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C Chiamulera

Publications and source records attributed to C Chiamulera.

17 recordsLinked to original sources
PubMed2001

Nicotine self-administration and withdrawal: modulation of anxiety in the social interaction test in rats.

RATIONALE: Most smokers report smoking has an anxiolytic effect, which may contribute to nicotine dependence. OBJECTIVE: To examine effects in the social interaction test (SI) of anxiety after 4 weeks' self-administered nicotine (15 infusions of 0.03 mg/kg, totalling 0.45 mg/kg per day), and after 24 and 72 h of withdrawal. The effect of exposure to the operant chamber on withdrawal responses was also examined. METHODS: Animals were trained to self-administer saline or nicotine and after 4 weeks they were tested in SI after their daily self-administration session. Animals were retested after 24 and 72 h withdrawal, when they were either taken directly from the home cage or were tested 5 min after a 30-min exposure to the operant chamber. RESULTS: Compared with the saline control group, the animals that had been self-administering nicotine for 4 weeks showed decreased social interaction with no decrease in locomotor activity, indicating a significant anxiogenic effect of the nicotine infusions. There was no change in social interaction after 24 and 72 h withdrawal from chronic nicotine, regardless of whether or not the rats were exposed to the operant chamber just prior to being tested. CONCLUSIONS: Nicotine self-administration is not maintained because of its anxiolytic effect, but despite, or because of, its anxiogenic effect. There was no evidence of an anxiogenic response after either 24 or 72 h of withdrawal and thus increased anxiety on withdrawal from nicotine does not seem to contribute to nicotine self-administration.

Animals↗
PubMed2001

Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice.

Both ionotropic and metabotropic glutamate receptors (mGluRs) are involved in the behavioral effects of pyschostimulants; however, the specific contributions of individual mGluR subtypes remain unknown. Here we show that mice lacking the mGluR5 gene do not self-administer cocaine, and show no increased locomotor activity following cocaine treatment, despite showing cocaine-induced increases in nucleus accumbens (NAcc) dopamine (DA) levels similar to wild-type (WT) mice. These results demonstrate a significant contribution of mGlu5 receptors to the behavioral effects of cocaine, and suggest that they may be involved in cocaine addiction.

Animals↗
PubMed2000

Chronic nicotine treatment decreases neurofilament immunoreactivity in the rat ventral tegmental area.

Region-specific decreases of neurofilament proteins have been described in the ventral tegmental area of rats chronically treated with either morphine or cocaine. The aim of the present study was to assess if the levels of neurofilament proteins are changed in the ventral tegmental area by chronic treatment with nicotine. Immunoreactivity for NF-68, NF-160 and NF-200 was determined using NR4, BF10 and RT97 antibodies, respectively. Measurements were performed using computer-assisted microdensitometry of brain sections from rats exposed to chronic nicotine treatment (0.4 mg/kg/dayx6 days) or to saline. Chronic nicotine treatment reduced NF-160 and NF-200 immunoreactivity by 44.5% (P<0.01) and 22.5% (P<0. 05), respectively, in the ventral tegmental area but not in the substantia nigra. A trend towards reduction was observed for NF-68 immunoreactivity in the ventral tegmental area. These preliminary results suggest that nicotine shares the same properties with cocaine and morphine to reduce neurofilament proteins in the ventral tegmental area, a key brain structure of the reward system.

Animals↗
PubMed1999

Molecular mechanisms of the positive reinforcing effect of nicotine.

Animal models of nicotine dependence are fundamental experimental tools for the understanding of the neurobiological and molecular processes underlying smoking behaviour. Substance use is controlled by four main processes: positive reinforcing effects, aversive effects, discriminative effects and stimulus-conditioned effects of the drug. In this article, the molecular and neural bases of the positive reinforcing effects of nicotine are summarized, focusing on data obtained in experiments including unambiguous and objective measurements of the reinforcing properties of nicotine. Operant behaviour paradigms, in particular intravenous nicotine self-administration, offer such a possibility within a solid theoretical framework. Nicotine self-administration produces changes in the mesocorticolimbic DA system, a key component of the reward system, as do other addictive drugs. The role of the mesocorticolimbic DA system as the main substrate of the reinforcing properties of nicotine is supported by converging experiments, including the evidence that nicotine self-administration is attenuated in mutant mice lacking the beta2 subunit of neural acetylcholine nicotinic receptor. The long-term adaptive molecular changes in the target neurons of the terminal fields of the mesocorticolimbic DA system, including transcriptional regulation mediated by c-fos family gene products on other genes, suggest that the mesolimbic DA projection to the nucleus accumbens is mainly involved in the stimulus-reward learning process. These data represent an initial set of information only, which may help to develop a more complete and reliable model of the molecular dynamics underlying the reinforcing effects of nicotine.

