[Effect of stress on prepulse inhibition: a systematic review]. / Efecto del estrés sobre la inhibición por prepulso: revisión sistemática.

INTRODUCTION: Prepulse inhibition, one of the main indices of the autonomous inhibitory capacity of the central nervous system, is deficient in psychiatric pathologies associated with dopaminergic system alterations, such as schizophrenia, post-traumatic stress disorder, or substance use disorder. Stress is one of the main risk factors related to the development of these psychiatric disorders. AIM: To know the relationship between stress and prepulse inhibition as possible biomarker and predictor of related pathologies, based on recent literature. SUBJECTS AND METHODS: A systematic review was carried out in PubMed and Web of Science databases from 2011 to 2020. RESULTS: The studies reviewed, including both animal model studies and clinical articles, have shown that intense or repeated stress, whether social, physical or drug-induced, leads to a deterioration of prepulse inhibition, while moderate stress seems to improve its levels. CONCLUSIONS: The results demonstrate a clear relationship between stress and a deficit in prepulse inhibition, which occurs mainly through the dopaminergic system and the corticotropin-releasing factor in the extended amygdala. Prepulse inhibition levels reflect the state of brain dopaminergic activity, being able to identify the most vulnerable subjects to develop stress-related psychiatric pathologies.

TITLE: Efecto del estrés sobre la inhibición por prepulso: revisión sistemática.Introducción. La inhibición por prepulso, uno de los principales índices de la capacidad inhibitoria autónoma del sistema nervioso central, es deficitaria en patologías psiquiátricas asociadas con alteraciones del sistema dopaminérgico, como la esquizofrenia, el trastorno de estrés postraumático o el trastorno por uso de sustancias. El estrés es uno de los principales factores de riesgo relacionado con el desarrollo de estos trastornos psiquiátricos. Objetivo. Conocer la relación entre el estrés y la inhibición por prepulso como posible biomarcador y predictor de determinadas patologías asociadas a él, revisando la bibliografía reciente. Sujetos y métodos. Se realizó una revisión sistemática en las bases de datos PubMed y Web of Science desde 2011 hasta 2020. Resultados. Tanto los estudios con modelos animales como clínicos han demostrado que un estrés intenso o repetido, ya sea social, físico o inducido por fármacos, produce un deterioro de la inhibición por prepulso, mientras que un estrés moderado parece mejorar sus niveles. Conclusiones. Existe una clara relación entre el estrés y una disminución de la inhibición por prepulso, la cual se produce a través del sistema dopaminérgico, principalmente, y el factor liberador de corticotropina en la amígdala extendida. Los niveles de inhibición por prepulso reflejarían el estado de la actividad dopaminérgica cerebral y podrían señalar los sujetos más vulnerables a desarrollar patologías psiquiátricas relacionadas con el estrés.

Baseline prepulse inhibition of the startle reflex predicts the sensitivity to the conditioned rewarding effects of cocaine in male and female mice.

RATIONALE: Prepulse inhibition (PPI) of the startle reflex is a model of pre-attentional inhibitory function. The dopamine baseline in the nucleus accumbens plays a key role in PPI regulation as well as in the rewarding effects of cocaine. OBJECTIVES: The aim of this study was to evaluate the predictive ability of PPI to identify the more vulnerable mice of both sexes to the conditioned rewarding effects of cocaine. METHODS: Male and female OF1 mice were first tested in the PPI paradigm to classify them as high or low PPI. Afterwards, they were evaluated in the conditioned place preference (CPP) paradigm induced by cocaine (1, 6 and 12 mg/kg). Moreover, the D1R and D2R protein expressions in the striatum of high and low PPI animals were analysed by Western blot. RESULTS: Only high-PPI mice acquired CPP induced by low doses of cocaine (1 and 6 mg/kg), while the low-PPI mice needed a higher dose of cocaine (12 mg/kg) to acquire the CPP, but once mice were conditioned, males did not extinguish the conditioned preference and females reinstated the preference with lower doses of cocaine than their control counterparts. Low-PPI animals, especially females, showed higher basal levels of D2R than those with a higher PPI. CONCLUSIONS: Low-PPI mice presented a lower sensitivity to the conditioned rewarding effects of cocaine, but once they were conditioned with a higher dose, they displayed a stronger, perseverant conditioned preference. The predictive capacity of PPI to detect the more vulnerable mice to the conditioned effects of cocaine is discussed.

