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…

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…

Effects of DA D1 and D2 antagonists on the sensitisation to the motor effects of morphine in mice

Abstract Acute morphine administration produces hyperactivity in mice and repeated treatment induces an enhancement of this effect. In this experiment, we study the sensitisation to the hyperactivity induced by intermittent morphine administration (40 mg/kg) and the effects of dopamine (DA) antagonists on this phenomenon. Animals received three injections, separated by 48 h, and after each injection, their activity was registered between 30 and 60 min. In Experiment 1, animals were divided into two groups, which received saline and morphine (S–S–M) or only morphine (M–M–M). In Experiment 2, animals were divided into 12 groups. Half, which was designed to study the effects of DA antagonists …

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 …

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…

Social Housing Conditions Modulate the Long-Lasting Increase in Cocaine Reward Induced by Intermittent Social Defeat

Social defeat is considered the most representative animal model for studying the consequences of social stress. Intermittent social defeat (ISD) has proved to enhance the response to cocaine hedonic properties. In the present research, we evaluated if different social housing conditions, as housing with a familiar conspecific or with a female, exert a protective effect modulating the negative consequences of ISD as the increased sensitivity to cocaine and the induction of anxiety-like behavior. To achieve this objective, non-stressed or ISD OF1 male mice were divided into five different experimental groups according to their social environment: standard housing (four adult males per cage);…

Sensitization to the rewarding effects of morphine depends on dopamine

The influence of dopamine (DA) on sensitization to the rewarding effects of morphine was evaluated. The effects of pre-treatment with saline or morphine plus naloxone, CGS 10746B, haloperidol, SCH 23390 and raclopride, on the place conditioning induced by 2 mg/kg morphine were evaluated. This dose was ineffective in saline pre-treated animals but induced a clear conditioned place preference in mice pre-treated with morphine, CGS 10746B or haloperidol. Conversely, animals pre-treated with morphine plus naloxone, CGS 10746B, SCH 23390, raclopride and the high dose of haloperidol did not acquire place preference. Our results demonstrated that DA release and subsequent DA D1 and D2 receptor act…

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)…

Effect of adolescent exposure to WIN 55212-2 on the acquisition and reinstatement of MDMA-induced conditioned place preference.

The present study employs a conditioned place preference procedure (CPP) to examine the effects of exposure to the cannabinoid agonist WIN 55212-2 (WIN) (0.1 and 0.5mg/kg) during adolescence on the reinforcing properties of +/-3,4-methylenedioxymetamphetamine hydrochloride (MDMA) (1.25 and 2.5mg/kg) in mice. On postnatal day (PD) 27, animals received a daily injection of the assigned treatment on 5 consecutive days, and three days later the place conditioning procedure was initiated (PD 35). The results suggest that pre-exposure to cannabinoids strengthens the properties of MDMA and favors reinstatement of the craving for the drug, which endorses the gateway hypothesis.

Sex-dependent effects of early maternal deprivation on MDMA-induced conditioned place preference in adolescent rats: Possible neurochemical correlates

Abstract The early neonatal stage constitutes a sensitive period during which exposure to adverse events can increase the risk of neuropsychiatric disorders. Maternal deprivation (MD) is a model of early life stress that induces long-term behavioural and physiological alterations, including susceptibility to different drugs of abuse. In the present study we have used the conditioned place preference (CPP) paradigm to address the influence of MD on the rewarding effects of 3,4-methylenedioxymetamphetamine (MDMA) in adolescent animals of both sexes. We have previously observed in adolescent rats that MD induces modifications in the serotonergic and endocannabinoid systems, which play a role i…

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…

Antagonism of corticotropin-releasing factor CRF 1 receptors blocks the enhanced response to cocaine after social stress

Numerous studies have shown that social defeat stress induces an increase in the rewarding effects of cocaine. In this study we have investigated the role played by the main hypothalamic stress hormone, corticotropin-releasing factor (CRF), in the effects that repeated social defeat (RSD) induces in the conditioned rewarding effects and locomotor sensitization induced by cocaine. A total of 220 OF1 mice were divided into experimental groups according to the treatment received before each social defeat: saline, 5 or 10 mg/kg of the nonpeptidic corticotropin-releasing factor CRF1 receptor antagonist CP-154,526, or 15 or 30 µg/kg of the peptidic corticotropin-releasing factor CRF2 receptor ant…

Efecto de la cocaína sobre la inhibición por prepulso de la respuesta de sobresalto

Introduccion. La inhibicion por prepulso (IPP) de la respuesta de sobresalto es una medida de sincronizacion sensitivomotora basada en la respuesta del reflejo de sobresalto. Un deficit en la IPP se ha observado en pacientes psiquiatricos, especialmente con esquizofrenia, asi como en sujetos vulnerables a desarrollarla. Asimismo, los consumidores de cocaina presentan un alto indice de patologias psiquiatricas como la esquizofrenia. Objetivo. Conocer las alteraciones que el consumo de cocaina puede producir en la IPP. Desarrollo. Se realiza una revision exhaustiva de los estudios, tanto clinicos como con modelos animales, que hayan evaluado la IPP tras el consumo o la administracion de cocai…

Prepulse Inhibition and Vulnerability to Cocaine Addiction

Acute social defeat stress increases the conditioned rewarding effects of cocaine in adult but not in adolescent mice.

