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Biomedical subjects

Jorge Manzanares

Publications and source records attributed to Jorge Manzanares.

At least 19 recordsLinked to original sources
PubMed2006

Gene transcription alterations associated with decrease of ethanol intake induced by naltrexone in the brain of Wistar rats.

Preclinical and clinical studies suggest that the administration of the opioid antagonist naltrexone decreases the intake of ethanol. However, the neuroplastic adaptations in the brain associated to reduction of ethanol consumption remains to be elucidated. The aim of the study was to identify gene transcription alterations underlying the attenuation of voluntary ethanol intake by administration of naltrexone in rats. Increasing doses of naltrexone (0.7 mg/kg, 4 days and 1.4 mg/kg/day, 4 days) to rats with acquired high preferring ethanol consumption (>3.5 g of ethanol/kg/day) decreased voluntary ethanol intake (50%). Voluntary ethanol consumption altered mu-opioid receptor function in the cingulate cortex, caudate-putamen (CPu), nucleus accumbens core (Acb C) and shell (Acb S), the expression of tyrosine hydroxylase (TH) in the ventral tegmental area and substantia nigra, proenkephalin (PENK) in the piriform cortex, olfactory tubercle, CPu, Acb C and Acb S, ventromedial nucleus (VMN) and paraventricular nucleus (PVN) of the hypothalamus, corticotropin releasing factor (CRF) in PVN, cannabinoid CB(1) receptor (CB1-R) in the CPu, hippocampus and VMN, and serotonin transporter (5-HTT) in the dorsal and median raphe nuclei. The reduction of ethanol intake induced by naltrexone was associated with a blockade or significant reduction of the changes produced by ethanol in the expression of these genes in key regions related to drug dependence. These results point to a role for the mu-opioid receptor, TH, PENK, CRF, CB1-R, and 5-HTT genes in specific brain regions in the modulation of neuroadaptative mechanisms associated to the decrease of ethanol intake induced by naltrexone.

Alcohol Drinking↗
PubMed2005

Synthesis and structure-activity relationships of a new model of arylpiperazines. 8. Computational simulation of ligand-receptor interaction of 5-HT(1A)R agonists with selectivity over alpha1-adrenoceptors.

We have designed and synthesized a new series of arylpiperazines V exhibiting high 5-HT(1A)R affinity and selectivity over alpha(1)-adrenoceptors. The new selective 5-HT(1A)R ligands contain a hydantoin (m = 0) or diketopiperazine (m = 1) moiety and an arylpiperazine moiety separated by one methylene unit (n = 1). The aryl substituent of the piperazine moiety (Ar) consists of different benzofused rings mimicking the favorable voluminous substituents at ortho and meta positions predicted by 3D-QSAR analysis in the previously reported series I. In particular, (S)-2-[[4-(naphth-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-a]pyrazine [(S)-9, CSP-2503] (5-HT(1A), K(i) = 4.1 nM; alpha(1), K(i) > 1000 nM) has been pharmacologically characterized as a 5-HT(1A)R agonist at somatodendritic and postsynaptic sites, endowed with anxiolytic properties. Ligand (S)-9 is predicted, in computer simulations, to bind Asp(3.32) in TMH 3, Thr(5.39) and Ser(5.42) in TMH 5, and Trp(6.48) in TMH 6. We propose that agonists modify, by means of an explicit hydrogen bond, the conformation of Trp(6.48) from pointing toward TMH 7, in the inactive gauche+ conformation, to pointing toward the ligand binding site, in the active trans conformation.

Adenylyl Cyclases↗
PubMed2005

Anxiolytic-like effect of a serotonergic ligand with high affinity for 5-HT1A, 5-HT2A and 5-HT3 receptors.

