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

The possible interactions between Delta9-tetrahydrocannabinol (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 THC administration on the somatic manifestations and the aversive motivational state associated to nicotine withdrawal in mice. Acute 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 THC administration. THC also reversed conditioned place aversion associated to naloxone precipitated nicotine withdrawal. We have then evaluated whether this effect of THC was due to possible adaptive changes induced by chronic nicotine on CB1 cannabinoid receptors. The stimulation of GTPS-binding proteins by the cannabinoid agonist WIN 55,212-2 and the density of CB1 cannabinoid receptor binding labelled with [3H] CP-55,940 were not modified by chronic nicotine treatment in the different brain structures investigated. Finally, we evaluated the consequences of 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 THC administration did not modify c-Fos expression under these experimental conditions. Taken together, these results indicate that THC administration attenuated somatic signs of nicotine withdrawal and this effect was not associated to compensatory changes on CB1 cannabinoid receptors during chronic nicotine administration. In addition, THC also ameliorated the aversive motivational consequences of nicotine withdrawal.

Role of the cannabinoid system in the effects induced by nicotine on anxiety-like behaviour in mice

Rationale: Acute behavioural effects and motivational responses induced by nicotine can be modulated by the endocannabinoid system supporting the existence of a physiological interaction between these two systems. Objectives: The present study was designed to examine the possible involvement of the cannabinoid system in the anxiolytic- and anxiogenic-like responses induced by nicotine in mice. Methods: Animals were only exposed once to nicotine. The acute administration of low (0.05, sc) or high (0.8 mg/kg, sc) doses of nicotine produced opposite effects in the elevated plus-maze, i.e., anxiolytic- and anxiogenic-like responses, respectively. The effects of the pretreatment with the CB1 cannabinoid receptor antagonist, rimonabant (0.25, 0.5 and 1 mg/kg, ip), and the cannabinoid agonist, 9-tetrahydrocannabinol (0.1 mg/kg, ip), were evaluated on the anxiolytic- and anxiogenic-like responses induced by nicotine. Results: Rimonabant completely abolished nicotine-induced anxiolytic-like effects and increased the anxiogenic-like responses of nicotine, suggesting an involvement of CB1 receptors in these behavioural responses. On the other hand, 9-tetrahydrocannabinol failed to modify nicotine anxiolytic-like responses, but attenuated its anxiogenic-like effects. In addition the association of non-effective doses of 9-tetrahydrocannabinol and nicotine produced clear anxiolytic-like responses. Conclusions: These results demonstrate that the endogenous cannabinoid system is involved in the regulation of nicotine anxiety-like behaviour in mice, and provide new findings to support the use of cannabinoid antagonists in the treatment of tobacco addiction.

CB1 knockout mice display impaired functionality of 5-HT1A and 5-HT2A/C receptors

Interaction between brain endocannabinoid (EC) and serotonin (5-HT) systems was investigated by examining 5-HT-dependent behavioural and biochemical responses in CB1 receptor knockout mice. CB1 knockout animals exhibited a significant reduction in the induction of head twitches and paw tremor by the 5-HT2A receptor selective agonist ()DOI, as well as a reduced hypothermic response following administration of the 5-HT1A receptor agonist (±)-8-OH-DPAT. Additionally, exposure to the tail suspension test induced enhanced despair responses in CB1 knockout mice. However, the tricyclic antidepressant imipramine and the 5-HT selective reuptake inhibitor fluoxetine induced similar decreases in the time of immobility in the tail suspension test in CB1 receptor knockout and wild-type mice. No differences were found between both genotypes with regard to 5-HT2A receptor and 5-HT1A receptors levels, measured by autoradiography in different brain areas. However, a significant decrease in the ability of the 5-HT1A receptor agonist (±)-8-OH-DPAT to stimulate 35SGTPS binding was detected in the hippocampal CA1 area of CB1 receptor knockout mice. This study provides evidence that CB1 receptors are involved in the regulation of serotonergic responses mediated by 5-HT2A and 5-HT1A receptors, and suggests that a reduced coupling of 5-HT1A receptors to Gi/o proteins in the hippocampus might be involved in these effects.

