Abstracts of Minisymposium organized by Prof. M. Gothert

Forty years of Polish-German cooperation: Landmarks in thedevelopment of partnership

Władysław Lason

Institute of Pharmacology, Polish Academy of Sciences, Smetna 12,

31-343 Krakow, Poland

The friendly and fruitful cooperation between German andPolish pharmacologists was initiated at the Congress of PolishPharmacological Society in Lodz in 1973 by Prof. Ulrich Trendelen-burg and Prof. Jerzy Maj, ex-soldiers who served in enemy armiesduring the second world war. Having the traumatic experiencethey strongly believed that making new human relationships isnecessary and possible and that joint activities even in a relativelynarrow field of science, like pharmacology can contribute to thisprocess. This idea was supported by Prof. Eric Westermann whoinvited young Polish pharmacologists to participate in theCongress of the German Pharmacological Society (DPhG) inHanover three years later. Since then researchers representingboth nations regularly and actively have taken part in scientificevents organized across the communist ‘‘iron curtain’’. Thus, Polishresearchers participated in the Congresses of DPhG in Munich,Travem?de, Freiburg, Akwizgran, Mannheim, Hamburg and Koln.On the other hand, many German pharmacologists were activeparticipants of eighteen Congresses organized by the PolishPharmacological Society, e.g. in Szczecin, Katowice, Poznan,Warsaw, Lublin, Bialystok, Gdansk, Białystok, Krakow and others.The Polish Pharmacological Society bestowed the title of aHonorary Member on professor Ulrich Trendelenburg in 1980and professor Manfred Gothert in 1998 for their great achieve-ments in pharmacology and their efforts in promoting this sciencein Poland. It should be emphasized that during the difficult periodunder communist rule, the enormous help of German pharmacol-ogists to Polish scientists in terms of providing the newestinformation, pharmacological tools and expertise as well as infounding fellowships for Polish scientists cannot be overestimated.Several hundred good quality joint scientific reports werepublished and a number of scientists’ exchange programs weresuccessfully realized. The most comprehensive long-term collabo-rative scientific projects of Polish pharmacologists have beencarried out jointly with their colleagues from the Max-PlanckInstitute of Psychiatry, Max-Planck Institute of ExperimentalMedicine, University of Heidelberg, University in Hamburg, FreeUniversity in Berlin, Otto von Guericke University in Magdeburg,University of Ulm, University in Bonn and many others. In theunited Europe and in the post-genomic era marked by a rapid

implementation of modern molecular tools into pharmacologicalstudies, there have emerged new challenges for Polish and Germanscientists who wish to cooperate with each other. In relation tothis, one should mention an important initiative which took placein 2006 in Warsaw where professor Ernst-Ludwig Winnacker, theformer President of Deutsche Forschung Gemainschaft (DFG)inaugurated the first Liaison Scientists Network on the occasion ofthe conference on bilateral cooperation in the European ResearchArea. The aim of this network is to support the existing cooperationbetween Polish and German scientists, including pharmacologists.Importantly, since 2005 it has been possible for German and Polishpharmacologists to apply to the DFG and to the Polish Ministry ofScience and Higher Education for funding for joint researchprojects.

http://dx.doi.org/10.1016/j.pharep.2014.02.006

Deciphering the functions of the endocannabinoid systemusing knockout mouse models

Onder Albayram, Andras Bilkei-Gorzo, Benjamin Gennequin,Ramona Gohrs, Imke Jenniches, Isabelle Lehmann, Kerstin Michel,David-Marian Otte, Ildico Racz, Anne Schmole, Hanna Schrage,Svenja Ternes, Alexandra Wojtalla, Andreas Zimmer