S-(-)-2-[[4-(napht-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-alpha]-pyrazine (CSP-2503) is a serotonin (5-HT) receptor ligand with selectivity and high affinity for 5-HT1A, 5-HT2A and 5-HT3 receptors. CSP-2503 reduced rectal temperature and 5-HT neuronal hypothalamic activity in mice, decreased electrical activity of raphe nuclei cells in rats and blocked the enhancement of adenylate cyclase activity induced by forskolin in HeLa cells transfected with the human 5-HT1A receptor. This compound also blocked head-twitches induced by the 5-HT(2A/2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Contractions of guinea pig ileum induced by the 5-HT3 receptor agonist 2-methyl-5-HT were prevented by CSP-2503. Moreover, it reduced the bradycardia reflex induced by 2-methyl-5-HT in anaesthetized rats. In the light/dark box and social interaction tests, CSP-2503 presented anxiolytic activity, an action shared by 5-HT1 agonists and 5-HT3 antagonists. Taken together, these results suggest that CSP-2503 is a new 5-HT1 receptor agonist with 5-HT2A and 5-HT3)receptor antagonist activities that might be useful in a number of conditions associated with anxiety.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2005

Effects of repeated administration with CP-55,940, a cannabinoid CB1 receptor agonist on the metabolism of the hepatic heme.

Drugs metabolised by cytochrome P450 (CYP) such as analgesics may induce acute attacks in patients with hepatic porphyrias. In recent years, preclinical and clinical studies have suggested that cannabinoid pharmaceutical preparations may be potentially useful in the treatment of pain. The purpose of the study was to examine the effects of CP-55,940, a cannabinoid CB1 receptor agonist, on the hepatic heme metabolism in mice. To this end, hepatic activities of aminolevulinic acid synthase (ALAS), heme oxygenase (HO) and CYP levels were determined in mice treated with CP-55,940 (0.5 mg/kg/day; i.p.; 5 or 24 days). Results showed that treatment with CP-55,940 decreased CYP concentrations by 80% and increased HO activity by 158%. However, ALAS activity also decreased by 37%, suggesting that regulatory free heme pool was not modified. Our findings indicate that CP-55,940 and its metabolites do not behave as porphyrinogenic drugs and may potentially be safe for treating pain in patients with acute porphyrias.

Animals↗
PubMed2005

Time course of opioid and cannabinoid gene transcription alterations induced by repeated administration with fluoxetine in the rat brain.

This study examined the time course effects (8, 16 and 31 days) of fluoxetine administration (1 mg/kg, p.o./day) on serotonin transporter (5-HTT), opioid, tyrosine hydroxylase (TH) and cannabinoid CB1 receptor gene expressions in selected regions of the rat brain. Treatment with fluoxetine progressively decreased (35-55%) 5-HTT gene expression in dorsal raphe nucleus at 8, 16 and 31 days. The results revealed that fluoxetine administration decreased (30%) proenkephalin gene expression in nucleus accumbens shell (AcbS) and caudate-putamen (CPu) (31 days) but was without effect in nucleus accumbens core AcbC. A pronounced and time related decrease (25-65%) in prodynorphin gene expression was detected in AcbC, AcbS, CPu, hypothalamic supraoptic and paraventricular nuclei at all time points as well as in proopiomelanocortin gene expression (20-30%) in the arcuate nucleus (ARC) of the hypothalamus. On days 16 and 31, tyrosine hydroxylase gene expression in ventral tegmental area and substantia nigra and cannabinoid CB1 receptor gene expression in the CPu decreased (approximately 45-50% from vehicle). In conclusion, fluoxetine by inhibiting the reuptake of serotonin produced pronounced and time related alterations in genes involved in the regulation of emotional behaviour, suggesting that these neuroplastic changes may be involved, at least in part, in the clinical efficacy of this drug in neuropsychiatric disorders.

Animals↗
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

Interactions between cannabinoid and opioid receptor systems in the mediation of ethanol effects.

Over the past few years, advances in the investigation of the neurochemical circuits involved in the development and treatment of alcohol dependence have identified peptides and receptors as potential key targets in the treatment of problems related to alcohol consumption. The endogenous opioid system is modified by alcohol intake in areas of the brain related to reward systems, and differential basal levels of opioid gene expression are found in rodents with a high preference for ethanol. This suggests a greater vulnerability to alcohol consumption in relation to differences in genetic background. Further evidence of the involvement of opioid peptides in alcohol dependence is the ability of the opioid antagonist naltrexone to reduce alcohol intake in animal models of dependence and in alcohol-dependent patients. Abundant evidence indicates that the activation of cannabinoid receptors stimulates the release of opioid peptides, therefore the cannabinoid receptor antagonists may presumably alter opioid peptide release, thus facilitating the reduction of ethanol consumption. However, little is known about the effects of ethanol on the endogenous cannabinoid system, the vulnerability of cannabinoid receptors to alcohol intake or their neurochemical implications in reducing consumption of alcohol. In this paper, we review the role of opioid and cannabinoid receptor systems, their vulnerability to alcohol intake and the development of dependence, and the targeting of these systems in the treatment of alcoholism.