Animals↗
PubMed1997

Common neural substrates for the addictive properties of nicotine and cocaine.

Regional brain activation was assessed by mapping of Fos-related protein expression in rats trained to self-administration of intravenous nicotine and cocaine. Both drugs produced specific overlapping patterns of activation in the shell and the core of the nucleus accumbens, medial prefrontal cortex, and medial caudate areas, but not in the amygdala. Thus, the reinforcing properties of cocaine and nicotine map on selected structures of the terminal fields of the mesocorticolimbic dopamine system, supporting the idea that common substrates for these addictive drugs exist.

Amygdala↗
PubMed1997

Evidence against a permissive role of the metabotropic glutamate receptor 1 in acute excitotoxicity.

Excitotoxicity has been proposed to contribute to neuronal loss in a broad spectrum of neurodegenerative conditions such as ischemia, hypoglycaemic coma or cerebral trauma. Excitotoxic neuronal injury appears to be mediated mainly by the over-activation of glutamate receptors, especially N-methyl-D-aspartate receptors, with subsequent excessive Ca2+ influx. Concurrent with the activation of glutamate-gated ion channels, metabotropic glutamate receptors (mGluR), which are G-protein coupled receptors, are also expected to be activated. Excessive stimulation of phospholipase C-coupled mGluR, mGluR1 and mGluRS, has been suggested to have neurotoxic consequences. However, the contribution of mGluR activation on excitotoxicity is still unclear and controversial. Here we report that, following ischemic and excitotoxic brain injuries, inactivation of mGluR1 does not prevent excitotoxic neuronal damage. Given the evidence that agonists at this group of mGluR promoted neuronal death in cerebrocortical cultures after oxygen-glucose deprivation or after N-methyl-D-aspartate exposure, our findings suggest that mGluR-mediated excitotoxicity is unlikely associated with mGluR1 but rather with other PLC-coupled mGluR.

Analysis of Variance↗
PubMed1996

Nicotine reinstatement of nicotine self-administration after long-term extinction.

The effect of non-contingent priming injections of nicotine on the reinstatement of drug-seeking behaviour was studied in rats following the long-term extinction of nicotine self-administration. Male rats were trained to lever press for 0.03 mg/kg per infusion of intravenous nicotine. Nicotine maintained a robust self-administration behaviour (11.5 +/- 1.2; mean+/-SEM infusions/1-h session). When nicotine availability was discontinued, and only a non-contingent saline infusion was presented to the experimental subjects at the beginning of each daily session, responding for the drug-paired lever decreased to low values. After 4-13 sessions, responding extinguished. During this "extinction" period, non-contingent priming infusions of nicotine 0.001, 0.003, 0.01 or 0.03 mg/kg per infusion induced reinstatement of responding for the drug-paired lever. The increased responding, compared with the corresponding previous day on saline, was observed at all four nicotine doses but was not statistically significant for the higher priming dose (0.03 mg/kg per infusion). These preliminary results indicate that nicotine priming is able to induce reinstatement of drug-seeking behaviour in rats similarly to other reinforcing drugs. The present findings show analogies with similar phenomena described in ex-smokers and support the addictive role of nicotine in tobacco smoking.

Animals↗
PubMed1996

Effects of the metabotropic glutamate receptor antagonist MCPG on spatial and context-specific learning.

The effects of the metabotropic glutamate receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine (MCPG) on performance in a water maze and in context-specific associative learning were examined in rats previously implanted with cannulae. MCPG (20.8 micrograms) injected intraventricularly (i.c.v.) before testing impaired the performance of rats in the spatial version of the Morris water maze, but 1/10 of this dose did not. Memory retention, evaluated 24 hr post-training, was also affected by the high dose of MCPG. However, performance in a cued version of the water maze was not impaired by the high dose, excluding effects of the drug on perceptual faculties. The effects of the MCPG were further characterized on performance in another hippocampus-dependent spatial learning task, the context-dependent fear conditioning task. MCPG (20.8 micrograms, i.c.v.) did not interfere with conditioned freezing to context in this task. For comparison, a group of rats was injected with the NMDA receptor blocker MK801. MK801 at a dose that disrupted the performance in the spatial version of the Morris water maze (0.08 mg/kg), significantly reduced freezing compared to controls. These experiments indicate that MCPG-sensitive metabotropic receptors may be required for only a restricted subset of spatial learning tasks, while NMDA receptors may play an integral role in all spatial learning.

Animals↗
PubMed1996

The reinforcing properties of nicotine are associated with a specific patterning of c-fos expression in the rat brain.

