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).

The natural hallucinogen 5-MeO-DMT, component of Ayahuasca, disrupts cortical function in rats: reversal by antipsychotic drugs

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural hallucinogen component of Ayahuasca, an Amazonian beverage traditionally used for ritual, religious and healing purposes that is being increasingly used for recreational purposes in US and Europe. 5MeO-DMT is of potential interest for schizophrenia research owing to its hallucinogenic properties. Two other psychotomimetic agents, phencyclidine and 2,5-dimethoxy-4-iodo-phenylisopropylamine (DOI), markedly disrupt neuronal activity and reduce the power of low frequency cortical oscillations (<4 Hz, LFCO) in rodent medial prefrontal cortex (mPFC). Here we examined the effect of 5-MeO-DMT on cortical function and its potential reversal by antipsychotic drugs. Moreover, regional brain activity was assessed by blood-oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). 5-MeO-DMT disrupted mPFC activity, increasing and decreasing the discharge of 51 and 35% of the recorded pyramidal neurons, and reducing (−31%) the power of LFCO. The latter effect depended on 5-HT1A and 5-HT2A receptor activation and was reversed by haloperidol, clozapine, risperidone, and the mGlu2/3 agonist LY379268. Likewise, 5-MeO-DMT decreased BOLD responses in visual cortex (V1) and mPFC. The disruption of cortical activity induced by 5-MeO-DMT resembles that produced by phencyclidine and DOI. This, together with the reversal by antipsychotic drugs, suggests that the observed cortical alterations are related to the psychotomimetic action of 5-MeO-DMT. Overall, the present model may help to understand the neurobiological basis of hallucinations and to identify new targets in antipsychotic drug development.

Generic drugs in Spain: price competition vs. moral hazard

This paper examines competition between generic and brand-name drugs in the regulated Spanish pharmaceutical market. A nested logit demand model is specified for the three most consumed therapeutic subgroups in Spain: statins (anticholesterol), selective serotonin reuptake inhibitors (antidepressants) and proton pump inhibitors (antiulcers). The model is estimated with instrumental variables from a panel of monthly prescription data from 1999 to 2005. The dataset distinguishes between three different levels of patients’ copayments within the prescriptions and the results show that the greater the level of insurance that the patient has (and therefore the lower the patient’s copayment), the lower the proportion of generic prescriptions made by physicians. It seems that the low level of copayment has delayed the penetration of generics into the Spanish market. Additionally, the estimation of the demand model suggests that the substitution rules and promotional efforts associated with the reference pricing system have increased generic market share, and that being among the first generic entrants has an additional positive effect.

CB1 cannabinoid receptor modulates MDMA acute responses and reinforcement

Background: 3, 4-methylenedioxymethamphetamine (MDMA) is a popular recreational drug widely abused by young people. The endocannabinoid system is involved in the addictive processes induced by different drugs of abuse. However, the role of this system in the pharmacological effects of MDMA has not been yet clarified.Methods: Locomotion, body temperature and anxiogenic-like responses were evaluated after acute MDMA administration in CB1 knockout mice. Additionally, MDMA rewarding properties were investigated in the place conditioning and the intravenous self-administration paradigms. Extracellular levels of DA in the nucleus accumbens were also analyzed after a single administration of MDMA by in vivo microdialysis. Results: Acute MDMA administration increased locomotor activity, body temperature and anxiogenic-like responses in wild type mice, but these responses were lower or abolished in knockout animals. MDMA produced similar conditioned place preference and increased dopamine extracellular levels in the nucleus accumbens in both genotypes. Nevertheless, CB1 knockout mice failed to self-administer MDMA at any of the doses used. Conclusions: These results indicate that CB1 cannabinoid receptors play an important role in the acute prototypical effects of MDMA, and are essential in the acquisition of an operant behavior to self-administer this drug.

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.