Development and validation of AMANDA, a new algorithm for selecting highly relevant regions in Molecular Interaction Fields

Descriptors based on Molecular Interaction Fields (MIF) are highly suitable for drug discovery, but their size (thousands of variables) often limits their application in practice. Here we describe a simple and fast computational method that extracts from a MIF a handful of highly informative points (hot spots) which summarize the most relevant information. The method was specifically developed for drug discovery, is fast, and does not require human supervision, being suitable for its application on very large series of compounds. The quality of the results has been tested by running the method on the ligand structure of a large number of ligand-receptor complexes and then comparing the position of the selected hot spots with actual atoms of the receptor. As an additional test, the hot spots obtained with the novel method were used to obtain GRIND-like molecular descriptors which were compared with the original GRIND. In both cases the results show that the novel method is highly suitable for describing ligand-receptor interactions and compares favorably with other state-of-the-art methods.

Attenuation of nicotine-induced antinociception, rewarding effects, and dependence in mu-opioid receptor knock-out mice

The involvement of μ-opioid receptors in different behavioral responses elicited by nicotine was explored by using μ-opioid receptor knock-out mice. The acute antinociceptive responses induced by nicotine in the tail-immersion and hot-plate tests were reduced in the mutant mice, whereas no difference between genotypes was observed in the locomotor responses. The rewarding effects induced by nicotine were then investigated using the conditioning place-preference paradigm. Nicotine produced rewarding responses in wild-type mice but failed to produce place preference in knock-out mice, indicating the inability of this drug to induce rewarding effects in the absence of μ-opioid receptors. Finally, the somatic expression of the nicotine withdrawal syndrome, precipitated in dependent mice by the injection of mecamylamine, was evaluated. Nicotine withdrawal was significantly attenuated in knock-out mutants when compared with wild-type mice. In summary, the present results show that μ-opioid receptors are involved in the rewarding responses induced by nicotine and participate in its antinociceptive responses and the expression of nicotine physical dependence.

Cannabinoid addiction: behavioral models and neural correlates

The use of cannabis sativa preparations as recreational drugs can be traced back to the earliest civilizations. However, animal models of cannabinoid addiction allowing the exploration of neural correlates of cannabinoid abuse have been developed only recently. We review these models and the role of the CB1 cannabinoid receptor, the main target of natural cannabinoids, and its interaction with opioid and dopamine transmission in reward circuits. Extensive reviews on the molecular basis of cannabinoid action are available elsewhere (Piomelli et al., 2000;Schlicker and Kathmann, 2001).

Absence of delta-9-tetrahydrocannabinol dysphoric effects in dynorphin-deficient mice

The involvement of dynorphin on Delta-9-tetrahydrocannabinol (THC) and morphine responses has been investigated by using mice with a targeted inactivation of the prodynorphin (Pdyn) gene. Dynorphin-deficient mice show specific changes in the behavioral effects of THC, including a reduction of spinal THC analgesia and the absence of THC-induced conditioned place aversion. In contrast, acute and chronic opioid effects were normal. The lack of negative motivational effects of THC in the absence of dynorphin demonstrates that this endogenous opioid peptide mediates the dysphoric effects of marijuana.

Cannabinoid withdrawal syndrome is reduced in pre-proenkephalin knock-out mice

The functional interactions between the endogenous cannabinoid and opioid systems were evaluated in pre-proenkephalin-deficient mice. Antinociception induced in the tail-immersion test by acute Delta9-tetrahydrocannabinol was reduced in mutant mice, whereas no difference between genotypes was observed in the effects induced on body temperature, locomotion, or ring catalepsy. During a chronic treatment with Delta9-tetrahydrocannabinol, the development of tolerance to the analgesic responses induced by this compound was slower in mice lacking enkephalin. In addition, cannabinoid withdrawal syndrome, precipitated in Delta9-tetrahydrocannabinol-dependent mice by the injection of SR141716A, was significantly attenuated in mutant mice. These results indicate that the endogenous enkephalinergic system is involved in the antinociceptive responses of Delta9-tetrahydrocannabinol and participates in the expression of cannabinoid abstinence.

