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Biomedical subjects

Rafael Maldonado

Publications and source records attributed to Rafael Maldonado.

At least 37 records · Page 2Linked to original sources
PubMed2005

The role of the cannabinoid system in nicotine addiction.

Nicotine, the main psychoactive component in tobacco smoke, appears to play a major role in tobacco addiction, producing a high morbidity and mortality in the world. A great amount of research has been developed to elucidate the neural pathways and neurotransmitter systems involved in such a complex addictive behaviour. One possible candidate is the cannabinoid system, which has been reported to participate in the addictive properties of other drugs of abuse. This review is focused on the recent pharmacological and molecular studies assessing cannabinoid-nicotine interactions, with special attention to those studies evaluating the behavioural responses related to the development of nicotine addiction.

Animals↗
PubMed2005

Lack of CB1 cannabinoid receptor impairs cocaine self-administration.

Acute rewarding properties are essential for the establishment of cocaine addiction, and multiple neurochemical processes participate in this complex behavior. In the present study, we used the self-administration paradigm to evaluate the role of CB1 cannabinoid receptors in several aspects of cocaine reward, including acquisition, maintenance, and motivation to seek the drug. For this purpose, both CB1 receptor knockout mice and wild-type littermates were trained to intravenously self-administer cocaine under different schedules. Several cocaine training doses (0.32, 1, and 3.2 mg/kg/infusion) were used in the acquisition studies. Only 25% of CB1 knockout mice vs 75% of their wild-type littermates acquired a reliable operant responding to self-administer the most effective dose of cocaine (1 mg/kg/infusion), and the number of sessions required to attain this behavior was increased in knockout mice. Animals reaching the acquisition criteria were evaluated for the motivational strength of cocaine as a reinforcer under a progressive ratio schedule. The maximal effort to obtain a cocaine infusion was significantly reduced after the genetic ablation of CB1 receptors. A similar result was obtained after the pharmacological blockade of CB1 receptors with SR141716A in wild-type mice. Moreover, the cocaine dose-response curve was flattened in the knockout group, suggesting that the differences observed between genotypes were related to changes in the reinforcing efficacy of the training dose of cocaine. Self-administration for water and food was not altered in CB1 knockout mice in any of the reinforcement schedules used, which emphasizes the selective impairment of drug reinforcement in these knockout mice. Finally, cocaine effects on mesolimbic dopaminergic transmission were evaluated by in vivo microdialysis in these mice. Acute cocaine administration induced a similar enhancement in the extracellular levels of dopamine in the nucleus accumbens of both CB1 knockout and wild-type mice. This work clearly demonstrates that CB1 receptors play an important role in the consolidation of cocaine reinforcement, although are not required for its acute effects on mesolimbic dopaminergic transmission.

Analysis of Variance↗
PubMed2005

Kappa- and delta-opioid receptor functional activities are increased in the caudate putamen of cannabinoid CB1 receptor knockout mice.

The purpose of this study was to examine the functional interaction between endogenous opioid and cannabinoid receptor systems in the caudate putamen and nucleus accumbens. We therefore examined by autoradiography the functional activity and density of micro-, kappa- and delta-opioid receptors in both brain regions of cannabinoid CB1 receptor knockout mice. Functional activity was estimated by measuring agonist-stimulated [35S]GTPgammaS binding. Results showed that deletion of the CB1 cannabinoid receptor markedly increased kappa-opioid (50%) and delta-opioid (42%) receptor activities whereas no differences were found in micro-opioid receptor in the caudate putamen. In contrast, binding autoradiography showed a similar density of micro-, kappa- and delta-opioid receptors between mutant and wild-type mice. No differences were found in densities or activities of micro-, kappa- and delta-opioid receptors between mutant and wild-type mice in the nucleus accumbens. Taken together, our results revealed that deletion of CB1 cannabinoid receptors produced a pronounced increase in the activity of kappa- and delta-opioid receptors in the caudate putamen. This endogenous interaction between opioid and cannabinoid receptors may be relevant to further understand a variety of neuroadaptative processes involving the participation of opioid receptors, such as motor behaviour, emotional responses and drug dependence.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2004

Role of different brain structures in the behavioural expression of WIN 55,212-2 withdrawal in mice.