Demand for pharmaceutical drugs: A choice modelling experiment

Despite the importance of supplier inducement and brand loyalty inthe drug purchasing process, little empirical evidence is to be foundwith regard to the influence that these factors exert on patients decisions. Under the new scenario of easier access to information,patients are becoming more demanding and even go as far asquestioning their physicians prescription. Furthermore, newregulation also encourages patients to adopt an active role in thedecision between brand-name and generic drugs. Using a statedpreference model based on a choice survey, I have found evidenceof how significant physicians prescription and pharmacists recommendation become throughout the drug purchase process and,to what extent, brand loyalty influences the final decision. Asfar as we are aware, this paper is the first to explicitlytake consumers preferences into account rather than focusingon the behavior of health professionals.

Effects of recreational fishing on three fish species from the Posidonia oceanica meadows off Minorca (Balearic archipelago, western Mediterranean)

Experimental fishing and visual censuses were conducted at nine Posidonia oceanica sites off Minorca exposed to different levels of fishing intensity to assess the effects of recreational fishing on the species that dominate the catch. Total catch per unit effort (CPUE) was highly seasonal and a statistically significant interaction term existed between the season and the level of fishing intensity. CPUE decreased everywhere at the end of the fishing season (autumn), but such a reduction was more intense at those sites exposed to the highest level of fishing. Visual censuses confirmed that there was a lower abundance of vulnerable fish in autumn. Differences vanished in spring probably because fish reshuffled between the considered sites throughout the winter, when the level of fishing intensity was extremely low. Although the average total lengths of Serranus scriba and Diplodus annularis were unaffected by the level of fishing intensity, the average total length of Coris julis was smaller at the most heavily fished sites. In conclusion, recreational fishing has a relevant impact on most of the exploited species and some of the seasonality reported for the Posidonia oceanica fish assemblages might be caused by the seasonality of the fishery.

Quantification of human adenoviruses in European recreational waters

The presence of human adenoviruses in recreational water might cause disease in the population upon exposure. Human adenoviruses detected by PCR could also serve as indicators of the virological water quality. In order to assess the applicability of human adenoviruses to the evaluation of the faecal contamination in European bathing waters, a real-time quantitative PCR assay was developed for the quantification of human adenoviruses in 132 samples collected from 24 different recreational marine and freshwater sites in nine European countries.Selected samples presenting positive nested-PCR results for human adenoviruses were analyzed using quantitative PCR and 80 samples from a total of 132 produced quantitative results with mean values of 3.2x102 10 per 100 ml of water, human adenovirus 41 being the most prevalent serotype. Human adenoviruses were quantified in samples from all 15 surveillance laboratories. Statistical analysis showed no homogeneous linear relation between humanadenoviruses and E. coli, intestinal enterococci or somatic coliphages concentrations in the tested samples when considering all the data together. Significant correlations between human adenoviruses and at least one of the other indicators were observed only when data from individual Laboratories were considered. The quantification of human adenoviruses may provide complementary information in relation to the use of bacterial standards in the control of water quality in bathing water.

Quantification of human adenoviruses in European recreational waters

The presence of human adenoviruses in recreational water might cause disease in the population upon exposure. Human adenoviruses detected by PCR could also serve as indicators of the virological water quality. In order to assess the applicability of human adenoviruses to the evaluation of the faecal contamination in European bathing waters, a real-time quantitative PCR assay was developed for the quantification of human adenoviruses in 132 samples collected from 24 different recreational marine and freshwater sites in nine European countries.Selected samples presenting positive nested-PCR results for human adenoviruses were analyzed using quantitative PCR and 80 samples from a total of 132 produced quantitative results with mean values of 3.2x102 10 per 100 ml of water, human adenovirus 41 being the most prevalent serotype. Human adenoviruses were quantified in samples from all 15 surveillance laboratories. Statistical analysis showed no homogeneous linear relation between humanadenoviruses and E. coli, intestinal enterococci or somatic coliphages concentrations in the tested samples when considering all the data together. Significant correlations between human adenoviruses and at least one of the other indicators were observed only when data from individual Laboratories were considered. The quantification of human adenoviruses may provide complementary information in relation to the use of bacterial standards in the control of water quality in bathing water.