Involvement of the extracellular signal-regulated kinase cascade for cocaine-rewarding properties

A central feature of drugs of abuse is to induce gene expression in discrete brain structures that are critically involved in behavioral responses related to addictive processes. Although extracellular signal-regulated kinase (ERK) has been implicated in several neurobiological processes, including neuronal plasticity, its role in drug addiction remains poorly understood. This study was designed to analyze the activation of ERK by cocaine, its involvement in cocaine-induced early and long-term behavioral effects, as well as in gene expression. We show, by immunocytochemistry, that acute cocaine administration activates ERK throughout the striatum, rapidly but transiently. This activation was blocked when SCH 23390 [a specific dopamine (DA)-D1 antagonist] but not raclopride (a DA-D2 antagonist) was injected before cocaine. Glutamate receptors of NMDA subtypes also participated in ERK activation, as shown after injection of the NMDA receptor antagonist MK 801. The systemic injection of SL327, a selective inhibitor of the ERK kinase MEK, before cocaine, abolished the cocaine-induced ERK activation and decreased cocaine-induced hyperlocomotion, indicating a role of this pathway in events underlying early behavioral responses. Moreover, the rewarding effects of cocaine were abolished by SL327 in the place-conditioning paradigm. Because SL327 antagonized cocaine-induced c-fos expression and Elk-1 hyperphosphorylation, we suggest that the ERK intracellular signaling cascade is also involved in the prime burst of gene expression underlying long-term behavioral changes induced by cocaine. Altogether, these results reveal a new mechanism to explain behavioral responses of cocaine related to its addictive properties.

Motivational effects of cannabinoids are mediated by μ-opioid and k-opioid receptor

Repeated THC administration produces motivational and somaticadaptive changes leading to dependence in rodents. Toinvestigate the molecular basis for cannabinoid dependenceand its possible relationship with the endogenous opioid system,we explored Δ9-tetrahydrocannabinol (THC) activity in mice lacking μ-, δ- or κ-opioid receptor genes. Acute THCinduced hypothermia, antinociception, and ypolocomotion remained unaffected in these mice, whereas THC tolerance and withdrawal were minimally modified in mutant animals. In contrast, profound phenotypic changes are observed in several place conditioning protocols that reveal both THC rewarding and aversive properties. Absence of μ receptors abolishes THC place preference. Deletion of κ receptors ablates THC place aversion and furthermore unmasks THC place preference. Thus, an opposing activity of μ- and κ-opioid receptors in modulating reward pathways forms the basis for the dual euphoric–dysphoric activity of THC.

Lack of CB1 receptor activity impairs serotonergic negative feedback

Serotonergic and endocannabinoid systems are important substrates for the control of emotional behavior and growing evidence show an involvement in the pathophysiology of mood disorders. In the present study, the absence of the activity of the CB1 cannabinoid receptor impaired serotonergic negative feedback in mice. Thus, in vivo microdialysis experiments revealed increased basal 5-HT extracellular levels and attenuated fluoxetine-induced increase of 5-HT extracellular levels in the prefrontal cortex of CB1 knockout compared to wild-type mice. These observations could be related to the significant reduction in the 5-HT transporter binding site density detected in frontal cortex and hippocampus of CB1 knockout mice. The lack of CB1 receptor also altered some 5-HT receptors related to the 5-HT feedback. Extracellular recordings in the dorsal raphe nucleus revealed that the genetic and pharmacological blockade of CB1 receptor induced a 5-HT1A autoreceptor functional desensitization. In situ hybridization studies showed a reduction in the expression of the 5-HT2C receptor within several brain areas related to the control of the emotional responses, such as the dorsal raphe nucleus, the nucleus accumbens and the paraventricular nucleus of the hypothalamus, whereas an overexpression was observed in the CA3 area of the ventral hippocampus. These results reveal that the lack of CB1 receptor induces a facilitation of the activity of serotonergic neurons in the dorsal raphe nucleus by altering different components of the 5-HT feedback as well as an increase in 5-HT extracellular levels in the prefrontal cortex in mice.