We have evaluated several responses induced by the cannabinoid agonist WIN 55,212-2 related to its addictive properties, including rewarding effects and the development of physical dependence in mice. Moreover, we have studied the specific involvement of several brain regions with high density of CB1 cannabinoid receptors, such as striatum, hippocampus, amygdala and cerebellum, in the behavioural expression of SR 141716A-precipitated WIN 55,212-2 withdrawal. The systemic administration of the CB1 receptor antagonist SR 141716A (10 mg kg(-1), s.c.) precipitated behavioural signs of withdrawal in mice chronically treated with WIN 55,212-2 (1 and 2 mg kg(-1), intraperitoneal (i.p.)), revealing the development of physical dependence. The microinjection of SR 141716A (1.5 and 3 micrograms) into the cerebellum induced severe manifestations of abstinence in mice dependent on WIN 55,212-2 (1 mg kg(-1), i.p.). Out of 10 signs evaluated, seven were statistically significant: wet dog shakes, body tremor, paw tremor, piloerection, mastication, genital licks and sniffing. When the cannabinoid antagonist was administered into the hippocampus and the amygdala, a moderate but significant withdrawal syndrome was also observed. However, no signs of abstinence were induced when SR 141716A was microinjected into the striatum. WIN 55,212-2 produced rewarding effects in the place-conditioning paradigm in mice pre-exposed to a priming injection of the drug. These results show a reliable behavioural model to reveal rewarding effects and physical dependence induced by the repeated administration of WIN 55,212-2 in mice. The cerebellum and to a lesser extent the hippocampus and the amygdala participate in the behavioural expression of cannabinoid withdrawal.

Animals↗
PubMed2004

Study of the behavioural responses related to the potential addictive properties of MDMA in mice.

We investigated several behavioural responses induced by repeated administration of MDMA in mice that could be related to its potential abuse liability. Mice treated with MDMA at the dose of 10 mg/kg displayed a significant conditioned place preference with respect to saline treated controls, while lower doses (0.3, 1.0, 3.3 mg/kg) had no effect. The development of physical dependence was also investigated. Mice were treated with MDMA (10 mg/kg) twice daily for 5 days. On day 6, following a single administration of MDMA mice received the following monoaminergic antagonists: metergoline (0.1 and 1 mg/kg), ritanserin (0.25 and 1 mg/kg), timolol (2 and 10 mg/kg), prazosin (0.25 and 1 mg/kg), SCH 23390 (0.05 and 0.25 mg/kg), raclopride (0.1 and 0.5 mg/kg) or vehicle, and several somatic manifestations of withdrawal were evaluated for 45 min. Metergoline induced paw tremor, face rubbing, as well as an increase in locomotor activity in mice chronically treated with MDMA. Ritanserin, and timolol induced only paw tremor, while SCH 23390 and raclopride did not produce any somatic manifestation indicative of abstinence. The possible modification of the rewarding properties of MDMA (10 mg/kg) by the monoaminergic antagonists producing the most relevant somatic signs of withdrawal namely, metergoline (0.1 and 1 mg/kg) and timolol (2 and 10 mg/kg) were tested in the conditioned place preference paradigm. Results showed that metergoline did not significantly modify the rewarding properties of MDMA, whereas only the highest dose of timolol was able to decrease MDMA reward. No signs of dopaminergic neurotoxicity were observed following chronic treatment with MDMA as revealed by [(3)H] mazindol binding. The possible motivational and affective components of the withdrawal syndrome were assessed in the suppression of operant responding for food, the conditioned place aversion, and the lit/dark paradigms. Results showed that the somatic symptoms observed were not accompanied by any aversive/dysphoric or anxiogenic-like behaviours. These results reveal the rewarding properties of MDMA in mice, and suggest that chronic MDMA administration does not induce classical manifestations of physical dependence in mice.

Animals↗
PubMed2004

Prevention of fentanyl-induced delayed pronociceptive effects in mice lacking the protein kinase Cgamma gene.