Surveillance of adenoviruses and noroviruses in European recreational waters

Exposure to human pathogenic viruses in recreational waters has been shown to cause disease outbreaks. In the context of Article 14 of the revised European Bathing Waters Directive 2006/7/EC (rBWD, CEU, 2006) a Europe-wide surveillance study was carried out to determine the frequency of occurrence of two human enteric viruses in recreational waters. Adenoviruses were selected based on their near-universal shedding and environmental survival, and noroviruses (NoV) selected as being the most prevalent gastroenteritis agent worldwide. Concentration of marine and freshwater samples was done by adsorption/elution followed by molecular detection by (RT)-PCR. Out of 1410 samples, 553 (39.2%) were positive for one or more of the target viruses. Adenoviruses, detected in 36.4% of samples, were more prevalent than noroviruses (9.4%), with 3.5% GI and 6.2% GII, some samples being positive for both GI and GII. Of 513 human adenovirus-positive samples, 63 (12.3%) were also norovirus-positive, whereas 69 (7.7%) norovirus-positive samples were adenovirus-negative. More freshwater samples than marine water samples were virus-positive. Out of a small selection of samples tested for adenovirus infectivity, approximately one-quarter were positive. Sixty percent of 132 nested-PCR adenovirus-positive samples analysed by quantitative PCR gave a mean value of over 3000 genome copies per L of water. The simultaneous detection of infectious adenovirus and of adenovirus and NoV by (RT)PCR suggests that the presence of infectious viruses in recreational waters may constitute a public health risk upon exposure. These studies support the case for considering adenoviruses as an indicator of bathing water quality.

Solid-phase synthesis and DNA binding studies of dichloroplatinum(II) conjugates of dicarba analogues of octreotide as a new anticancer drugs

The first dichloroplatinum(II) conjugates of dicarba analogues of octreotide , which is expected to act as a"tumour-targeting device", have been efficiently synthesized following a stepwise solid-phase approach; these compounds emulate the mechanism of cisplatin since they form a 1,2-intrastrand cross-link with two consecutive guanines of an oligonucleotide.

Neuronal nicotinic receptors as new targets foramphetamine-induced oxidative damage and neurotoxicity

Amphetamine derivatives such as methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are drugs widely abused in a recreational context. This has led to concern because of the evidence that they are neurotoxic in animal models and cognitive impairments have been described in heavy abusers. The main targets of these drugs are plasmalemmal and vesicular monoamine transporters, leading to reverse transport and increased monoamine efflux to the synapse. As far as neurotoxicity is concerned, increased reactive oxygen species (ROS) production seems to be one of the main causes. Recent research has demonstrated that blockade of 7 nicotinic acetylcholine receptors (nAChR) inhibits METH- and MDMA-induced ROS production in striatal synaptosomes which is dependent on calcium and on NO-synthase activation. Moreover, 7 nAChR antagonists (methyllycaconitine and memantine) attenuated in vivo the neurotoxicity induced by METH and MDMA, and memantine prevented the cognitive impairment induced by these drugs. Radioligand binding experiments demonstrated that both drugs have affinity to 7 and heteromeric nAChR, with MDMA showing lower Ki values, while fluorescence calcium experiments indicated that MDMA behaves as a partial agonist on 7 and as an antagonist on heteromeric nAChR. Sustained Ca increase led to calpain and caspase-3 activation. In addition, modulatory effects of MDMA on 7 and heteromeric nAChR populations have been found.

El consum de drogues i cocaïna dels joves de l’IES Miquel Martí i Pol de Roda de Ter

En l’actualitat, l’ús i el consum de substàncies il·legals pels joves de l’IES Miquel Martí i Pol de Roda de Ter és un fenomen associat a l’oci, per tant es tracta d’un consum recreatiu per fer referència al consum que fan els joves que el que busquen és diversió i plaer, moltes vegades, sense percebre’n el risc. Pel que fa a les drogues legals, alcohol i tabac són les substàncies psicoactives de major consum. La cocaïna és pels joves la segona substància consumida, rere el cànnabis, que és la més estesa entre la població adolescent i joves de l’IES. Es pot dir que existeixen una sèrie de situacions de caràcter personal i social que poden predisposar certes persones a consumir drogues. Aquestes circumstàncies són els anomenats factors de risc, com són l’autoestima, absència de normes i límits, manca d’informació, manca de comunicació, entre d’altres. També hi ha d’altres situacions socioculturals i característiques individuals que fan que se’n redueixi la possibilitat de consum, aquests serien els anomenats factors de protecció com són l’economia, tenir aficions, disposar d’adults de referència, etc. Conèixer i comprendre aquests factors és fonamental per poder realitzar un abordatge educatiu i preventiu basat en la reducció de riscos i en la responsabilitat i l’autonomia de les persones usuàries de drogues.

