenged in order to counteract hyperactivity induced by 50 mg/kg of morphine. A wide range of doses of morphine (50, 25, 12.5, 6.25, or 3.12 mg/kg) were evaluated on spontaneous locomotor activity. A significant increase was observed only with the two higher doses tested (25 and 50 mg/kg). No decrease was found with any of the doses used at any period of time. After analyzing doses of SCH 23390 (0.5, 0.1, and 0.05 mg/kg), raclopride (0.5, 0.25, and 0.125 mg/kg) and risperidone (0.1, 0.05, and 0.025 mg/kg) administered alone, only the 0.5 mg/kg dose of SCH 23390 decreased locomotor activity. The three compounds counteracted morphine-induced hyperactivity, but with SCH 23390 it was only achieved with the dose of 0.5 mg/kg, which also decreased spontaneous locomotor activity and induced catalepsy. On the other hand, raclopride and risperidone neutralized morphine-induced hyperactivity at doses that did not affect locomotor activity, although the former induced catalepsy when administered with morphine. It is concluded that although the blockade of D(1) and D(2) DA receptors decreases morphine-induced hyperactivity, this action is not specific, contrary to the action of risperidone, which counteracts this hyperactivity without any other motor effects.

Animals↗

PubMed2000

Predicting how equipotent doses of chlorpromazine, haloperidol, sulpiride, raclopride and clozapine reduce locomotor activity in mice.

Distinguishing the specific effects of neuroleptics on one particular behaviour from its non-specific effects on motility is not easy. In this study, the effects of five neuroleptics on spontaneous motor activity were compared and the ED(50) values of these drugs to impair activity were calculated. Male and female mice were evaluated in an actimeter or in a shuttle-box used as an open field after the administration of chlorpromazine (0.4, 1.2, 3.6 mg/kg), haloperidol (0.1, 0.3, 0.9 mg/kg), raclopride (0.1, 0.3, 0.9 mg/kg), sulpiride (10, 30, 90 mg/kg) and clozapine (0.4, 1.2, 3.6 mg/kg), and two automatic and two observational activity measures were obtained. A very high correlation between automatic and observational measures, absence of sex differences, and a dose-dependent decrease of activity were observed with every compound. The results allow us to make accurate comparisons between these drugs in their potency in reducing spontaneous motor activity.

Animals↗

PubMed2000

Naloxone-induced opiate withdrawal produces long-lasting and context-independent changes in aggressive and social behaviors of postdependent male mice.

The purpose of this study was to determine whether an environment associated with naloxone-induced morphine withdrawal affects aggressive or social behaviors in postdependent mice. Morphine-dependent or saline-treated mice received 3 naloxone injections in 1 of 2 different environments (A or B); 15 days afterward, when the mice were completely drug free, an aggression test was carried out in Environment A. All the mice suffering morphine withdrawal showed a significant increase in aggression, irrespective of the environment in which the withdrawal took place. In these conditions, the impact of morphine dependence and the 3 induced withdrawals was so profound that the environment could not be discriminative. In addition, modifications in the behavioral profile of postdependent mice that suffered only spontaneous withdrawal were long-lasting, with the mice carrying out more attacks during social investigation without presenting threat postures.

Aggression↗