It has recently been reported in several nociceptive models of rats that the antinociceptive effect of fentanyl, an opioid analgesic widely used in the management of per-operative pain, was followed by paradoxical delayed hyperalgesia dependent on N-methyl-D-aspartate (NMDA) mechanisms. Events upstream of the NMDA receptor, especially the activation of the protein kinase Cgamma (PKCgamma), have been involved in the persistence of pain states associated with central sensitisation. In order to evaluate the contribution of the PKCgamma in early and delayed fentanyl nociceptive responses, we studied these effects in knock-out mice deficient in such a protein. We found that fentanyl antinociception was followed by the spontaneous appearance of prolonged hyperalgesia in the paw pressure and formalin tests, and allodynia in the Von Frey paradigm. In PKCgamma deficient mice, an enhancement of the early fentanyl antinociceptive effects was observed, as well as a complete prevention of the fentanyl delayed hyperalgesic/allodynic effects. Finally, naloxone administration in mice that had recovered their pre-fentanyl nociceptive threshold, precipitated hyperalgesia/allodynia in wild-type but not in mutant mice. This study identifies the PKCgamma as a key element that links opioid receptor activation with the recruitment of opposite systems to opioid analgesia involved in a physiological compensatory pain enhancement.

Animals↗
PubMed2004

Modulation of anxiety-like behavior and morphine dependence in CREB-deficient mice.

The transcription factor cAMP-responsive element binding protein (CREB) has been shown to regulate different physiological responses including drug addiction and emotional behavior. Molecular changes including adaptive modifications of the transcription factor CREB are produced during drug dependence in many regions of the brain, including the locus coeruleus (LC), but the molecular mechanisms involving CREB within these regions have remained controversial. To further investigate the involvement of CREB in emotional behavior, drug reward and opioid physical dependence, we used two independently generated CREB-deficient mice. We employed the Cre/loxP system to generate mice with a conditional CREB mutation restricted to the nervous system, where all CREB isoforms are lacking in the brain (Crebl(NesCre)). A genetically defined cohort of the previously described hypomorphic Crebl(alphadelta) mice, in which the two major transcriptionally active isoforms (alpha and delta) are disrupted throughout the organism, were also used. First, we investigated the responses to stress of the CREB-deficient mice in several paradigms, and we found an increased anxiogenic-like response in the both Creb1 mutant mice in different behavioral models. We investigated the rewarding properties of drugs of abuse (cocaine and morphine) and natural reward (food) using the conditioned place-preference paradigm. No modification of motivational responses of morphine, cocaine, or food was observed in mutant mice. Finally, we evaluated opioid dependence by measuring the behavioral expression of morphine withdrawal and electrophysiological recordings of LC neurons. We showed an important attenuation of the behavioral expression of abstinence and a decrease in the hyperactivity of LC neurons in both Creb1 mutant mice. Our results emphasize the selective role played by neuronal CREB in emotional-like behavior and the somatic expression morphine withdrawal, without participating in the rewarding properties induced by morphine and cocaine.

Analysis of Variance↗
PubMed2004

The rewarding properties of MDMA are preserved in mice lacking mu-opioid receptors.

The involvement of mu-opioid receptors in the rewarding properties of MDMA was explored in mu-opioid receptor knockout mice using the conditioning place preference paradigm. The associated release of dopamine in the nucleus accumbens was investigated by in vivo microdialysis. A significant rewarding effect of MDMA (10 mg/kg, i.p.) was observed in both wild-type and mu-opioid receptor knockout mice. MDMA (10 mg/kg, i.p.) also induced similar increases in dopamine and decreases in 3,4-dihydroxyphenylacetic acid and homovanillic acid in the nucleus accumbens dialysates of both wild-type and mu-opioid receptor knockout mice. No significant differences in basal levels of dopamine, 3,4-dihydroxyphenylacetic or homovanillic acids between wild-type and mu-opioid receptor knockout mice were observed. In summary, the present results suggest that, in contrast to what has been reported for other drugs of abuse such as opioids, ethanol, nicotine and Delta(9)-tetrahydrocannabinol, mu-opioid receptors do not play a major role in the rewarding properties of MDMA. These differences could be due to distinct mechanisms controlling dopamine release in the nucleus accumbens and suggest that the effects of MDMA on dopaminergic neurons are independent of micro -opioid receptors.

Adrenergic Uptake Inhibitors↗
PubMed2004

Adenosine A2A receptors are involved in physical dependence and place conditioning induced by THC.