Alcohol Drinking↗
PubMed2004

Role of endocannabinoid system in mental diseases.

In the last decade, a large number of studies using Delta9-tetrahydrocannabinol (THC), the main active principle derivative of the marijuana plant, or cannabinoid synthetic derivatives have substantially contributed to advance the understanding of the pharmacology and neurobiological mechanisms produced by cannabinoid receptor activation. Cannabis has been historically used to relieve some of the symptoms associated with central nervous system disorders. Nowadays, there are anecdotal evidences for the use of cannabis in many patients suffering from multiple sclerosis or chronic pain. Following the historical reports of the use of cannabis for medicinal purposes, recent research has highlighted the potential of cannabinoids to treat a wide variety of clinical disorders. Some of these disorders that are being investigated are pain, motor dysfunctions or psychiatric illness. On the other hand, cannabis abuse has been related to several psychiatric disorders such as dependence, anxiety, depression, cognitive impairment, and psychosis. Considering that cannabis or cannabinoid pharmaceutical preparations may no longer be exclusively recreational drugs but may also present potential therapeutic uses, it has become of great interest to analyze the neurobiological and behavioral consequences of their administration. This review attempts to link current understanding of the basic neurobiology of the endocannabinoid system to novel opportunities for therapeutic intervention and its effects on the central nervous system.

Analgesia↗
PubMed2004

Impaired action of anxiolytic drugs in mice deficient in cannabinoid CB1 receptors.

The role of cannabinoid CB(1) receptors in the action of anxiolytics was examined. Deletion of CB(1) receptors resulted in increased anxiety-like behaviours in light/dark box, elevated plus maze and social interaction tests. Mutant mice presented basal low corticosterone concentrations and low proopiomelanocortin gene expression in the anterior lobe of the pituitary gland compared to wild-type mice. Ten minutes of restraint stress resulted in a twofold increase in corticosterone concentrations in the plasma of mutant mice, compared to wild-type mice. Bromazepam (50 or 100 microg/kg) markedly increased the time spent in light area in wild-type animals, though both doses were without effect in mutant mice. Administration of buspirone (1 or 2 mg/kg) produced anxiolytic effects in wild-type mice. In contrast, only the highest dose of buspirone had anxiolytic results in mutant mice. Our findings reveal that CB(1) receptors are involved in the regulation of emotional responses, and play a pivotal role in the action mechanism of anxiolytics. They suggest that alterations in the functional activity of the CB(1) receptor may be related to the emergence of anxiety disorders, and may affect treatment with anxiolytics.

Animals↗
PubMed2004

Repeated administration with Delta9-tetrahydrocannabinol regulates mu-opioid receptor density in the rat brain.

Several studies have demonstrated reciprocal, as well as synergistic interactions between cannabinoid and opioid systems. The aim of this study was to explore the time-related effects of repeated administration of Delta9-tetrahydrocannabinol on mu-opioid receptor autoradiography in various brain regions of the rat. To this aim, the effects of Delta9-tetrahydrocannabinol (Delta9-THC, 5 mg/kg/day; i.p.) were examined after 1, 3, 7 and 14 days of repeated administration on regions containing mu-opioid receptors: (i) forebrain [caudate-putamen, nucleus accumbens (core and shell) and piriform cortex]; (ii) amygdala (medial pars and cortical posteromedial pars), hypothalamus (ventromedial and dorsomedial nuclei, zona incerta), hippocampal regions (CA1, CA2, CA3, dentate girus), hindbrain (substantia nigra and ventral tegmental area); and (iii) thalamus, including 12 thalamic nuclei. In most of these regions, repeated cannabinoid administration increases mu-opioid receptor density; however, the onset, degree of magnitude reached and time-related effects produced by administration with Delta9-tetrahydrocannabinol are dependent upon the brain region examined. It appears that the major increase in mu-opioid receptor density occurs 1 and 3 days after Delta9-THC administration. In some regions, this increase is maintained and, for most of the brain areas examined, this effect is no longer significant by 14 days of administration, suggesting tolerance to cannabinoid treatment. Taken together, the results of this study suggest that cannabinoids produce a time-related differential responsiveness in mu-opioid receptor density in several brain areas that may be relevant to an understanding of the alterations associated with cannabinoid exposure.

