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Monoaminooksidaza (MAO) razgrađuje biogene amine, uključujući neurotransmitore dopamin, histamin, serotonin i noradrenalin. Uloga ovog enzima u regulaciji raspoloženja, emocija i ponašanja upućuje na uključenost u patofiziologiju raznih neuropsihijatrijskih poremećaja. Kako trombociti i neuroni dijele brojne biokemijske procese, aktivnost trombocitne MAO-B može poslužiti kao periferni pokazatelj određenih promjena ponašanja i osobnosti. Posttraumatski stresni poremećaj (PTSP) je kompleksan psihijatrijski poremećaj koji nastaje nakon izlaganja traumatskom iskustvu, sa nepotpuno jasnom neurobiološkom podlogom. Istraživanja upućuju da su u razvoj i težinu simptoma PTSP-a uključene promjene neurotransmitorskih sustava, za koje su djelomično odgovorne i varijacije određenih gena, ali i okolišni čimbenici poput traume u djetinjstvu. Stoga je cilj istraživanja bio istražiti povezanost polimorfizama gena MAOB, aktivnosti trombocitne MAO-B, te traume u djetinjstvu, s razvojem i težinom simptoma PTSP-a u hrvatskih ispitanika. Značajne razlike u aktivnosti trombocitne MAO-B pronađene su između kontrolnih ispitanika i ratnih veterana s PTSP-om, te između bolesnika sa srednjim i teškim PTSP-om. Također je utvrđena povezanost gena MAOB s razvojem PTSP-a, kao i traumatskih događaja u djetinjstvu s težinom simptoma PTSP-a, te značajna interakcija polimorfizma rs1799836 gena MAOB i fizičkog zanemarivanja u djetinjstvu. Međutim, u svrhu razjašnjavanja uloge genetskih i okolišnih čimbenika, te njihovih kompleksnih interakcija u PTSP-u, potrebna su daljnja istraživanja. Monoamine oxidase (MAO) degrades biogenic amines, including neurotransmitters dopamine, histamine, serotonin and noradrenaline. The role of this enzyme in the regulation of mood, emotions and behavior suggest its involvement in the pathophysiology of various neuropsychiatric disorders. As platelets and neurons share numerous biochemical processes, platelet MAO-B activity might serve as peripheral marker of certain behavioral and personality changes. Post-traumatic stress disorder (PTSD) is complex psychiatric disorder developing after traumatic experience, with unclear neurobiological background. Research suggests that development and severity of PTSD symptoms include changes in neurotransmitter systems, partly due to certain gene variations, but also environmental factors such as childhood trauma. The study investigated associations of MAOB gene polymorphisms, platelet MAO-B activity, and childhood trauma, with development and severity of PTSD symptoms in Croatian subjects. Differences in platelet MAO-B activity were found between subjects with and without PTSD, and between patients with moderate and severe PTSD. Results demonstrated association between MAOB gene and development of PTSD, between childhood trauma and severity of PTSD symptoms; as well as significant interaction of rs1799836 MAOB gene polymorphism and physical neglect in childhood. However, further research is necessary to clarify the role of genetic and environmental factors and their complex interactions in PTSD.