[Effects of cocaine on prepulse inhibition of the startle response]. / Efecto de la cocaina sobre la inhibicion por prepulso de la respuesta de sobresalto.

INTRODUCTION: Prepulse inhibition (PPI) of the startle response is an index used to evaluate how the pre-attention system works. PPI is altered in patients with a mental disorder such as schizophrenia and in subjects who are vulnerable to it. Likewise, cocaine users also frequently exhibit psychiatric disorders as schizophrenia. AIM: To know the alterations that cocaine produces on PPI. DEVELOPMENT: A comprehensive review is carried out, covering both clinical and preclinical studies with animal models that have evaluated the effects of cocaine exposure on the PPI paradigm. Underlying neural bases and mechanisms of action are suggested to explain these findings. CONCLUSIONS: Cocaine alters PPI through its action on the dopaminergic system. Acute exposure of cocaine decreases PPI by increasing dopamine, while with chronic use, depending on withdrawal time, PPI can be restored. However, the effects of cocaine on PPI appear to depend on the baseline levels of PPI shown by the individual. Thus, since a deficit in PPI has been associated with a greater vulnerability to developing mental pathologies such as schizophrenia, PPI level in subjects could be considered as a biomarker of psychiatric vulnerability. Therefore, a better understanding of the effect of drugs such as cocaine on PPI may help to understand the development of dual pathology.

TITLE: Efecto de la cocaina sobre la inhibicion 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 cocaina. Se sugieren bases neurales y mecanismos de accion subyacentes para explicar los resultados. Conclusiones. La cocaina altera la IPP a traves de su accion sobre el sistema dopaminergico. La administracion aguda de cocaina disminuye la IPP al aumentar la dopamina, mientras que con el consumo cronico, dependiendo del tiempo de abstinencia, la IPP puede restablecerse. Sin embargo, los efectos de la cocaina sobre la IPP parecen depender de los niveles basales de la IPP que muestre el individuo. Asi, dado que un deficit en la IPP se ha relacionado con una mayor vulnerabilidad a desarrollar patologias mentales como la esquizofrenia, los niveles de la IPP en los sujetos podrian considerarse como un biomarcador de vulnerabilidad psiquiatrica. Por ello, conocer mejor el efecto que drogas como la cocaina ejercen sobre la IPP puede ayudar a comprender el desarrollo de la patologia dual.

Topiramate increases the rewarding properties of cocaine in young-adult mice limiting its clinical usefulness.

RATIONALE: Topiramate is an anticonvulsant drug which has been evaluated as a therapeutic option for the treatment of cocaine addiction during the last decade. OBJECTIVES: The purpose of this study was to evaluate the effects of topiramate on the reinforcing actions of cocaine. To this aim, the topiramate-mediated regulation of acquisition and extinction phases of the cocaine conditioned place preference (CPP) was assessed in young-adult mice using three experimental designs. METHODS: Topiramate (50 mg/kg, p.o.) was given as follows: (1) during cocaine (1 and 25 mg/kg, i.p.) conditioning sessions (4 days) and cocaine (25 mg/kg) post-conditioning session; (2) 2 weeks before and during cocaine conditioning (25 mg/kg); and (3) during extinction of CPP induced by cocaine (25 mg/kg). In the first experimental design, changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) gene expressions were measured in the ventral tegmental area (VTA). RESULTS: Topiramate significantly increased cocaine-induced CPP and delayed or failed to produce extinction after the first cocaine reinstatement extinction in the first and second experiments. Furthermore, treatment with topiramate after place conditioning blocked the extinction of cocaine-induced CPP. TH and DAT gene expression in the VTA was significantly lower both with topiramate alone and in combination with cocaine compared with animals receiving only cocaine. CONCLUSIONS: These findings suggest that topiramate increases the rewarding properties of cocaine, at least in part, by regulating dopaminergic signaling in the mesolimbic circuit. Consequently, the results of this study do not support the use of topiramate for the treatment of problems related to cocaine dependence. HIGHLIGHTS: • Topiramate increases the rewarding properties of cocaine in CPP • Topiramate alters dopaminergic signaling in the mesolimbic circuit • Topiramate delays the extinction of cocaine-induced CPP • TH and DAT gene expression in the VTA decreases with topiramate and/or with cocaine • Results show that it should limit the use of topiramate in cocaine-dependent subjects.