Animals↗
PubMed2004

Spontaneous cannabinoid withdrawal produces a differential time-related responsiveness in cannabinoid CB1 receptor gene expression in the mouse brain.

This study aimed to examine the behavioural and neurochemical (cannabinoid CB1 receptor gene expression) changes induced by spontaneous cannabinoid withdrawal in mice. Tolerance was assessed by measuring rectal temperature and motor activity in the open-field test after CP-55, 940 administration. Cannabinoid withdrawal symptoms were determined by measuring motor activity and behavioural signs of abstinence. Cessation of CP-55, 940 treatment in tolerant mice induced a spontaneous time-dependent behavioural withdrawal syndrome consisting of marked increases (140%) in motor activity, number of rearings (170%), decreases in grooming (57%), wet dog shakes (73%) and rubbing behaviours (74%) on day 1, progressively reaching values similar to vehicle-treated mice on day 3. Interestingly, this spontaneous cannabinoid withdrawal resulted in CB1 gene expression upregulation (20-30%) in caudate-putamen, ventromedial hypothalamic nucleus, central amygdaloid nucleus and CA1, whereas in the CA3 field of hippocampus, a significant decrease (15-20%) was detected. Taken together, the results of this study suggest that cessation of CP-55, 940 administration in tolerant mice produces a behavioural cannabinoid withdrawal syndrome and a selective and differential responsiveness in CB1 receptor gene expression in several brain regions of the mice. These findings further suggest a time and regional differential role for cannabinoid receptors in short- and long-term neuroadaptations that occur after exposure to cannabis derivatives.

Animals↗
PubMed2004

Cannabinoid/opioid crosstalk in the central nervous system.

Promising therapeutic uses and a great variety of pharmacological effects are the leading forces that focus actual cannabinoid research. Cannabinoid and opioid systems share neuroanatomical, neurochemical, and paharmacological features. This fact supports the notion that actions induced by each one of these types of drugs involved an interaction between the endogenous opioid and endocannabinoid neuronal systems. Over the last decade our group and others have investigated cannabinoid/opioid crosstalk in the central nervous system by studying the mechanisms underlying pharmacological and biochemical interactions between the two systems in experimental paradigms of antinociception, drug reinforcement, and anxiety. The goal of this review is to revise the latest work done on this subject, with special emphasis on the research done with genetically modified animals. Whereas clinical progress is going ahead slowly, basic research in this area is progressing rapidly. Clinical applications derived from the cannabinoid/opioid crosstalk and based tightly on medical evidence are yet to come, but it is hoped that knowledge of this central messenger interaction will help to develop new alternatives for the treatment of some pathological states.

Animals↗
PubMed2003

Extinction of cocaine self-administration produces alterations in corticotropin releasing factor gene expression in the paraventricular nucleus of the hypothalamus.

The long-term effect of cocaine self-administration on corticotropin releasing factor (CRF) mRNA content in the hypothalamic CRF-containing neurons has not yet been established. The purpose of this study was to examine the time course effects of the extinction of cocaine self-administration behavior on CRF gene expression in the paraventricular nucleus of the hypothalamus (PVN) using in situ hybridization histochemistry (IHHS). Seventy-two littermate male Lewis rats were randomly assigned in triads to one of three conditions: (a) contingent intravenous self-administration of 1 mg/kg/injection of cocaine (CONT), (b) non-contingent injections of either 1 mg/kg/injection of cocaine (NONCONT) or (c) saline yoked (SALINE) to the intake of the self-administering subject. The self-administering rats were trained to self-administer cocaine under a fixed ratio 5 (FR5) schedule of reinforcement for a minimum of 3 weeks. After stable baseline levels of drug intake had been reached, saline was substituted for drug. Following this first extinction period, cocaine self-administration was reinstated for an additional period of 2 weeks. Immediately after cessation of the last session of cocaine self-administration (Day 0) and 1, 5 and 10 days after the second extinction period, animal brains in each triad were removed to be processed for IHHS. CRF mRNA levels in the PVN were significantly lower in the NONCONT cocaine group at Day 0 compared to CONT or SALINE groups. On Day 1, hypothalamic CRF gene expression significantly decreased in the CONT cocaine group with respect to the SALINE group, but there were no differences between the cocaine groups or among the NONCONT cocaine and SALINE groups. After 5 and 10 days of extinction, no differences were found in CRF mRNA content in the PVN between the three conditions of this study. These results suggest that, after the extinction of cocaine self-administration, changes in hypothalamic CRF gene expression are differentially affected depending upon the type of cocaine administration, and that the stages of cocaine withdrawal might not be associated with enduring changes in hypothalamic CRF mRNA levels.