Stressful experiences modify activity in areas of the brain involved in the rewarding effects of psychostimulants. In the present study we evaluated the influence of acute social defeat (ASD) on the conditioned rewarding effects of cocaine in adolescent (PND 29-32) and adult (PND 50-53) male mice in the conditioned place preference (CPP) paradigm. Experimental mice were exposed to social defeat in an agonistic encounter before each session of conditioning with 1mg/kg or 25mg/kg of cocaine. The effects of social defeat on corticosterone levels were also evaluated. Adult mice exposed to ASD showed an increase in the conditioned reinforcing effects of cocaine. Only these mice developed cocaine…

Pre-treatment with high doses of cocaine decreases the reinforcing effects of cocaine in the conditioned place preference paradigm.

The aim of the present study was to determine if pre-exposure to high doses of cocaine can subsequently alter the rewarding effects of this drug. Adult male mice received a pretreatment of physiological saline, or 12.5 or 25 mg/kg of cocaine (one injection a day for five days). After an interval of six days without injections, the rewarding effects of low doses of cocaine (0.5, 1 or 1.5 mg/kg) were evaluated in the conditioned place preference (CPP) paradigm. Doses of 1 and 1.5 mg/kg induced a clear CPP in animals pre-treated with saline but were ineffective in those pre-treated with 25 mg/kg of cocaine. Only the dose of 1.5 mg/kg induced CPP in mice pre-treated with 12.5 mg/kg of cocaine. …

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…

The effects of dopamine D 2 and D 3 antagonists on spontaneous motor activity and morphine-induced hyperactivity in male mice

Rationale: Dopaminergic neurotransmission, in particular the mesolimbic pathway, is involved in spontaneous locomotor activity and in morphine-induced hyperactivity, since the drugs acting on DA receptors can modify the action of morphine and this effect could be dependent on the type of DA receptor affected. Objective: In this study, the action of U-99194A maleate, haloperidol, sulpiride and morphine (5, 10, 20, 40 mg/kg) on locomotor activity in male mice was evaluated. Likewise, the effects of these dopaminergic antagonists on morphine-induced hyperactivity were studied. Methods: Animals treated with U-99194A maleate (2.5, 5, 10, 20 mg/kg), haloperidol (0.075, 0.1 mg/kg), sulpiride (20, …

Long-term effects of delayed motherhood in mice on postnatal development and behavioural traits of offspring

BACKGROUND: Some epidemiological evidence tentatively suggests that children born to older parents may have lower intellectual development and maturity than children whose parents are younger. This study aims to analyse the long-term effects of delayed motherhood in mice on postnatal development and behavioural traits later in life. METHODS: Hybrid females, either at the age of 10 weeks or 51 weeks, were individually housed with a randomly selected 12-14 week old hybrid male. After a postweaning resting period of 1 week, dams were caged again with a new randomly selected 12-14 week old male. This sequence of events was repeated until old females reached the end of their reproductive life. R…

Effect of the CB1 cannabinoid agonist WIN 55212-2 on the acquisition and reinstatement of MDMA-induced conditioned place preference in mice

AbstractBackgroundNumerous reports indicate that MDMA users consume other psychoactive drugs, among which cannabis is one of the most common. The aim of the present study was to evaluate, using the conditioned place preference, the effect of the cannabinoid agonist WIN 55,212-2 on the rewarding effects of MDMA in mice.MethodsIn the first experiment adolescent mice were initially conditioned with 1.25, 2.5 or 5 mg/kg of MDMA or 0.1 or 0.5 mg/kg of WIN and subsequently with both drugs. Reinstatement of the extinguished preference by priming doses was performed in the groups that showed CPP. In the second experiment, animals were conditioned with 2.5 or 5 mg/kg of MDMA and, after extinction, r…

Memantine blocks sensitization to the rewarding effects of morphine

Knowledge regarding the specific brain changes and neural plasticity processes produced by repeated drug exposure may be used to advance the understanding of the neurobiology of addiction in order to design appropriate medications. In the present study, the influence of N-methyl-d-aspartate (NMDA) glutamatergic receptors on sensitization to the motor and rewarding effects of morphine was evaluated. The effects of pre-exposure to saline or 20 mg/kg morphine plus the NMDA receptor antagonist memantine (10 or 20 mg/kg) on motor activity and place conditioning induced by a low dose of morphine (2 mg/kg) were assessed. The dose of 2 mg/kg of morphine was ineffective in mice pre-exposed to saline…

Effects of Cannabinoid Exposure during Adolescence on the Conditioned Rewarding Effects of WIN 55212-2 and Cocaine in Mice: Influence of the Novelty-Seeking Trait.