Katehol-O-metiltransferaza (COMT) je enzim odgovoran za metabolizam različitih kateholamina, poput neurotransmitora dopamina. Kodiran je genom COMT koji sadrži brojne polimorfizme, a neki od njih utječu na ekspresiju i aktivnost enzima te tako moduliraju koncentraciju kateholaminskih neurotransmitora u sinapsi. Brojne studije upućuju na ulogu dopaminske neurotransmisije u patogenezi depresije i shizofrenije. Depresivni simptomi, iako rijetko istraživani i nejasne biološke podloge, vrlo su učestali u shizofreniji, a povezuju se sa slabijim terapijskim ishodom i nižom kvalitetom života, većom komorbidnošću, lošim radnim i psihosocijalnim funkcioniranjem te povećanim rizikom relapsa i suicida. Pojedina istraživanja sugerirala su povezanost COMT genskih polimorfizama i pojedinih simptoma shizofrenije, međutim određene studije nisu potvrdile ove rezultate. Stoga je cilj ovog istraživanja utvrditi postoji li povezanost polimorfizama rs4680 i rs4818 gena COMT sa depresivnim simptomima u bolesnika sa shizofrenijom. Nakon provedene genotipizacije uzoraka s obzirom na COMT polimorfizme rs4680 i rs4818 i procjene shizofrenih ispitanika prema PANSS-D i CDSS ljestvici, u ispitanika sa shizofrenijom pronađena je povezanost depresivnog simptoma Rano buđenje sa genotipom AA rs4680 polimorfizma te depresivnog simptoma Osjećaj krivnje sa genotipom CG rs4818 polimorfizma. Haplotipska analiza utvrdila je neravnotežu udruživanja rs4680 i rs4818 polimorfizama, što upućuje da se nasljeđuju zajedno u bloku. Haplotip CG značajno se češće pojavljuje u shizofrenih, nego u kontrolnih ispitanika. Catechol-O-methyltransferase (COMT) is an enzyme responsible for the metabolism of various catecholamines, such as neurotransmitter dopamine. It is encoded by the COMT gene, that contains numerous polymorphisms, some of which affect expression and activity of the enzyme, thereby modulating the concentration of catecholamine neurotransmitters in the synapse. Numerous studies have suggested the role of dopamine neurotransmission in the pathogenesis of depression and schizophrenia. Depressive symptoms, although rarely explored and with undetermined biological background, are very common in schizophrenia and are associated with poorer therapeutic outcomes and lower quality of life, higher comorbidity, poor work and psychosocial functioning, and an increased risk of relapse and suicide. Due to the lack of data in previous studies, the aim of this study was to determine whether there is an association between rs4680 and rs4818 COMT polymorphisms and depressive symptoms in patients with schizophrenia. Genotyping of researched polymorphisms and the PANSS-D and CDSS scales were used to assess depressive symptoms in patients with schizophrenia. Results demonstrated that the depressive symptom Early awakening was associated with rs4680 AA genotype, whereas depressive symptom Feeling of guilt was associated with rs4818 genotype CG in subjects with schizophrenia. The haplotype analysis revealed that rs4680 and rs4818 polymorphisms are in linkage disequilibrium and therefore probaby inherited in the haploblock. The CG haplotype was significantly more frequent in schizophrenia patients than in control subjects.

Depresija je jedan od najučestalijih psihijatrijskih poremećaja današnjice, a obilježavaju ga sniženo raspoloženje, gubitak interesa i zadovoljstva, osjećaj krivnje i manje vrijednosti, poremećaji apetita i sna, smanjena koncentracija, nedostatak životne energije te povećani suicidalni rizik. Pojavnost ove ozbiljne bolesti vrlo je složena i uključuje brojne rizične gene i okolišne čimbenike, a njezin nastanak pokušavaju objasniti razne teorije. Prema monoaminskoj hipotezi, na kojoj se zasniva aktualna farmakološka terapija, u podlozi depresije nalazi se poremećaj monoaminskih (serotonin, dopamin, noradrenalin) neurotransmitorskih sustava u mozgu. Katehol-O-metiltransferaza (COMT) je enzim koji razgrađuje kateholamine, uključujući neurotransmitore dopamin i noradrenalin, koji igraju važnu ulogu u nastanku depresivnih simptoma. Enzim je kodiran genom COMT koji se kod ljudi nalazi na 22. kromosomu, a sadrži veliki broj polimorfizama koji mogu imati utjecaj na neurotransmisiju i time pridonijeti razvoju depresije. Iako su raznovrsne studije istraživale varijante gena COMT vezano uz neurofiziološke, bihevioralne i kliničke fenotipove depresije, kao i uz odgovor na terapiju antidepresivnim lijekovima, rezultati iz literature često su oprečni. Kako