Analysis of Variance↗
PubMed2003

Design and synthesis of S-(-)-2-[[4-(napht-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-a]pyrazine (CSP-2503) using computational simulation. A 5-HT1A receptor agonist.

Based on a computational model for 5-HT(1A)R-ligand interaction and QSAR studies, we have designed and synthesized a new series of arylpiperazines 2-8 which exhibit high 5-HT(1A)R affinity and selectivity over alpha(1)-adrenergic receptors. Among them, compound CSP-2503 (4) has been pharmacologically characterized as a 5-HT(1A)R agonist at somatodendritic and postsynaptic sites, endowed with anxiolytic properties.

Amino Acid Sequence↗
PubMed2003

Behavioural and gene transcription alterations induced by spontaneous cannabinoid withdrawal in mice.

This study examined behavioural signs that occur during tolerance development to cannabinoid treatment and hormonal and gene expression alterations induced by spontaneous cannabinoid withdrawal in mice. Tolerance to CP-55,940 treatment developed for hypothermia, ambulatory and exploratory locomotor activity. Cessation of cannabinoid treatment resulted in a behavioural withdrawal syndrome characterized by a pronounced increase in ambulatory activity and rearings. Corticosterone plasma concentrations dramatically increased 24 and 72 h after cessation of cannabinoid treatment. Similarly, an increase (40%) in cannabinoid [35S]GTPgammaS binding autoradiography was detected on days 1 and 3 of abstinence. Spontaneous cannabinoid withdrawal produced time-related significant alterations in gene transcription: (i) decreased (20%) tyrosine hydroxylase (TH) mRNA levels in the ventral tegmental area and increased (50%) in substantia nigra; (ii) increased proenkephalin (PENK) gene expression more than 100% in caudate-putamen, nucleus accumbens, olfactory tubercle and piriform cortex; (iii) increased (20-40%) pro-opiomelanocortin (POMC) gene expression in the arcuate nucleus of the hypothalamus. These results suggest that spontaneous cannabinoid withdrawal occur after cessation of CP-55,940 treatment. This 'syndrome' includes behavioural, hormonal and gene transcription alterations that seems to be part of the regulation of neuronal plasticity induced by spontaneous cannabinoid withdrawal.

Animals↗
PubMed2002

Gastrin-releasing peptide mediated regulation of 5-HT neuronal activity in the hypothalamic paraventricular nucleus under basal and restraint stress conditions.

The purpose of this study was to examine the gastrin-releasing peptide (GRP) mediated regulation of 5-HT neuronal activity in the paraventricular nucleus of the hypothalamus under basal and restraint stress conditions. Intracerebroventricular (icv) administration of GRP (1, 10, 100 ng/rat) increased 5-HIAA concentrations in the paraventricular nucleus (PVN) of the hypothalamus, but was without effect in the accumbens, suprachiasmatic and arcuate nuclei. Administration of (Leu(13)-psi-CH(2)NH-Leu(14)) Bombesin (10, 100 and 1000 ng/rat; icv), a GRP antagonist, had no effect by itself on PVN serotonergic activity; however, a dose of 1 microg/rat of this compound, completely blocked the increase of 5-HIAA concentrations induced by GRP (10 ng). Restraint stress increased serotonergic activity -as shown by an elevation of 5-HIAA in the PVN- as well as plasma ACTH and corticosterone. This stress-induced activation of both the serotonergic neurons and the hypothalamus-pituitary-adrenal axis was blocked by CRF and GRP antagonists. Interestingly, when the activation of hypothalamic 5-HT neurons was induced by GRP administration, alpha-helical (9-41) CRF was ineffective. These data suggest that GRP, by acting on GRP receptors but not via CRF receptors, increases 5-HT neuronal activity in the PVN. In turn, it appears that endogenous GRP and CRF receptor ligands are both simultaneously involved in the regulation of the increase in 5-HT neuronal activity, ACTH and corticosterone secretion, under stress conditions.

Adrenocorticotropic Hormone↗