A2A adenosine and CB1 cannabinoid receptors are highly expressed in the central nervous system, where they modulate numerous physiological processes including adaptive responses to drugs of abuse. Both purinergic and cannabinoid systems interact with dopamine neurotransmission (through A2A and CB1 receptors, respectively). Changes in dopamine neurotransmission play an important role in addictive-related behaviours. In this study, we investigated the contribution of A2A adenosine receptors in several behavioural responses of Delta9-tetrahydrocannabinol (THC) related to its addictive properties, including tolerance, physical dependence and motivational effects. For this purpose, we first investigated acute THC responses in mice lacking A2A adenosine receptors. Antinociception, hypolocomotion and hypothermia induced by acute THC administration remained unaffected in mutant mice. Chronic THC treatment developed similar tolerance to these acute effects in wild-type and A2A-knockout mice. However, differences in the body weight pattern were found between genotypes during such chronic treatment. Interestingly, the somatic manifestations of SR141716A-precipitated THC withdrawal were significantly attenuated in mutant mice. The motivational responses of THC were also evaluated by using the place-conditioning paradigm. A significant reduction of THC-induced rewarding and aversive effects was found in mice lacking A2A adenosine receptors in comparison with wild-type littermates. Binding studies revealed that these behavioural changes were not associated with any modification in the distribution and/or functional activity of CB1 receptors in knockout mice. Therefore, this study shows, for the first time, a specific involvement of A2A receptors in the addictive-related properties of cannabinoids.

Animals↗
PubMed2004

Delta9-tetrahydrocannabinol decreases somatic and motivational manifestations of nicotine withdrawal in mice.

The possible interactions between Delta9-tetrahydrocannabinol (Delta9-THC) and nicotine remain unclear in spite of the current association of cannabis and tobacco in humans. The aim of the present study was to explore the interactions between these two drugs of abuse by evaluating the consequences of Delta9-THC administration on the somatic manifestations and the aversive motivational state associated with nicotine withdrawal in mice. Acute Delta9-THC administration significantly decreased the incidence of several nicotine withdrawal signs precipitated by mecamylamine or naloxone, such as wet-dog-shakes, paw tremor and scratches. In both experimental conditions, the global withdrawal score was also significantly attenuated by acute Delta9-THC administration. This effect of Delta9-THC was not due to possible adaptive changes induced by chronic nicotine on CB1 cannabinoid receptors, as the density and functional activity of these receptors were not modified by chronic nicotine administration in the different brain structures investigated. We also evaluated the consequences of Delta9-THC administration on c-Fos expression in several brain structures after chronic nicotine administration and withdrawal. c-Fos was decreased in the caudate putamen and the dentate gyrus after mecamylamine precipitated nicotine withdrawal. However, acute Delta9-THC administration did not modify c-Fos expression under these experimental conditions. Finally, Delta9-THC also reversed conditioned place aversion associated to naloxone precipitated nicotine withdrawal. Taken together, these results indicate that Delta9-THC administration attenuated somatic signs of nicotine withdrawal and this effect was not associated with compensatory changes on CB1 cannabinoid receptors during chronic nicotine administration. In addition, Delta9-THC also ameliorated the aversive motivational consequences of nicotine withdrawal.

Analgesics, Non-Narcotic↗
PubMed2004

Glomerular enlargement assessed by paired donor and early protocol renal allograft biopsies.

The aim of the study was to evaluate the evolution of glomerular volume 4 months after transplantation. Mean glomerular volume (Vg) was estimated according to the Weibel and Gomez method in a donor and a protocol biopsy done at 139 +/- 58 d in 41 stable grafts. Biopsies were also evaluated according to the Banff schema. Vg increased after transplantation from 4.1 +/- 1.4 to 5.1 +/- 2.4 x 10(6) micro3 (p=0.02). In patients with chronic allograft nephropathy in the protocol biopsy (n=14), the Vg enlargement was -0.3 +/-x 10(6) micro3 while in patients without chronic allograft nephropathy (n=27), glomerular enlargement was 1.6 +/- 2.1 x 10(6) micro3 (p=0.01). There was a negative association between glomerular volume in the donor biopsy and glomerular enlargement after transplantation (R=- 0.34, p=0.03). Multivariate regression analysis confirmed that Vg in the donor biopsy and chronic allograft nephropathy in the protocol biopsy were independent predictors of glomerular enlargement after transplantation (R=0.48, p=0.01). Moreover, Vg in the protocol biopsy correlated with creatinine clearance at the time of biopsy (R=0.38, p=0.01). Glomeruli enlarge after transplantation and glomerular volume after 4 months correlates with creatinine clearance, suggesting that glomerular enlargement is a necessary condition for renal adaptation to the recipient. Glomerular enlargement is impaired in patients with chronic allograft nephropathy.