Institute of Molecular Psychiatry, University of Bonn, Sigmund-

Freud-Str. 25, 53127 Bonn, Germany

Genetic mouse models together with pharmacological tools areinstrumental for functional studies in biomedical research.Powerful methods for the manipulation of the mouse genomewere first developed in the late 80s and have been constantlyrefined during the past two decades. The development of theCRISPR/Cas technology has now pushed the efficacy of genomeengineering and its applicability to different species to a new level,thus enabling researchers to produce sophisticated genomicalterations with a relatively small investment in time and effort.CB1 receptor agonists and antagonists have an importanttherapeutic potential for the treatment of different chronicdisorders, such as pain conditions or the metabolic syndrome.However, reported adverse CNS side effects have limited theclinical utility of these compounds. This presentation will providean overview of mouse models that were used to investigate thenumerous physiological roles of the endocannabinoid system,which is instrumental for the development of new drugs withfewer side effects. A particular focus will be on age-related

Pharmacological Reports 66 (2014) 330–333

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cognitive functions, affective and hedonic behaviours. Thus, micelacking the neuronal cannabinoid CB1 receptor show a strikingacceleration of the age-related cognitive decline, accompaniedby an enhanced neuronal loss and increased neuroinflammation.A similar phenotype was also observed in mice lacking CB1specifically on GABAergic neurons. The role of endogenouscannabinoids in age-related changes will also be addressed usingknockout mouse models with deletions in endocannabinoidsynthesizing and degrading enzymes.

http://dx.doi.org/10.1016/j.pharep.2014.02.007

Cannabinoid modification of cocaine action

Małgorzata Filip 1,2, Przemysław Adamczyk 1, Beata Bystrowska 2,Irena Smaga 2, Edmund Przegalinski 1

1 Laboratory of Drug Addiction Pharmacology, Institute of

Pharmacology, Polish Academy of Sciences, Smetna 12,

PL 31-343 Krakow, Poland2 Department of Toxicology, Faculty of Pharmacy, Jagiellonian Univer-

sity, College of Medicine, Medyczna 9, PL 30-688 Krakow, Poland

The endocannabinoid (eCB) system includes endogenous lipidmolecules, such as anandamide and 2-arachidonoylglycerol (2-AG), the type 1 and type 2 cannabinoid (CB) receptors and severalspecific membrane-bound biosynthetic and degradative enzymes.This system is involved in a host of homeostatic and physiologicfunctions including synaptic transmission, neuronal firing andneurotransmitter release [Di Marzo, Proc Natl Acad Sci USA, 2011].It also mediates goal-maintained behaviors and pathologiesaffecting these processes. More recent evidence suggests thatthe CB transmission may control drug addiction, however, theliterature regarding CB effects on the actions of drugs of abuseremains contradictory [Filip et al., Pharmacol Rep, 2006; Oliere etal., Front Psychiatry, 2013; Panlilio et al., Pharmacol Ther, 2013].

We addressed the role of the CB receptors in the expression ofcocaine-induced rewarding and seeking behaviors in intravenousself-administration and a drug-free extinction training proceduresin rats. With using selective pharmacological tools at CB1 (AM 251,an antagonist) and CB2 (SR144528, an antagonist) receptor sites,we found that constitutive activation of CB receptors does notmaintain cocaine reinforcement. We also show inhibitory effects ofCB1 and CB2 receptor antagonists on drug-primed cocaine-seekingbehavior. In contrast to CB1 receptors, CB2 receptors do not affectcue-induced reinstatement of cocaine-seeking behavior. Neuroa-daptive changes in the eCB system following repeated i.v. cocaineand its withdrawal were determined ex vivo in autoradiographic(CB1 receptor binding measurements with [3H]CP 55,940) andneurochemical (the tissue eCB concentrations analyzed via an LC–MS/MS method) studies. With using the same experimentalprotocols as in behavioral pharmacological studies and a ‘‘yoked’’procedure to separate pharmacological vs. motivational effects ofcocaine, we demonstrated selective CB1 receptor control overmotivational and cognitive processes. In some rat brain regions wefound alterations in levels of anandamide and 2-AG that weremaintained over a long-lasting extinction period. Our findingssupport the evidence that the eCB system is involved inreinforcement and extinction of reinforced behaviors and thatthe lipid-derived molecules may represent promising targets forthe development of new treatments for cocaine addiction.Acknowledgements: These studies were supported by thestatutory activity of the Laboratory of Drug Addiction Pharmacol-ogy (Krakow) and of the Department of Toxicology (Krakow).

