Desenvolupament d’un model d’avaluació continuada multidisciplinari i retroactiu de les matèries troncals del Departament de Farmacologia i Química Terapèutica

El nom de l'autor d'aquest document és el del coordinador/responsable del projecte, els noms dels integrants de l'equip docent que hi ha participat apareixen en els annexes del documents.2015PID‐UB/031És constatable que la major part de l’alumnat del grau de Farmàcia de la UB enfoca l’estudi de les assignatures d’una manera compartimentada i destinada a superar l’avaluació, sense considerar que molts dels coneixements els hauran d’aplicar en les matèries que cursin després. D’aquesta manera, o bé els obliden d’un curs a l’altre o bé mostren dificultats en aplicar-los a les noves matèries. Per això, el professorat del Departament de Farmacologia, Toxicologia i Química Terapèutica hem portat a terme un projecte (2015-2019) destinat a posar en pràctica una sèrie d’actuacions docents de forma coordinada, que comprenen des d’activitats docents (seminaris, casos...) a proves avaluadores entre primer i quart curs del grau, per consolidar els conceptes més transversals entre les assignatures que impartim (Química Orgànica i Farmacèutica, Farmacologies i Toxicologia) i conscienciar l’alumnat d’aquesta continuïtat i transversalitat, així com per ensenyar-li’ls a utilitzar-los en els nous entorns pels que passaran. Alhora, els resultats de les avaluacions permeten, de forma retroactiva, introduir canvis o adaptar les activitats docents dels cursos més inicials per corregir les mancances detectades. En general, després d’aquestes actuacions hem observat una certa millora en alguns coneixements, sobretot si es compara entre l’inici i el final d’un mateix curs.PMID/RIMDA Codi Projecte: 2015PID‐UB/031. Sense finançament

Efecto del MK-801 y otros ligandos PCP y Sigma sobre la neurotransmisión noradrenérgica periférica

[spa] EL MK-801 (dizocilpino), además de su conocido efecto como antagonista NMDA, es capaz de potenciar el efecto contráctil de la noradrenalina (NA), tanto exógena como neurogénica, en la porción epididimal del conducto deferente de rata. Se descarta la participación de receptores NMDA en este efecto, así como un favorecimiento de la liberación de NA, y todos los resultados apuntan a que se debe a una inhibición de la recaptación del neurotransmisor. Además del MK-801, otros ligandos PCP y Sigma ensayados potenciaron las contracciones por NA exógena, con un orden: fenciclidina (PCP) mayor que tenociclidina (TCP) mayor que MK-801 mayor que (+)-3-PPP mayor que dextrorfano (DX) mucho mayor que dextrometorfano (DM) y, en lo que respecta a estimulación eléctrica lo hicieron: (+)-3-PPP mayor que PCP mayor que MK-801 mayor que DM mayor que TCP mucho mayor que DX. No se descarta la participación de receptores Sigma en este ultimo efecto. Se confirma, asimismo, la interacción de todos los compuestos ensayados con el transportador de NA en el conducto deferente de rata, ya que inhibieron con CI50 de orden micromolar la union de un marcador especifico como la (3H)nixoxetina, cuyo perfil de unión a este tejido fue caracterizado previamente (KD=1.6 Microm., BMAX=1625 FMoles/mg). Todos ellos también inhibieron, CON CI50 Microm, la captación de (3H)NA en secciones de este órgano. Esta interacción, en el caso del MK-801, se traduce en un ligero incremento de la presión arterial en rata anestesiada con pentobarbital y en una potenciación del efecto presor de la NA como efecto periférico

Identificación de un transportador de adenosina a partir de estudios sobre el receptor benzodiacepínico periférico

Tesi de Llicenciatura per a la obtenció del Grau de Farmàcia. Facultat de Farmàcia. Universitat de Barcelona. Director: Jordi Camarasa García, Elena Escubedo Rafa. 1992

Heteromeric nicotinic receptors are involved in the sensitization and addictive properties of MDMA in mice