Adolescent exposure to cannabinoids enhances the behavioural effects of cocaine, and high novelty-seeking trait predicts greater sensitivity to the conditioned place preference (CPP) induced by this drug. Our aim was to evaluate the influence of novelty-seeking on the effects of adolescent cannabinoid exposure. Adolescent male mice were classified as high or low novelty seekers (HNS and LNS) in the hole-board test. First, we evaluated the CPP induced by the cannabinoid agonist WIN 55212-2 (0.05 and 0.075 mg/kg, i.p.) in HNS and LNS mice. Then, HNS and LNS mice were pretreated i.p. with vehicle, WIN 55212-2 (0.1 mg/kg), or cannabinoid antagonist rimonabant (1 mg/kg) and were subsequently con…

Rhodiola rosea Impairs Acquisition and Expression of Conditioned Place Preference Induced by Cocaine

A novel approach to the treatment of adverse effects of drugs of abuse is one which makes use of natural products. The present study investigated the effect ofRhodiola roseaL. hydroalcoholic extract (RHO) on cocaine-induced hyperactivity and conditioned place preference (CPP) in mice. In a first experiment, mice received RHO (15, 20 or 25 mg/kg, IG), cocaine (25 mg/kg, i.p.) (COC), or a combination of both drugs (COC + RHO15, COC + RHO20, and COC + RHO25), and their locomotor activity was evaluated. In a second experiment, the effects of RHO on the acquisition, expression, and reinstatement of cocaine CPP (induced by drug priming or social defeat stress) were evaluated. RHO alone did not in…

Prenatal cocaine alters later responses to morphine in adult male mice.

Mice prenatally exposed to cocaine (25 mg/kg), physiological saline or non-treated during the last 6 days of pregnancy were evaluated as adults for the rewarding properties of 2 mg/kg of morphine, using the conditioned place preference (CPP) procedure. Likewise, isolated animals underwent a social interaction test with conspecifics after receiving the same morphine dose. Unlike control or animals pre-treated with saline, subjects prenatally treated with cocaine did not develop CPP with this dose of morphine. Only cocaine-exposed animals showed increased threat, avoidance and fleeing during the social encounter. No differences in motor effects of morphine were observed. Analysis of monoamine…

Rewarding effects and reinstatement of MDMA-induced CPP in adolescent mice.

Although the rewarding effects of 3,4-methylenedioxy-metamphetamine (MDMA) have been demonstrated in self-administration and conditioned place preference (CPP) procedures, its addictive potential (ie, the vulnerability to relapse, measured by its ability to induce reinstatement of an extinguished response), remains poorly understood. In this study, the effects of MDMA (5, 10, and 20 mg/kg) on the acquisition, extinction and reinstatement of CPP were evaluated in mice, using two different protocols during acquisition of CPP. In the first experiment, animals were trained using a two-session/day schedule (MDMA and saline for 4 consecutive days), whereas in the second experiment, they were trai…

Cannabidiol prevents several of the behavioral alterations related to cocaine addiction in mice.

Abstract Cocaine dependence is a highly prevalent disease in modern society and lacks an effective treatment. Cannabidiol (CBD), a major non-psychoactive constituent of Cannabis sativa, has been shown to be a promising tool in the management of some neuropsychiatric disorders, including cocaine abuse. However, its therapeutic effects on the behavioral outcomes related to cocaine addiction remain unclear. The present research evaluates the effects of CBD (30, 60 and 120 mg/kg; injected intraperitoneally) on the acquisition, expression, extinction and reinstatement of cocaine (10 mg/kg)-induced conditioned place preference (CPP; Study 1); cocaine (25 mg/kg)-induced locomotor stimulation (Stud…

Ethanol intake in male mice exposed to social defeat: Environmental enrichment potentiates resilience

Large preclinical evidence shows that exposure to social defeat (SD) increases vulnerability to drug abuse, increasing the consumption of ethanol. However, not all subjects are equally affected by the changes induced by stress. Previous reports have evidenced that the resilient phenotype to depressive-like behaviors after SD is associated with the resistant phenotype to cocaine-increased rewarding effects and the smaller neuroinflammatory response. The aim of the present study was to further clarify whether the resilient profile to depressive-like behavior also predicts a protection against the increase in ethanol intake induced by SD. The neuroinflammatory profile was studied after the end…