uloga varijanti gena COMT u razvoju depresije nije jasna, cilj istraživanja bio je utvrditi postoji li u osoba oboljelih od depresije povezanost varijanti rs4680 i rs4818 gena COMT s težinom depresivnih simptoma. Rezultati ovog istraživanja pokazali su da nema statistički značajne povezanosti dviju varijanti gena COMT sa simptomima depresije, osim rs4680 varijante s hipohondrijskim simptomima HAMD ljestvice. Depression is one of the most common psychiatric disorders nowadays characterized by reduced mood, loss of interest and satisfaction, guilt and low self-value, appetite and sleep disorders, reduced concentration, lack of life energy and increased suicid risk. The occurence of this serious disease is very complex and it involves many risk genes and environmental factors so various theories try to explain its origin. According to the monoamine hypothesis, on which current pharmacological therapy is based, depression is characterized by the disruption of monoamine (serotonin, dopamine, noradrenaline) neurotransmitter systems of the brain. Catechol-O-methyltransferase (COMT) is an enzyme that degrades catecholamines, including neurotransmitter dopamine and noradrenaline, which play an important role in the occurrence of depression symptoms. The enzyme is encoded by the gene COMT, which is located on the 22nd chromosome in humans and it contains a large number of polymorphisms that may have an effect on neurotransmission and thus contribute to the development of depression. Although various studies have investigated COMT gene variants associated with neurophysiological, behavioral and clinical phenotypes of depression, as well as responding to antidepressant therapy, the literature results are often contradictory. As the role of the COMT gene in the development of depression is not clear, the aim of the study was to determine whether there is any association between the rs4680 and rs4818 COMT genetic polymorphisms with the severity of depression symptoms in depressed patients. The results of this study showed that there was no statistically significant association of the two COMT gene variants with severity of depression symptoms, except rs4680 with hypochondriacal symptoms of HAMD scale.

Složena etiologija i biološka podloga shizofrenije te skromne spoznaje o utjecaju infekcija na razvoj ove bolesti, potaknule su ovo istraživanje neuroimunomodulatornog učinka parazita Toxoplasma gondii (TG) u shizofreniji. Rezultati upućuju da TG seropozitivni bolesnici imaju težu kliničku sliku bolesti, karakteriziranu većim brojem bolničkih liječenja, dužim psihijatrijskim tretmanom i češćom refrakternošću na terapiju. Međutim, TG seropozitivni bolesnici, usprkos starije dobi i češćeg uzimanja atipičnih antipsihotika, imaju nižu koncentraciju triglicerida, omjer triglicerida i lipoproteina visoke gustoće (HDL), opseg bokova i tjelesnu težinu, te posljedično i manji rizik razvoja kardiovaskularnih bolesti. U našem istraživanju nisu utvrđene statistički značajne razlike u koncentraciji trombocitnog serotonina i aktivnosti trombocitne monoaminooksidaze tipa B (MAO-B), kao niti u koncentraciji C reaktivnog proteina (CRP-a) i interleukina 6 (IL-6) između TG seropozitivnih i TG seronegativnih ispitanika sa shizofrenijom. Stoga su potrebna daljna istraživanja koja će dodatno razjasniti povezanost infekcije sa TG i razvoja shizofrenije. Complex etiology and biological basis of schizophrenia, and modest knowledge regarding effects of infections on its development, stimulated this study of Toxoplasma gondii (TG) neuroimmunomodulatory effect in schizophrenia. Results suggest that TG seropositive patients have more severe clinical presentation, with higher number of hospitalisations, longer psychiatric treatment and more frequent treatment-resistance. However, TG seropositive patients, despite older age and more frequent usage of atypical antipsychotics, had lower triglyceride concentration, triglyceride/high-density lipoprotein cholesterol (HDL-C) ratio, hip circumference and body weight, suggesting lower risk for cardiovascular disease. No differences in concentrations of platelet serotonin levels and higher platelet monoamino oxidase type B (MAO-B) activity, as well as of C-reactive protein (CRP) and interleukin-6 (IL-6) levels between TG seropositive and TG seronegative subjects with schizophrenia were found. Further research is needed to further clarify the association between TG infection and development of schizophrenia.