Corrigendum to "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".

[This corrects the article DOI: 10.1155/2016/6481862.].

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 conditioned with WIN 55212-2 (0.05 mg/kg, i.p.) or cocaine (1 or 6 mg/kg, i.p.). Only HNS mice conditioned with the 0.075 mg/kg dose acquired CPP with WIN 55212-2. Adolescent exposure to this cannabinoid agonist increased the rewarding effects of 1 mg/kg of cocaine in both HNS and LNS mice, and in HNS mice it also increased the reinstating effect of a low dose of cocaine. Our results endorse a role for individual differences such as a higher propensity for sensation-seeking in the development of 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-induced CPP with the subthreshold dose of cocaine, and they needed a higher number of extinction sessions for the 25mg/kg cocaine-induced CPP to be extinguished. In adolescent mice, on the other hand, ASD reduced the conditioned reinforcing effects of cocaine, since CPP was not produced with the lower dose of cocaine and was extinguished faster when they were conditioned with 25mg/kg. Adult mice exposed to social defeat displayed higher levels of corticosterone than their controls and adolescent mice. Our results confirm that the effect of social defeat stress on the acquisition and reinstatement of the CPP induced by cocaine varies depending on the age at which this stress is experienced.

Sex differences in the long-lasting consequences of adolescent ethanol exposure for the rewarding effects of cocaine in mice.

RATIONALE: The practice of binge drinking is very common among adolescents of both sexes. It can have long-term consequences with respect to drug consumption during adulthood, but knowledge on these effects in females is limited. OBJECTIVES: The long-lasting effects of intermittent exposure to ethanol (EtOH) during adolescence on different cocaine-elicited behaviours, including locomotor reactivity, conditioned place preference (CPP) and intravenous self-administration, were evaluated in male and female adult mice. It was hypothesized that an EtOH binge during adolescence would increase sensitivity to the effects of a sub-threshold dose of cocaine and has a differential impact on the drug's effects in males and females. METHODS: Adolescent OF1 mice (postnatal day (PND) 26) underwent a 2-week pre-treatment schedule consisting of 16 doses of EtOH (2.5 g/kg) or saline (twice daily administrations separated by a 4-h interval i.p.) administered on two consecutive days separated by an interval of 2 days. Three weeks later (PND > 60), we assessed locomotor activity responses induced by an acute injection of different doses of cocaine in experiment 1 and the rewarding effects of cocaine on the CPP (1 mg/kg) and intravenous self-administration (1 mg/kg/infusion) paradigms in experiment 2. RESULTS: Pre-exposure to EtOH during adolescence altered motor reactivity to cocaine in a dose- and sex-dependent manner, increased sensitivity to cocaine in CPP and enhanced self-administration in adult mice. CONCLUSIONS: The effects of intermittent exposure to ethanol during adolescence are evident in adulthood, during which greater sensitivity and intake of cocaine is observed and differ in each sex.

Higher sensitivity to the conditioned rewarding effects of cocaine and MDMA in High-Novelty-Seekers mice exposed to a cocaine binge during adolescence.