http://dx.doi.org/10.1016/j.pharep.2014.02.008

Cannabinoids and adolescent behaviour

Rainer Spanagel, Miriam Schneider

Institute of Psychopharmacology, Central Institute of Mental Health,

University of Heidelberg, Medical Faculty Mannheim, Germany

Adolescence, the transitional stage between childhood andadulthood, is characterized by drastic processes of neuronal andbehavioural adjustment. These developmental alterations areessential across species to allow the transition from an immatureindividual toward an independent adult, capable of reproduction.At the same time, adolescent neurodevelopment also comprises acritical period of vulnerability for unintentional self-harm,suboptimal choices and behaviours, and the emergence ofneuropsychiatric disorders. Detailed mechanisms of adolescentbrain development and concomitant behavioural changes are stilllargely unknown. Adolescent behavioural characteristics can beobserved in various mammalian species during development (e.g.humans, non-human primates, rodents, elephants). Among thesebehavioral features, enhanced reward processing may representone of the key features triggering other behaviors, such as riskychoices, impulsivity and the vulnerability toward drug use/abuse.It is well known that reward processing and the sensitivitytowards drug and natural rewards are subjected to considerablechanges throughout lifetime and we have recently shown thatreward sensitivity peaks during mid-adolescence [Friemel et al.,Front Behav Neurosci, 2010]. This peak in reward sensitivity isclosely linked to pronounced neuronal processing of reward-related stimuli in the dorsal striatum. Enhanced signalling ofendogenous opioids and/or endocannbinoids (ECB) might beinvolved in augmented reward sensitivity during mid-adoles-cence. However, our and other results show the involvement ofthe endogenous opioid system in the mediation of hedonicproperties rather than motivational aspects of reward processing[Schneider et al., Behav Brain Res, 2010]. Furthermore, enhancedECB signalling has been reported to occur as a transient stateduring adolescent brain development. Hence, cannabinoidreceptor 1 (CB1) matures slowly during postnatal development,with peak levels of receptor binding, protein levels and levels ofthe endogenous ligand N-arachidonoylethanolamide (AEA) beingreached around early/mid-adolescence. Since the ECB systemrepresents a crucial mediator of various processes of neuroplas-ticity, the transient boost in ECB signaling which appears to occurduring adolescence, may provide increased plasticity andbehavioral flexibility required specifically during this develop-mental stage. We therefore hypothesized that enhanced ECBsignalling is critical involved in the peak of reward sensitivityduring adolescence. By the use of a novel rat model with enhancedECB signalling we demonstrate that this is indeed the case. Adultrats with enhanced ECB signalling are much more sensitive tonatural and drug rewards. For example, these mutant rats showincreased development and expression of cocaine sensitizationand acute stimulatory effects of cocaine were also much morepronounced in mutant than wild-type rats. We further show thatother behavioural features of adolescent behaviour are alsomediated by enhanced ECB signalling. In conclusion, the adoles-cent state comprises a complex behavioural phenotype that bearsmany vulnerability factors for psychiatric disorders. Increasedreward processing during adolescence appears to represent a keyfeature in mediating this heightened susceptibility and enhancedECB signalling seem to be critical for initiating and mediatingaugmented reward processing and other behavioural features ofadolescence.

http://dx.doi.org/10.1016/j.pharep.2014.02.009

Abstracts of Minisymposium organized by Prof. M. Gothert / Pharmacological Reports 66 (2014) 330–333 331