Post-traumatski stresni poremećaj (PTSP) je kompleksan psihijatrijski poremećaj koji se javlja nakon traumatskog iskustva. Poremećaji spavanja, poput noćnih mora i nesanice, jedno su od glavnih obilježja PTSP-a. Iako neurobiološka podloga PTSP-a nije potpuno jasna, ona uključuje kompleksne interakcije genetskih i okolišnih čimbenika. Serotoninski sustav radi svoje uloge u nadzoru raspoloženja, pobudljivosti i spavanja, važan je za razvoj simptoma PTSP-a. Cilj istraživanja bio je utvrditi moguću povezanost polimorfizma u genu za serotoninski prijenosnik i koncentracije trombocitnog serotonina s poremećajima spavanja u 393 hrvatskih ratnih veterana s PTSP-om. Genotipovi polimorfizma 5-HTTLPR bili su slično raspoređeni u veterana s PTSP-om i u kontrolnim ispitanicima. Raspodjela genotipova polimorfizma 5-HTTLPR bila je također slična u veterana s PTSP-om sa ili bez komorbidne depresije, dok je koncentracija trombocitnog serotonina bila niža u veterana s PTSP-om i komorbidnom depresijom u usporedbi s onima bez komorbidne depresije. Veća koncentracija trombocitnog serotonina i veća učestalost LL genotipa polimorfizma 5-HTTLPR u usporedbi s nositeljima S alela utvrđena je u veterana s PTSP-om sa simptomima rane nesanice u usporedbi s veteranima bez rane nesanice. S druge strane, različiti poremećaji spavanja nisu bili značajno povezani s genotipovima polimorfizma 5-HTTLPR ili s promijenjenom koncentracijom trombocitnog serotonina u veterana s PTSP-om i komorbidnom depresijom. Post-Traumatic Stress Disorder (PTSD) is a complex psychiatric disorder that develops after traumatic experience(s). Sleep disorders, including nightmares and insomnia, are one of the main features of PTSD. Although the neurobiological basis of PTSD is unclear, it involves complex interactions of genetic and environmental factors. Due to its role in controlling mood, arousal, and sleep, serotonin system is important for development of PTSD symptoms. The aim of the study was to determine the possible association of serotonin transporter gene polymorphism and platelet serotonin concentration with sleep disorders in 393 Croatian war veterans with PTSD. 5-HTTLPR polymorphism genotypes were similarly distibuted in veterans with PTSD and control subjects. The distribution of 5-HTTLPR polymorphism genotypes was similar in veterans with PTSD with and without comorbid depression, while platelet serotonin concentrations were lower in veterans with PTSD and comorbid depression in comparison to veterans without comorbid depression. Higher platelet serotonin concentration and higher incidence of LL 5-HTTLPR polymorphism genotypes compared to S alleles was found in veterans with PTSD with symptoms of early insomnia compared to veterans without early insomnia. In veterans with PTSD and comorbid depression various sleep disorders were not associated with 5-HTTLPR polymorphism genotypes or with altered platelet serotonin concentration.