We have investigated the effect of nicotinic receptor ligands in the behavioral sensitization (hyperlocomotion) and rewarding properties (conditioned place preference paradigm, CPP) of 3,4-methylenedioxy-methamphetamine (MDMA) in mice. Each animal received intraperitoneal pretreatment with either saline, dihydro-β-erythroidine (DHβE, 1 mg/kg) or varenicline (VAR, 0.3 mg/kg), 15 min prior to subcutaneous saline or MDMA (5 mg/kg), for 10 consecutive days. On day 1, both DHβE and VAR inhibited the MDMA-induced hyperlocomotion. After 10 days of treatment, MDMA induced a hyperlocomotion that was not reduced (rather enhanced) in antagonist-pretreated animals. This early hyperlocomotion was accompanied by a significant increase in heteromeric nicotinic receptors in cortex that was not blocked by DHβE or VAR. Behavioral sensitization to MDMA was highest 2 weeks after the discontinuation of MDMA treatment. This additional increase in sensitivity was prevented in animals pretreated with DHβE or VAR. At this time, MDMA-treated mice showed a significant increase in heteromeric receptors in cortex that was prevented by DHβE and VAR. An involvement of α7 nicotinic receptors in this effect is ruled out. MDMA (10 mg/kg) induced positive CPP that was abolished by DHβE (2 mg/kg) and VAR (2 mg/kg). Moreover, chronic nicotine pretreatment (2 mg/kg, ip, b.i.d., for 14 days) caused MDMA, administered at a low dose (3 mg/kg), to induce CPP, which would otherwise not occur. Finally, present results point out that heteromeric nicotinic receptors are involved in locomotor sensitization and addictive potential induced by MDMA. Thus, varenicline might be a useful drug to treat both tobacco and MDMA abuse at once

3,4-Methylenedioxy-methamphetamine induces in vivo regional up-regulation of central nicotinic receptors in rats and potentiates the regulatory effects of nicotine on these receptors

Nicotine (NIC), the main psychostimulant compound of smoked tobacco, exerts its effects through activation of central nicotinic acetylcholine receptors (nAChR), which become up-regulated after chronic administration. Recent work has demonstrated that the recreational drug 3,4-methylenedioxymethamphetamine (MDMA) has affinity for nAChR and also induces up-regulation of nAChR in PC 12 cells. Tobacco and MDMA are often consumed together. In the present work we studied the in vivo effect of a classic chronic dosing schedule of MDMA in rats, alone or combined with a chronic schedule of NIC, on the density of nAChR and on serotonin reuptake transporters. MDMA induced significant decreases in [3H]paroxetine binding in the cortex and hippocampus measured 24 h after the last dose and these decreases were not modified by the association with NIC. In the prefrontal cortex, NIC and MDMA each induced significant increases in [3H]epibatidine binding (29.5 and 34.6%, respectively) with respect to saline-treated rats, and these increases were significantly potentiated (up to 72.1%) when the two drugs were associated. Also in this area, [3H]methyllycaconitine binding was increased a 42.1% with NIC + MDMA but not when they were given alone. In the hippocampus, MDMA potentiated the a7 regulatory effects of NIC (raising a 25.5% increase to 52.5%) but alone was devoid of effect. MDMA had no effect on heteromeric nAChR in striatum and a coronal section of the midbrain containing superior colliculi, geniculate nuclei, substantia nigra and ventral tegmental area. Specific immunoprecipitation of solubilised receptors suggests that the up-regulated heteromeric nAChRs contain a4 and b2 subunits. Western blots with specific a4 and a7 antibodies showed no significant differences between the groups, indicating that, as reported for nicotine, up-regulation caused by MDMA is due to post-translational events rather than increased receptor synthesis

Locomotor activating effects and addiction-like features of MDPV as assessed in preclinical studies: a review.

Introducción: La 3,4-Methylenedioxypyrovalerone (mdpv) es un componente de las denominadas sales de baño, aparecidas en el mercado a final de la década del 2000 debido a la falta de precursores de síntesis de mdma, y su uso va en aumento. El ob- jetivo de este trabajo es clarificar sus características farmacológicas y potencialidades adictivas. Método: Mediante búsquedas en PubMed, 21 estudios relacionados con la química, farmacología o potencial adictivo del mdpv fueron seleccionados. Resulta- dos: El mdpv muestra ser capaz de inducir una potente hiperlocomoción, preferencias condicionadas, sensibilización conductual, autoadministración y altos puntos de corte en pruebas de razón progresiva. Conclusión: Los estudios revisados apuntan a que el mdpv es un potente psicoestimulante con un potencial adictivo similar al de la cocaí- na o la metanfetamina. Su abuso continuado podría llevar a una epidemia de adictos al mdpv.Introduction: 3,4-Methylenedioxypyrovalerone (mdpv) is a major component of the new psychoactive substances termed “bath salts”. These substances appeared on the drug market at the end of the last century given the lack of mdma precursors, caused by its worldwide prosecution by governments and police agencies, and its growing use. The goal of this work was to clarify its pharmacological features and addiction-like potentiali- ties. Methods: By PubMed searches, 21 studies related to mdpv chemistry, pharmaco logy or addictive features were selected. Results: mdpv is seen to be able to induce potent hyperlocomotion, conditioned place preference, behavioural sensitisation, self- administration and high breakpoints in progressive ratio schedules. Conclusion: The reviewed studies indicate that mdpv is a powerful psychostimulant with a similar addictive potential to that of cocaine or methamphetamine. Its abuse can lead to an epidemic of mdpv addicts

Serotonin is involved in the psychostimulant and hypothermic effect of 4-methylamphetamine in rats.