Individual differences in the induction of sensitisation or tolerance to the motor effects of morphine in mice

Acute morphine administration produces hyperactivity in most strains of mice and some studies indicate that repeated treatment can induce a potentiation of this effect (sensitisation). With the object of determining whether the hyperactivity induced by morphine in OF1 mice shows sensitisation after repeated administration, we tested the effect of the pre-exposure to six daily injections of morphine on the subsequent hyperactivity induced by the same dose of this drug. Animals were treated with 40 mg/kg of morphine for seven days. After the last injection they were tested in an actimeter at different points at time (15, 30, 45 and 60 min). This repeated schedule of treatment produced sensiti…

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…

Vicarious Social Defeat Increases Conditioned Rewarding Effects of Cocaine and Ethanol Intake in Female Mice

Stress is a critical factor in the development of mood and drug use disorders. The social defeat model is not appropriate for female rodents due to their low level of aggression. Therefore, a robust female model of social stress needs to be developed and validated. The aim of the present study was to unravel the long-lasting effects of vicarious social defeat (VSD) on the conditioned rewarding effects of cocaine and ethanol intake in female mice. Although VSD seems to be a good model for inducing behavioral and physiologic endophenotypes induced by stress, there are no studies to date that characterize the effect of VSD on cocaine or alcohol use. The results confirm that VSD females showed …

Conditioned place preference paradigm can be a mouse model of relapse to opiates

With the object of determining the usefulness of the conditioned place preference (CPP) paradigm as a model of relapse to opiates, the effects of the re-exposure to morphine are explored in male mice which had undergone a process of extinction of conditioning. Morphine (40 mg/kg) produces a CPP which lasts up to 15 days after conditioning. When it has completely extinguished (45 days), a non contingent re-exposure to the drug again produces the same preference. These results suggest that the CPP paradigm may be used in mice to study the mechanisms of relapse to opiates in addicts.

Preclinical evidence of new opioid modulators for the treatment of addiction.

Addiction to opiates is one of the most severe forms of substance dependence, and despite a variety of pharmacological approaches to treat it, relapse is observed in a high percentage of subjects. New pharmacological compounds are necessary to improve the outcome of treatments and reduce adverse side effects. Moreover, drugs that act on the opioid system can also be of benefit in the treatment of alcohol or cocaine addiction. AREA COVERED BY THIS REVIEW: Recent preclinical studies of pharmacological agents for the treatment of opiate addiction (2008 to the present date).The reader will be informed of the latest drugs shown in animal models to modify dependence on opiates and the reinforcing…

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 plac…

Effects of CNQX and MPEP on sensitization to the rewarding effects of morphine

The present study was conducted to evaluate the influence of the glutamatergic receptors α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and metabotropic glutamate 5 (mGlu5) receptors on sensitization to the rewarding effects of morphine. The effects of pre-treatment with saline or 20 mg/kg morphine plus the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (5 or 10 mg/kg) or the metabotropic Glu5 receptor antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP) (5 or 10 mg/kg) on the place conditioning induced by a low dose of morphine (2 mg/kg) were assessed. The 2 mg/kg dose of morphine was ineffective in animals pre-treated with saline but induced a clear con…

Effects of acute social stress on the conditioned place preference induced by MDMA in adolescent and adult mice

Exposure to social defeat stress increases the rewarding effects of psychostimulants in animal models, but its effect on 3,4-methylenedioxymethylamphetamine (MDMA) reward has received little attention. In the present study, we evaluated the influence of social defeat on the rewarding effects of MDMA in adolescent [postnatal day (PND) 29-40] and adult (PND 50-61) male mice using the conditioned place preference paradigm. Experimental mice were exposed to social defeat in an agonistic encounter before each session of conditioning with 1.25 or 10 mg/kg of MDMA. The effects of social defeat on corticosterone levels and the motor or the anxiogenic effects of MDMA were also evaluated. Mice expose…

Involvement of nitric oxide synthesis in sensitization to the rewarding effects of morphine

Abstract Knowledge about the specific brain changes and neural plasticity processes produced by repeated exposure to a drug is essential to progress in the field of neurobiology of addiction and the development of effective medication. In the present study, the influence of nitric oxide synthesis on sensitization to the rewarding effects of morphine has been evaluated. The effects of pre-treatment of mice with saline or 20 mg/kg of morphine plus the nitric oxide synthase inhibitor 7-nitroindazole (7NI) (12.5 or 25 mg/kg) on the place conditioning induced by a low dose of morphine (2 mg/kg) were assessed. The dose of 2 mg/kg of morphine was ineffective in animals pre-treated with saline but …