Demencija predstavlja sindrom globalnog i progresivnog oštećenja stečenih kognitivnih sposobnosti pri očuvanoj svijesti, s posebno zahvaćenim funkcijama pamćenja, učenja, apstraktnog mišljenja, orijentacije i poimanja vidno-prostornih odnosa. Progresivne se demencije za sada ne mogu potpuno izliječiti niti značajnije zaustaviti pa, s obzirom na ubrzano starenje stanovništva i produljenje životnog vijeka, u skorijoj budućnosti predstavljaju jedan od vodećih medicinskih, društvenih i ekonomskih globalnih problema. Sve više istraživanja upućuje na moguću ulogu serotoninskog sustava u različitim kognitivnim funkcijama poput učenja i pamćenja i to posebice receptora 5-HT6. Utvrđena je i povezanost pojedinih polimorfizama u genu za receptor 5-HT6 s Alzheimerovom bolesti, iako su rezultati istraživanja oprečni. Cilj ovoga istraživanja bio je utvrditi moguću povezanost polimorfizma C267T (rs1805054) u genu za serotoninski receptor 5-HT6 (HTR6) s razvojem progresivnih demencija. Rezultati našeg istraživanja nisu uputili na povezanost polimorfizma rs1805054 gena HTR6, s razvojem demencije u bolesnika s blagim kognitivnim poremećajem, Alzheimerovom bolesti i ostalim oblicima demencija poput vaskularne demencije, frontotemporalne demencije i demencije s Lewyjevim tjelešcima. U svrhu razjašnjavanja uloge serotoninskog receptora 5-HT6 i gena HTR6 u razvoju demencije, potrebna su daljnja opširnija istraživanja koje će uključiti različite populacije, različite tipove demencija i veći broj ispitanika. Dementia is a syndrome of global and progressive deterioration of acquired cognitive skills with preserved consciousness, where memory, learning, abstract thinking, orientation and understanding of visual-spatial relationships are particularly affected. As the progressive dementias for now cannot be healed or significantly halted, given the aging population and increasing life expectance, in the near future dementia will become one of the leading medical, social and economic global problems. Increasing number of studies suggest the potential role of the serotonergic system, particularly 5-HT6 receptors, in various cognitive functions such as learning and memory. The associations of individual polymorphisms in the gene coding for 5-HT6 receptor with Alzheimer's disease have been found, although the results are controversial. The aim of this study was to determine the possible association of polymorphism C267T (rs1805054) in the HTR6 gene, coding for the serotonin 5-HT6 receptor, with the development of progressive dementia. The results of our study have not suggested the association of rs1805054 polymorphism in the HTR6 gene with the development of dementia in patients with mild cognitive impairment, Alzheimer's disease and other types of dementia such as vascular dementia, frontotemporal dementia and dementia with Lewy bodies. Further extensive studies including different populations, different types of dementia and higher number of participants are needed in order to elucidate the role of serotonin 5-HT6 receptor and HTR6 gene in the pathogenesis of dementia.

Dehidroepiandrosteron-sulfat (DHEAS) je neurosteroid uključen u važne funkcije mozga poput neuralne plastičnosti, učenja, pamćenja i ponašanja, te pokazuje potencijal u liječenju različitih neuropsihijatrijskih poremećaja, uključujući i ishemijski moždani udar. Učinci DHEAS-a u središnjem živčanom sustavu posredovani su putem GABA i glutamatnog neurotransmitorskog sustava, ali i drugih. Cilj rada bio je ispitati učinke primjene DHEAS-a na rekombinantne GABAA receptore, usporedbom djelovanja ovog neurosteorida na embrionalne stanice bubrega čovjeka (HEK 293), netransficirane i stabilno transficirane GABAA receptorima 122S, te istražiti njegovo potencijalno neuroprotektivno djelovanje u modelu deprivacije kisika i glukoze, te reperfuzije in vitro (OGDR). Istraživanje je pokazalo da se DHEAS ponaša kao alosterički antagonist rekombinantnih GABAA receptora, ali da njegova produljena primjena ne utječe na broj, afinitet, kao ni na funkcionalnu povezanost receptorskih veznih mjesta. Rezultati su također pokazali da DHEAS, primijenjen i prije i nakon OGDR djeluje protektivno na stanice HEK 293, te da se citoprotektivan učinak ovog neurosteroida barem dijelom ostvaruje putem GABAA receptora. Dehydroepiandrosterone sulfate (DHEAS) is a neurosteroid involved in various important brain functions such as neural plasticity, learning, memory and behavior, demonstrating the potential to treat a variety of neuropsychiatric disorders, including ischemic stroke. Effects of DHEAS in the central nervous system are mediated through GABAergic, glutamatergic and other neurotransmitter systems. The aim of this study was to investigate the effects of DHEAS on recombinant GABAA receptors by comparing the effects of this neurosteorid on human embryonic kidney (HEK) 293 cells, stably transfected and untransfected with 122S GABAA receptors, and to explore the potential neuroprotective effect of this neurosteroid using in vitro model of oxygen and glucose deprivation and reperfusion (OGDR). The study has shown that DHEAS acts as an allosteric antagonist of recombinant GABAA receptors, but that its prolonged administration does not affect the number, affinity, or the functional coupling of receptor binding sites. The results also suggested that DHEAS, applied both before and after OGDR has protective effect on HEK 293 cells, and that cytoprotective effect of this neurosteroid is at least partly achieved via GABAA receptors.