Aquaporin 3 (AQP3) participates in the cytotoxic response to nucleoside-derived drugs

Background: Nucleoside analogs used in the chemotherapy of solid tumors, such as the capecitabine catabolite50-deoxy-5-fluorouridine (50-DFUR) trigger a transcriptomic response that involves the aquaglyceroporin aquaporin 3 along with other p53-dependent genes. Here, we examined whether up-regulation of aquaporin 3 (AQP3) mRNA incancer cells treated with 50-DFUR represents a collateral transcriptomic effect of the drug, or conversely, AQP3participates in the activity of genotoxic agents. Methods: The role of AQP3 in cell volume increase, cytotoxicity and cell cycle arrest was analyzed using loss-of-function approaches. Results: 50-DFUR and gemcitabine, but not cisplatin, stimulated AQP3 expression and cell volume, which was partially and significantly blocked by knockdown of AQP3. Moreover, AQP3 siRNA significantly blocked other effects of nucleoside analogs, including G1/S cell cycle arrest, p21 and FAS up-regulation, and cell growth inhibition. Short incubations with 5-fluorouracil (5-FU) also induced AQP3 expression and increased cell volume, and the inhibition of AQP3 expression significantly blocked growth inhibition triggered by this drug. To further establish whether AQP3 induction is related to cell cycle arrest and apoptosis, cells were exposed to long incubations with escalating doses of 5-FU. AQP3 was highly up-regulated at doses associated with cell cycle arrest, whereas at doses promoting apoptosis induction of AQP3 mRNA expression was reduced. Conclusions: Based on the results, we propose that the aquaglyceroporin AQP3 is required for cytotoxic activity of 5’-DFUR and gemcitabine in the breast cancer cell line MCF7 and the colon adenocarcinoma cell line HT29, and is implicated in cell volume increase and cell cycle arrest.

Aquaporin 3 (AQP3) participates in the cytotoxic response to nucleoside-derived drugs

Background: Nucleoside analogs used in the chemotherapy of solid tumors, such as the capecitabine catabolite50-deoxy-5-fluorouridine (50-DFUR) trigger a transcriptomic response that involves the aquaglyceroporin aquaporin 3 along with other p53-dependent genes. Here, we examined whether up-regulation of aquaporin 3 (AQP3) mRNA incancer cells treated with 50-DFUR represents a collateral transcriptomic effect of the drug, or conversely, AQP3participates in the activity of genotoxic agents. Methods: The role of AQP3 in cell volume increase, cytotoxicity and cell cycle arrest was analyzed using loss-of-function approaches. Results: 50-DFUR and gemcitabine, but not cisplatin, stimulated AQP3 expression and cell volume, which was partially and significantly blocked by knockdown of AQP3. Moreover, AQP3 siRNA significantly blocked other effects of nucleoside analogs, including G1/S cell cycle arrest, p21 and FAS up-regulation, and cell growth inhibition. Short incubations with 5-fluorouracil (5-FU) also induced AQP3 expression and increased cell volume, and the inhibition of AQP3 expression significantly blocked growth inhibition triggered by this drug. To further establish whether AQP3 induction is related to cell cycle arrest and apoptosis, cells were exposed to long incubations with escalating doses of 5-FU. AQP3 was highly up-regulated at doses associated with cell cycle arrest, whereas at doses promoting apoptosis induction of AQP3 mRNA expression was reduced. Conclusions: Based on the results, we propose that the aquaglyceroporin AQP3 is required for cytotoxic activity of 5’-DFUR and gemcitabine in the breast cancer cell line MCF7 and the colon adenocarcinoma cell line HT29, and is implicated in cell volume increase and cell cycle arrest.