THC prevents MDMA neurotoxicity in mice

The majority of MDMA (ecstasy) recreational users also consume cannabis. Despite the rewarding effects that both drugs have, they induce several opposite pharmacological responses. MDMA causes hyperthermia, oxidative stress and neuronal damage, especially at warm ambient temperature. However, THC, the main psychoactive compound of cannabis, produces hypothermic, anti-inflammatory and antioxidant effects. Therefore, THC may have a neuroprotective effect against MDMA-induced neurotoxicity. Mice receiving a neurotoxic regimen of MDMA (20 mg/kg ×4) were pretreated with THC (3 mg/kg ×4) at room (21°C) and at warm (26°C) temperature, and body temperature, striatal glial activation and DA terminal loss were assessed. To find out the mechanisms by which THC may prevent MDMA hyperthermia and neurotoxicity, the same procedure was carried out in animals pretreated with the CB1 receptor antagonist AM251 and the CB2 receptor antagonist AM630, as well as in CB1, CB2 and CB1/CB2 deficient mice. THC prevented MDMA-induced-hyperthermia and glial activation in animals housed at both room and warm temperature. Surprisingly, MDMA-induced DA terminal loss was only observed in animals housed at warm but not at room temperature, and this neurotoxic effect was reversed by THC administration. However, THC did not prevent MDMA-induced hyperthermia, glial activation, and DA terminal loss in animals treated with the CB1 receptor antagonist AM251, neither in CB1 and CB1/CB2 knockout mice. On the other hand, THC prevented MDMA-induced hyperthermia and DA terminal loss, but only partially suppressed glial activation in animals treated with the CB2 cannabinoid antagonist and in CB2 knockout animals. Our results indicate that THC protects against MDMA neurotoxicity, and suggest that these neuroprotective actions are primarily mediated by the reduction of hyperthermia through the activation of CB1 receptor, although CB2 receptors may also contribute to attenuate neuroinflammation in this process.

Voice Transformations for Extreme Vocal Effects

Extreme Vocal Effects (EVE) in music are so recent that few studies have been carried out about how they are physiologically produced and whether they are harmful or not for the human voice.Voice Transformations in real-time are possible nowadays thanks to new technologies and voice processing algorithms. This Master's Thesis pretends to define and classify these new singing techniques and to create a mapping between the physiological aspect of each EVE to its relative spectrumvariations.Voice Transformation Models based on these mappings are proposed and discussed for each one of these EVEs. We also discuss different transformation methods and strategies in order to obtain better results.A subjective evaluation of the results of the transformations is also presented and discussed along with further work, improvements, and working lines on this field.

Especificitats de la narrativa audiovisual informativa a Internet: anàlisi de les rutines de producció i dels vídeos produïts per La Vanguardia Digital, VilaWeb i 3cat24.cat

El present projecte d’investigació és el treball de recerca del Doctorat en Comunicació Pública (bienni 2007-2009) i es proposa de desenvolupar-lo com a tesi doctoral. Vol estudiar les especificitats de la narrativa audiovisual informativa a Internet de tres mitjans digitals decomunicació catalans. Per a fer-ho es proposa una metodologia qualitativa dividida en dos blocs: el primer, a partir de l'observació, entrevistes en profunditat i enquestes, vol investigar les novesrutines de producció audiovisual en aquests tres mitjans, condicionades per un nou entorn digital; el segon, a partir de la narratologia, vol analitzar els efectes d'aquestes rutines i d'aquest nou entorn enel producte audiovisual resultant

El mirall de Narcís: mirada i identitat al cinema clàssic de Hollywood

Aquest treball se situa en el marc de l'estudi de les mirades en el cinema clàssic de Hollywood. S'interroga, en concret, sobre una mirada: la que alguns personatgesdirigeixen a la seva imatge especular. A la llum del mite de Narcís, es proposa escatirquin és el desig que va unit a aquesta mirada i quins efectes produeix sobre aquells que hi recorren, sobretot pel que fa a la fonamentació de la seva subjectivitat.Després de la identificació i l'examen de les figures cinematogràfiques que mostrenpunts de contacte amb la figura de Narcís, s'ha procedit a una exploració de les imatgesque les mostren mirant-se al mirall, per tal de precisar els trets que defineixen la sevamirada. Finalment, s'han resseguit certes variacions i prolongacions del mite de Narcís, presents també al cinema clàssic, per tal de veure l'evolució que hi sofreixen tant la pròpia mirada com la relació dels personatges amb la seva imatge. Aquest recorregut ha permès d'extreure algunes conclusions sobre la qüestió principal que ens havíem plantejat