Rats were trained for nicotine intravenous infusions in a self-administration paradigm. The effect of nicotine self-administration on regional brain activity was studied by mapping changes of c-fos expression. Specific nicotine effects were determine by comparing the patterning of Fos-like immunoreactivity (Fos-Ll) in nicotine self-administering rats with that in three different control groups. Controls included rats exposed to the same manipulation as nicotine self-administering rats who received intravenous saline instead of nicotine. In addition, two groups of untrained sham-operated rats exposed daily to the same operant boxes were included: one group had the same food restriction used in the operant training, the other was fed ad libitum. Nicotine self-administration, exposure to saline and food restriction increased Fos-Ll in 43, 33 and three brain regions, respectively, when compared with the control group fed ad libitum. Computer-assisted image analysis of Fos-Ll profiles performed on 16 relevant limbic and sensory structures showed that in saline-treated rats a significant (P < 0.01) increase of Fos-Ll profiles was observed in medial prefrontal cortex, lateral septum, core and ventral shell of nucleus accumbens, claustrum, amygdaloid nuclei, paraventricular thalamic nucleus and lateral geniculate nucleus. A significant (P < 0.01) further increase produced by nicotine was found in medial prefrontal cortex and ventral shell of nucleus accumbens. Interestingly, cingulate and piriform cortex, superior colliculus and medial terminal nucleus of the accessory optic tract were specifically activated by nicotine but not saline. These results show that nicotine self-administration activates sensory structures, as well as limbic structures involved in natural rewarding pathways. The results suggest the involvement of restricted terminal regions of the mesocorticolimbic dopaminergic system in the maintenance of nicotine self-administration.

Analysis of Variance↗
PubMed1995

Nicotine reinforcement in rats with histories of cocaine self-administration.

Few reports have described conditions under which nicotine self-administration occurs in rats. In this study, rats which initially lever pressed for cocaine infusion (0.05 mg/kg) during 1 h experimental sessions continued to obtain similar infusion numbers when nicotine (0.03 mg/kg) was available. When saline was substituted for nicotine, infusions decreased from 11.8 +/- 4.5/h to 5.4 +/- 1.1/h but returned to pre-saline levels when it was reintroduced (12.0 +/- 5.4/h). These results indicate that nicotine can serve as a positive reinforcer for rats under the historical and schedule conditions described.

Animals↗
PubMed1993

Qualitative and quantitative analysis of the progressive cerebral damage after middle cerebral artery occlusion in mice.

The middle cerebral artery occlusion (MCAO) in mice induces a focal cerebral ischaemia at the level of the tempo-parietal cortex. Histological staining and immunohistochemical markers were used to characterize the temporal progression of the cerebral infarct: both qualitative and quantitative analyses were performed at different days after the MCAO. At 3 days after MCAO, an extensive necrosis of the cerebral parenchyma was accompanied by extravasation and by massive oedema. After 7 days, GFAP marker showed a gliotic reaction with alteration of the astrocytes membrane permeability (S100 marker). Positivity for acid phosphatase staining indicated the presence of macrophages. At Day 14 and 21 following MCAO, the histological profile was essentially similar. Interestingly, at Day 7, 14 and 21, a previously unreported gliosis was observed in the subthalamic area. Quantitative analysis showed a significantly large infarct volume at Day 3 (7.88 +/- 1.95 mm3 +/- S.E.M.) compared to Day 7 (4.28 +/- 0.47 mm3 +/- S.E.M.). At Day 14 and Day 21 the infarct volumes were further decreased to 2.00 +/- 0.52 and 1.43 +/- 0.39 mm3 +/- S.E.M., respectively. These results suggest that it is important to consider the time of evaluation of cerebral ischaemia-induced cerebral infarct, especially in studies which aim to evaluate the neuroprotective effect of putative therapeutic agents.

Animals↗
PubMed1993

New anxiolytics in development.

Benzodiazepines (BDZ), the most popular drug of choice for treating anxiety disorders, present side-effects such as sedation, muscular disorders, abuse liability and synergistic effect with alcohol and CNS depressant drugs. At present, pharmacological research is focusing to find anxiolytic drugs as efficacious as benzodiazepines but without side-effects. This review reports the status of the pharmaceutical research and development on novel drugs for the treatment of anxiety disorders. A close analysis of the items selected by the N5C "Pharmaprojects" search (anxiolytic class) yielded the following classification: A) Drugs interacting with the GABA-A receptor complex, which includes BDZ-like drugs, partial BDZ agonists (beta-carbolines) and drugs interacting with the GABA-A complex through an as yet unidentified mechanism (15 compounds), B) Drugs acting as CCK-B antagonists (5 compounds), C) Drugs interacting with serotonergic function (30 compounds) subdivided into: (i) agonists at the 5-HT1A receptor, (ii) antagonists at the 5-HT2 receptor, and (iii) antagonists at the 5-HT3 receptor; D) Drugs with other mechanisms (22 compounds). Based on these results, it is not possible to identify a common mechanism through which the selected drugs under development exert their anxiolytic effect. Therefore, it appears that different biological mechanisms are specifically involved in the different anxiety disorders.