Adolescent↗
PubMed2003

Effects of nandrolone on acute morphine responses, tolerance and dependence in mice.

Anabolic-androgenic steroid exposure has been proposed to present a risk factor for the misuse of other drugs of abuse. We now examined whether the exposure to the anabolic-androgenic steroid, nandrolone, would affect the acute morphine responses, tolerance and dependence in rodents. For this purpose, mice received nandrolone using pre-exposure (for 14 days before morphine experiments) or co-administration (1 h before each morphine injection) procedures. Nandrolone treatments increased the acute hypothermic effects of morphine without modifying its acute antinociceptive and locomotor effects. Nandrolone also attenuated the development of tolerance to morphine antinociception in the hot plate test, but did not affect tolerance to its hypothermic effects, nor the sensitisation to morphine locomotor responses. After nandrolone pre-exposure, we observed an attenuation of morphine-induced place preference and an increase in the somatic manifestations of naloxone-precipitated morphine withdrawal. These results indicate that anabolic-androgenic steroid consumption may induce adaptations in neurobiological systems implicated in the development of morphine dependence.

Anabolic Agents↗
PubMed2003

Morphine withdrawal is modified in pituitary adenylate cyclase-activating polypeptide type I-receptor-deficient mice.

The pituitary adenylate cyclase-activating polypeptide type I-receptor (PAC1) is a G-protein-coupled receptor that is widely expressed in neurons of the central and peripheral nervous system. The strong expression of PAC1 in the second sensory neuron as well as in brainstem regions such as the locus coeruleus prompted us to elucidate the potential in vivo role of PAC1-mediated signalling in pain perception and opioid addiction using a PAC1-deficient mouse line. We observed a selective involvement of PAC1 in the mediation of visceral pain. While there was no impairment in acute somatic pain perception, PAC1-mutants exhibited a dramatically decreased response in the abdominal writhing test. These data in concert with data from the literature implicate PAC1 in the mediation of visceral and chronic pain. In addition, we observed that PAC1 did not influence the motivational aspects of opioid addictive properties, since morphine-induced rewarding effects and sensitization to locomotor responses were completely maintained in PAC1-deficient mice. However, there was a dramatic increase in physical withdrawal signs after naloxone-precipitated morphine withdrawal in PAC1 mutants. At the cellular level, electrophysiological examinations in locus coeruleus neurons from morphine-dependent wild-type and PAC1-deficient mice did not reveal any differences in firing rates. These data therefore suggested that most likely disruption of PAC1-mediated signalling in afferents towards the locus coeruleus but not within the intrinsic locus coeruleus system led to the enhancement of somatic withdrawal signs.

Analgesics, Opioid↗
PubMed2003

Participation of the opioid system in cannabinoid-induced antinociception and emotional-like responses.

Several anatomical, biochemical and pharmacological evidence support the existence of bidirectional interactions between cannabinoid and opioid systems. The present review is focused on the participation of the endogenous opioid system in the antinociceptive and emotional-like responses induced by cannabinoids, and the development of tolerance to cannabinoid pharmacological effects. Cannabinoid and opioid agonists produce antinociception by acting on similar structures within the central nervous system, and a peripheral mechanism has been also proposed for both compounds. Pharmacological studies have suggested that the endogenous opioid system could be involved in cannabinoid antinociception and the development of cannabinoid tolerance. Recent studies using knockout mice have also demonstrated the role of the opioid system in cannabinoid antinociception and tolerance, although some discrepancies with the previous pharmacological results have been reported when using knockout mice. On the other hand, cannabinoid administration can induce anxiolytic-like responses that are mediated at least in part by an endogenous opioid activity on micro- and delta-opioid receptors.