Shizofrenija predstavlja ozbiljan kronični psihijatrijski poremećaj čija je neurobiološka podloga još uvijek nedovoljno poznata. Bolest se liječi tzv. tipičnim i atipičnim antipsihoticima, no kod dijela bolesnika javljaju se negativni popratni učinci koji značajno otežavaju liječenje dovodeći do prekida terapije i učestalog povratka bolesti. Najpoznatiji popratni učinci tipičnih antipsihotika su akutne (distonija, parkinsonizam, akatizija) i kronične (tardivna diskinezija) ekstrapiramidne nuspojave (EPS), dok su najčešće nuspojave atipičnih antipsihotika povećanje tjelesne težine i metabolički sindrom. Atipični antipsihotici razlikuju se od tipičnih po većem afinitetu za serotoninske 5-HT2 receptore u odnosu na dopaminske D2 receptore, te po bržoj disocijaciji s D2 receptora. Saznanja o međudjelovanju dopaminskog i serotoninskog sustava u mozgu potaknula su pitanja o mogućem utjecaju serotoninskog sustava na pojavu EPS. Stoga je cilj istraživanja bio utvrditi moguću povezanost polimorfizma u genu za serotoninski receptor 5-HT1B u oboljelih od shizofrenije, s pojavom akutnih ekstrapiramidnih nuspojava nakon liječenja tipičnim antipsihotikom haloperidolom. U istraživanju je utvrđena značajna povezanost polimorfizma rs132120411 u genu za serotoninski 5-HT1B receptor s razvojem akatizije u bolesnika sa shizofrenijom nakon terapije haloperidolom. Dobiveni rezultati trebali bi pomoći kliničarima da individualiziraju farmakoterapiju, te da prevencijom neželjenih nuspojava antipsihotika povećaju uspješnost liječenja i kvalitetu života oboljelih od shizofrenije. Schizophrenia is a serious chronic psychiatric condition with neurobiological basis still largely unknown. Therapy consists of typical and atypical antipsychotic; however some patients develop side effects that severely affect treatment outcomes and lead to discontinuation of therapy and frequent relapse. Well known side effects of typical antipsychotics are acute (dystonia, parkinsonism, akathisia) and chronic (tardive dyskinesia) extrapyramidal side effects (EPS), while metabolic syndrome and weight gain are main side effects of atypical antipsychotics. Atypical antipsychotics differ from typical in higher affinity for serotonin 5-HT receptors and faster dissociation from dopamine D2 receptors. Findings on various interactions between serotonin and dopamine systems in the brain have raised questions about possible involvement of serotonin in EPS. Therefore, the aim of this research was to determine the possible association between rs13212041 polymorphism in the gene for the serotonin 5-HT1B receptor in patients with schizophrenia, with the development of acute EPS after treatment with typical antipsychotic drug haloperidol. The study found significant association of rs132120411 polymorphism in the gene coding for the serotonin 5-HT1B receptor with the development of akathisia in schizophrenia patients following haloperidol therapy. The results should help clinicians to individualize the pharmacotherapy and by preventing the unwanted side effects of antipsychotics to increase the treatment efficacy and quality of life of schizophrenia patients.