Anti-Anxiety Agents↗
PubMed1992

Activation of metabotropic receptors has a neuroprotective effect in a rodent model of focal ischaemia.

The role of the glutamate 'metabotropic' receptor was investigated in an experimental model of focal ischaemia-induced neurodegeneration. The metabotropic agonist, trans-1-amino cyclopentane-1,3-dicarboxylic acid (t-ACPD, 20 mg/kg i.p.), was administered to mice immediately after middle cerebral artery occlusion (MCAO), which causes cerebral infarct. Seven days after MCAO, the mean infarct volume value of the t-ACPD-treated group (mean +/- S.E. = 4.57 +/- 0.73 mm3) was significantly reduced, by 34.3%, compared to the vehicle-treated group (mean +/- S.E. = 6.95 +/- 0.59 mm3, P less than 0.01). This suggests that metabotropic receptor activation in the adult brain reduces excitotoxicity.

Animals↗
PubMed1992

Domoic acid toxicity in rats and mice after intracerebroventricular administration: comparison with excitatory amino acid agonists.

A behavioural study of the domoic acid (DOM)-induced convulsive behaviour after intracerebroventricular administration was carried out in rats and mice. DOM-induced behaviours were compared to those elicited by other excitatory amino acid (EAA) agonists N-methyl-D-aspartate (NMDA), alpha-amino-3- hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainic acid (KA), in such a way as to assess the possible similarities between DOM-induced effects and EAA subtype receptor activation in vivo. In rat, DOM (0.03-3 nmol/rat) caused a complex pattern of convulsive behaviour, quantified by means of a 15-point rating scale. DOM-induced behavioural profile was characterized at the lower doses by "preconvulsive" behaviours as wet dog shakes, hypermotility, mild facial clonus. At higher doses, DOM caused clonic convulsions followed by the "status epilepticus" syndrome (wet dog shakes, forelimb clonus, rearing, salivation). Rats treated with KA (0.3-10 nmol/rat) showed an almost identical behavioural profile. AMPA (1-10 nmol/rat)-induced convulsive behaviour was similar to DOM and KA only at the higher doses. NMDA (0.25-10 nmol/rat) caused clonic convulsions but not "status epilepticus". In mice, similar results were obtained: all the tested drugs induced generalized seizures, but only animals treated with DOM, KA and AMPA showed a prolonged sequence of seizures with forelimb clonus. Our results confirm the findings reported in the literature and support the hypothesis that DOM and KA act at the same EAA receptor.

Animals↗
PubMed1990

Effect of NMDA- and strychnine-insensitive glycine site antagonists on NMDA-mediated convulsions and learning.

Intracerebroventricular (ICV) injection of N-methyl-D-aspartate (NMDA) was shown to induce generalized seizures in mice. The competitive NMDA antagonists DL-2-amino-5-phosphonovaleroate (DL-AP7) and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), the NMDA "channel blocker" antagonist (+)-5-methyl-10,11-dihydro 5H-dibenzo-[a,d] cycloheptan-5,10-imine maleate (MK-801) and the strychnine-insensitive glycine antagonists kynurenic acid (KYNA) and 7-chloro-kynurenic acid (7-Cl-KYNA), when co-administered (ICV) with NMDA, antagonized NMDA-induced generalized seizures. Administration (ICV) of DL-AP7, CPP and MK-801 resulted in impared learning performance in a passive avoidance task in mice, with ED50 close to the anticonvulsant dose. The glycine antagonists KYNA and 7-Cl-KYNA at high doses significantly failed to affect performance in the same model of learning. The results indicate that compounds acting at the strychnine-insensitive glycine site may have a larger "therapeutic window" as anticonvulsants than antagonists of the NMDA receptor and channel.

2-Amino-5-phosphonovalerate↗
PubMedDate not supplied

Neural substrate of nicotine addiction as defined by functional brain maps of gene expression.

The distributed neural networks involved in the intravenous self-administration of nicotine and cocaine, and in a model of relapse of nicotine-taking after abstinence, were compared in Wistar rats. Post-mortem brain maps of c-fos-related antigens expression showed specific activation in prefrontal cortex, anterior cingulate and nucleus accumbens for both drugs, but of the anterior cingulate cortex only during relapse, suggesting that a subset of the neural network involved in drug self-administration is activated during relapse.

Animals↗