4-Methylamphetamine (4-MA) has recently emerged as a designer drug of abuse in Europe and it is consumed always with amphetamine. There have been reported some deaths and non-fatal intoxications related to 4-MA. We investigated the changes in locomotor activity and body temperature after 4-MA administration to male Sprague-Dawley rats. Our experiments were carried out at a normal or high ambient temperature. 4-MA (2.5-10 mg/Kg, given subcutaneously) increased, in a dose-dependent manner, the horizontal locomotor activity that was significantly reduced by ketanserin, p-cholorophenylalanine (pCPA) or haloperidol, but not by pindolol. In addition, we have studied the effect of 4-MA on core body temperature by means of an implanted electronic thermograph, enabling continuous measurement of body temperature. We observed a dose-dependent hypothermic response to 4-MA that reached a maximum 45 min after a single injection. We also evidenced slight tachyphylaxis to the hypothermic effect when 4-MA was administered four times in a 2 h interval. The pre-treatment of animals with pCPA or pindolol, but not with ketanserin, fully abolished the hypothermic effect of 4-MA. With all that, we conclude that hypothermia induced by 4-MA is due to the release of 5-HT which activates postsynaptic 5-HT1A receptors

Effect of the combination of mephedrone plus ethanol on serotonin and dopamine release in the nucleus accumbens and medial prefrontal cortex of awake rats

Cathinones, such as mephedrone (Meph), are often co-abused with alcoholic drinks. In the present study, we investigated the combined effects of Meph plus ethanol (EtOH) on neurotransmitter release in the nucleus accumbens (NAc) and the medial prefrontal cortex (mPFC). A guide canula was stereotaxically implanted into either the NAc or the mPFC of male Sprague-Dawley rats. Seven days after surgery, a microdialysis probe was inserted and rats were administered saline, EtOH (1 g/kg, i.p.), Meph (25 mg/kg, s.c.), or their combination, and dialysates were collected. Serotonin (5-HT), dopamine (DA), and their metabolites (5-HIAA, DOPAC and HVA) were determined through high-pressure liquid chromatography coupled to mass spectrometry. 5-HT and DA peaked 40 min after Meph administration (with or without EtOH co-treatment) in both areas. EtOH combined with Meph increased the 5-HT release compared with the rats receiving Meph alone (85% in NAc, 65% in mPFC), although the overall change in the area under the curve only reached statistical significance in the NAc. In mPFC, the increased release of 5-HT lasted longer in the combination than that in the Meph group. Moreover, EtOH potentiated the psychostimulant effect of Meph measured as a locomotor activity. Given that both 5-HT and DA are also related with reward and impulsivity, the observed effects point to an increased risk of abuse liability when combining Meph with EtOH compared with consuming these drugs alone

Dose and time-dependent selective neurotoxicity induced by mephedrone in mice.

Mephedrone is a drug of abuse marketed as 'bath salts'. There are discrepancies concerning its long-term effects. We have investigated the neurotoxicity of mephedrone in mice following different exposition schedules. Schedule 1: four doses of 50 mg/kg. Schedule 2: four doses of 25 mg/kg. Schedule 3: three daily doses of 25 mg/kg, for two consecutive days. All schedules induced, in some animals, an aggressive behavior and hyperthermia as well as a decrease in weight gain. Mephedrone (schedule 1) induced dopaminergic and serotoninergic neurotoxicity that persisted 7 days after exposition. At a lower dose (schedule 2) only a transient dopaminergic injury was found. In the weekend consumption pattern (schedule 3), mephedrone induced dopamine and serotonin transporter loss that was accompanied by a decrease in tyrosine hydroxylase and tryptophan hydroxylase 2 expression one week after exposition. Also, mephedrone induced a depressive-like behavior, as well as a reduction in striatal D2 density, suggesting higher susceptibility to addictive drugs. In cultured cortical neurons, mephedrone induced a concentration-dependent cytotoxic effect. Using repeated doses for 2 days in an elevated ambient temperature we evidenced a loss of frontal cortex dopaminergic and hippocampal serotoninergic neuronal markers that suggest injuries at nerve endings

Enantioselective synthesis of the ethyl analog of the marine alkaloid haliclorensin C

The enantioselective synthesis (3.7% overall yield in nine steps from 2) and biological screening of the ethyl analog of the macrocyclic marine alkaloid haliclorensin C (compound 5) are reported. Amino alcohol 3, generated by a LiNH2BH3-promoted reductive ring-opening/debenzylation sequence from phenylglycinol-derived lactam 2, was used as the starting chiral linear building block. Incorporation of the undecene chain via the nosyl derivative 12, methylenation of the pentanol moiety, and a ring-closing metathesis are the key steps of the synthesis