Sve više literaturnih podataka upućuje na važnu ulogu glutamata, glavnog ekscitacijskog neurotransmitora u mozgu, u posredovanju učinaka alkohola na ljude. Određena istraživanja uputila su na povezanost alkoholizma i gena za glutamatne receptore, poput gena GRIK1 koji kodira podjedinicu GluR5 kainatnih receptora. Pojedini polimorfizmi toga gena značajno utječu na djelovanje topiramata, lijeka koji se koristi u terapiji alkoholizma, a svoje učinke ostvaruje putem podjedinice GluR5 kainatnih receptora. Međutim, takvih istraživanja ima vrlo malo te su potrebne daljnje studije koje bi uključile različite etničke skupine, podtipove alkoholizma, te brojne druge čimbenike. Cilj istraživanja je utvrditi postoji li u ispitanika hrvatskog podrijetla povezanost polimorfizma rs2832407 gena GRIK1 s razvojem alkoholizma. U tu svrhu usporedili smo raspodjelu genotipova i alela gena GRIK1 metodom real-time PCR između 500-tinjak ispitanika ovisnih o alkoholu i 500-tinjak zdravih kontrolnih osoba, pri čemu smo pratili učinak spola i pušačkog statusa. Istražili smo i potencijalne razlike u frekvenciji genotipova i alela polimorfizma gena GRIK1 u osoba ovisnih o alkoholu podijeljenih s obzirom na suicidalno i agresivno ponašanje, dobi početka zlouporabe alkohola, kao i na tip alkoholizma prema Cloningerovoj klasifikaciji. Dobiveni rezultati trebali bi pridonijeti boljem razumijevanju uloge gena GRIK1 u razvoju ovisnosti o alkoholu te uspješnosti odgovora na terapiju, posebice u slučaju primjene topiramata. There are growing data suggesting an important role of glutamate, the main excitatory neurotransmitter for the brain in the effects of alcohol. Some studies demonstrated an association between alcoholism and genes coding glutamate receptors, such as GRIK1 gene which codes for Glu5 subunit of kainate receptors. Certain GRIK1 polymorphisms have a significant influence on the action of topiramat, a drug used in alcoholism treatment, which acts via Glu5 subunit of kainate receptors. However, as there are only few such studies, further research is needed, especially on different ethnic groups, alcoholism subgroups and including numerous other parameters. The aim of this study is to determine whether there is an association between GRIK1 gene polymorphism rs2832407 and development of alcoholism in subjects of Croatian origin. For that purpose we compared the frequency of GRIK1 genotypes and alleles, with real-time PCR method, between 500 alcohol-dependent patients and 500 healthy control subjects, considering the effect of gender and smoking status. We also investigated potential differences in the frequency of GRIK1genotypes and alleles in alcoholics, subdivided according to suicidal and aggressive behavior, the onset age for alcohol abuse and the type of alcoholism according to Cloninger classification. Our results should improve our understanding of the role of GRIK1 gene in alcoholism and its treatment, especially in the case of topiramat therapy.

Antikonvulzivni lijek gabapentin pokazuje pozitivne učinke u liječenju alkoholizma i njegovih posljedica. Iako mehanizmi odgovorni za različite učinke gabapentina nisu potpuno jasni, istraživanja upućuju da bi neuroprotektivno djelovanje gabapentin mogao ostvarivati putem receptora GABAA. Tretman etanolom kroz 96 sati u koncentracijama višim od 100 mM značajno smanjuje broj stanica HEK 293, netransfeciranih i transfeciranih receptorima α1β2γ2S GABAA. Citotoksični učinak etanola poništen je istovremenom primjenom 1 μM gabapentina kod transfeciranih, ali ne i netransfeciranih stanica HEK 293. Primjena 100 mM etanola kroz 96 sati izazvala je značajan porast broja veznih mjesta za konvulzive i benzodiazepine rekombinantnih receptora GABAA, dok se primjenom etanola u kombinaciji s 1 μM gabapentinom, 100 μM bikukulinom ili njihovom kombinacijom, broj receptorskih veznih mjesta vratio na kontrolne razine. Primjena etanola, kao i bikukulina izazvala je alosteričko razdvajanje veznih mjesta za GABA-u i benzodiazepine, dok je istovremena primjena gabapentina spriječila etanolom i bikukulinom izazvano slabljenje receptorskih funkcionalnih veza. Ekspresija glasničke