Analgesics↗
PubMed2003

Cannabinoid withdrawal syndrome is reduced in double mu and delta opioid receptor knockout mice.

Several studies have shown a functional relationship between the endogenous cannabinoid and opioid systems. However, acute effects of Delta9-tetrahydrocannabinol (THC) and physical dependence were not modified in knockout mice with single deletion of mu (MOR), delta (DOR) or kappa (KOR) opioid receptors. To further investigate the neurobiological basis of cannabinoid dependence, we have evaluated acute pharmacological responses, rewarding effects, tolerance and dependence to THC in double MOR/DOR knockout mice. Antinociception and hypolocomotion induced by acute THC administration remained unaffected, whereas the hypothermic effect was slightly attenuated in these double knockout mice. During chronic THC treatment, knockout mice developed slower tolerance to the hypothermic effect, but the development of tolerance to antinociceptive and hypolocomotor effects was unchanged. The rewarding properties of THC, measured in the conditioned place preference paradigm, were reduced in knockout mice. Interestingly, the somatic manifestations of THC withdrawal were also significantly attenuated in mutant mice, suggesting that a cooperative action of MOR and DOR is required for the entire expression of THC dependence.

Analgesics, Non-Narcotic↗
PubMed2003

Increase of morphine withdrawal in mice lacking A2a receptors and no changes in CB1/A2a double knockout mice.

CB1 cannabinoid and A2a adenosine receptors are highly expressed in the central nervous system where they modulate numerous physiological processes including emotional behaviour and the responses of several drugs of abuse. To investigate the contribution of these receptors in emotional-like responses and opioid dependence we have generated CB1/A2a double deficient mice (CB1-/-/A2a-/-). The spontaneous locomotor activity was reduced in double knockout as compared to wild-type animals. Emotional-like responses of CB1-/-/A2a-/- mice were investigated using the elevated plus-maze and the lit-dark box. Mutant mice exhibited an increased level of anxiety in both behavioural models. The specific involvement of CB1 and A2a receptors in morphine dependence was evaluated by using A2a knockout mice and CB1/A2a double mutant mice. The severity of naloxone-precipitated morphine withdrawal syndrome was significantly increased in the absence of A2a adenosine receptors whereas no modifications were observed in the double knockout mice. These results suggest that both receptors participate in the control of emotional behaviour and seem to play an opposite role in the expression of opioid physical dependence.

Animals↗
PubMed2003

Acute antinociceptive responses in single and combinatorial opioid receptor knockout mice: distinct mu, delta and kappa tones.

We have examined responses of mice lacking mu, delta and kappa opioid receptor (MOR, DOR and KOR, respectively) genes, as well as combinatorial mutants, in several pain models. This is the first truly comparative study of all three opioid receptor-deficient mice, with genotypes and gender analysis using mice on the hybrid 50% 129/SV : 50% C57BL/6 genetic background. In the tail-immersion test, only KOR-/- females showed decreased withdrawal latencies. This modification was also found in MOR/KOR and MOR/DOR/KOR, but not MOR/DOR mutants. The hotplate test revealed increased nociceptive sensitivity for MOR-/-, a phenotype which was also observed in double mutants involving the MOR deletion, and in the triple mutants. The tail-pressure test showed increased response for both MOR-/- and DOR-/- mutants, a modification which was enhanced in the triple-mutant mice. In the formalin test, MOR-/- and DOR-/- mice showed increased responses in the early and late phases, respectively, while the triple mutant tended to show enhanced nociception in both phases. Finally, the enhanced response of KOR-/- mice in the writhing test, which we have demonstrated previously, was confirmed in double MOR/KOR- and triple-mutant mice. Together, the data support the existence of an antinociceptive opioid tone. Each receptor presents a distinct pattern of activities, with mu receptors influencing responses to mechanical, chemical and thermal nociception at a supraspinal level, kappa receptors involved in spinally mediated thermal nociception and chemical visceral pain, and delta receptors modulating mechanical nociception and inflammatory pain. Phenotypes of mutant mice were subtle, suggesting a low endogenous opioid tone in the regulation of physiological pain.

Animals↗