RATIONALE: Exposure to drugs during adolescence can induce alterations in the central nervous system. The novelty-seeking personality trait influences differences observed among individuals exposed to drugs of abuse. OBJECTIVES: Long-term effects of intensive pre-treatment with cocaine during adolescence or adulthood were evaluated in High- and Low-Novelty Seeker (HNS and LNS) mice. It was hypothesized that a cocaine binge during adolescence would increase sensitivity to the rewarding effects of cocaine and MDMA, especially in HNS animals, and modify the spontaneous behaviour of adult animals. METHODS: Adolescent (PND 33) and adult (PND 60) mice were identified as HNS or LNS according to their performance in the hole-board test. Subsequently, they received pre-treatment with cocaine (three injections per day of an increasing dose for 10 days) or saline. Three weeks later, the mice performed the hole-board, elevated plus maze, spontaneous locomotor activity and cocaine- (1 mg/kg) or MDMA- (1.25 mg/kg) induced conditioning place preference (CPP) tests. In another set of mice, the effects of pre-treatment of cocaine during adulthood on MDMA- or cocaine-induced CPP were also evaluated 3 weeks later. RESULTS: Only HNS mice treated with cocaine during adolescence acquired MDMA- or cocaine-induced CPP in adulthood. Moreover, pre-exposure to cocaine during adolescence caused subsequent behavioural alterations, including reduced exploratory behaviour and increased locomotor reactivity. CONCLUSIONS: Cocaine binge administration during adolescence induces a higher sensitivity to the rewarding effects of MDMA and cocaine in HNS mice in adulthood. This may explain the greater vulnerability often seen among individuals exposed early in life to drugs of abuse.

Neurochemical substrates of MDMA reward: effects of the inhibition of serotonin reuptake on the acquisition and reinstatement of MDMA-induced CPP.

Different neurotransmitter brain systems have been implicated in the rewarding effects of 3,4-methylenedioxymetamphetamine (MDMA), including dopamine or serotonin. Serotonin selective reuptake inhibitors (SSRI) are a commonly prescribed therapy for psychiatric disorders, and the SSRI fluoxetine is recommended for MDMA users due to its neuroprotective effect against MDMAinduced neurotoxicity. In the present work, we employed the conditioned place preference (CPP) paradigm to study how the inhibition of serotonin reuptake with fluoxetine affected the rewarding and reinstating effects of MDMA in adolescent male mice. Firstly, we evaluated the motivational effects of fluoxetine (1 and 10 mg/kg), administered alone or with a sub-threshold dose of MDMA (1.25 mg/kg). In a second experiment we evaluated the effects of a pretreatment with fluoxetine (1 and 10 mg/kg) on the subsequent acquisition of a CPP induced by MDMA (1.25 mg/kg). The effects of a priming dose of fluoxetine (1 and 10 mg/kg), MDMA (5 or 1.25 mg/kg) or both drugs together on the reinstatement of a previously extinguished CPP induced by MDMA (10 mg/kg) were studied in a third experiment. Fluoxetine did not induce motivational effects but did increase the rewarding effects of a sub-threshold dose of MDMA, and pretreatment with the high dose of fluoxetine had the same effect. Fluoxetine did not induce cross-reinstatement of the MDMA CPP, but the combination of an ineffective priming dose of MDMA and the highest dose of fluoxetine did induce reinstatement of CPP. Neurochemical experiments demonstrated alterations in monoamine levels of MDMA treated mice produced by fluoxetine. As a whole, these results show that the inhibition of serotonin reuptake potentiates the acquisition and reinstatement of MDMA-induced CPP and supports a role for serotonin in MDMA-induced reward.

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.

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.

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.

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.

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.

The effects of dopamine D2 and D3 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, 40 mg/kg), or morphine (5, 10, 20, 40 mg/kg), and animals treated with these neuroleptics plus morphine were tested in an actimetre at different time points. RESULTS: It was found that an increase in locomotor activity was produced between 0 and 30 min after the administration of 20 mg/kg U-99194A maleate and between 30 and 60 min after the administration of 20 and 40 mg/kg morphine. This dose of U-99194A maleate and the high dose of sulpiride reverts the hyperactivity induced by 20 mg/kg morphine. Haloperidol reversed the hyperactivity induced by all doses of morphine. CONCLUSIONS: Our results confirm that the action of DA D2 and D3 receptors could be dependent on the dopaminergic state, in this case modified by the action of morphine.