RNA podjedinica α1, β2 i γ2S receptora GABAA nije se značajno promijenila pod dugotrajnim utjecajem etanola ili gabapentina, već samo njihove kombinacije. Iako rezultati podržavaju pretpostavku o uključenosti receptora GABAA u djelovanju gabapentina, potrebna su daljnja istraživanja za utvrđivanje mehanizma protektivnog učinka gabapentina u slučaju citotoksičnog djelovanja etanola. The anticonvulsant drug gabapentin showed positive results in the treatment of alcoholism and its consequences. Although mechanisms of gabapentin action are not fully understood, studies suggested that gabapentin neuroprotective effects could be achieved via GABAA receptors. Treatment with ethanol at concentrations higher than 100 mM for 96 hours reduced the number of HEK 293 cells, untransfected or transfected with α1β2γ2S GABAA receptors. The cytotoxic effect of ethanol was counteracted by co-administration of 1 μM gabapentin in transfected, but not in untransfected cells. Exposure to 100 mM ethanol induced an increase in the number of binding sites for benzodiazepines and convulsants, while this effect was reversed by simultaneous exposure to 1 μM gabapentin, 100 μM bicuculline or their combination. Administration of ethanol, as well as bicuculline, induced functional allosteric uncoupling of GABA and benzodiazepine binding site, which was prevented by simultaneous gabapentin treatment. Increase in mRNA expression of α1, β2 and γ2S GABAA receptor subunits was not influenced by the exposure to ethanol or gabapentin, but only by their co-administration. Although results support the hypothesis of the involvement of GABAA receptors in the actions of gabapentin, further research is needed to elucidate the mechanisms of gabapentin protective effects against ethanol-induced cytotoxicity.

Glutamat, glavni ekscitacijski neurotransmitor u mozgu, ima značajnu ulogu u posredovanju učinaka alkohola i razvoju alkoholizma. Od svih glutamatnih receptora, kainatni receptori kao i njihova uloga u alkoholizmu, do sada su najmanje istraženi. Jedan od gena za glutamatne receptore za koji se utvrdila povezanost s alkoholizmom je gen GRIK1 koji kodira za podjedinicu GluR5 kainatnih receptora. Iako istraživanja pokazuju da pojedini polimorfizmi u genu GRIK1 značajno utječu na djelovanje topiramata, lijeka učinkovitog u liječenju alkoholizma, potrebne su daljnje studije. Cilj istraživanja bio je istražiti postoji li povezanost polimorfizma rs2186305 u genu GRIK1 i alkoholizma u ispitanika hrvatskog podrijetla. Učestalost pojedinih genotipova i alela gena GRIK1 uspoređena je između alkoholičara i zdravih ispitanika, različitog spola i pušačkog statusa. Istražila se je i raspodjela genotipova i alela polimorfizma rs2186305 u skupinama alkoholičara podijeljenih s obzirom na dob početka zlouporabe alkohola, suicidalno i agresivno ponašanje, kao i na tip alkoholizma prema Cloningeru. Haplotipska analiza polimorfizma rs2186305 u kombinaciji s polimorfizmom rs2832407 napravljena je u zdravih osoba, kao i u osoba ovisnih o alkoholu. Dobiveni rezultati trebali bi pridonijeti boljem razumijevanju uloge gena koji kodira za podjedinicu GluR5 glutamatnih kainatnih receptora u razvoju alkoholizma, te doprinijeti istraživanjima novih potencijalnih ciljeva u liječenju ove kronične bolesti. Glutamate, the major excitatory neurotransmitter in the brain, has an important role in mediating the effects of alcohol and the development of alcoholism. Among different glutamate receptors, kainate receptors and their role in alcoholism are so far the least explored. One of the genes for glutamate receptors that has been found to be associated with alcoholism is GRIK1 gene, encoding the GluR5 subunit of kainate receptors. Although research shows that certain polymorphisms in the GRIK1 gene significantly affect the activity of topiramate, a drug effective in the treatment of alcoholism, further studies are needed. The aim of the research is to investigate the association between rs2186305 polymorphism of GRIK1 gene and alcoholism in subjects of Croatian origin. The frequency of GRIK1 genotypes and alleles was compared between alcoholics and healthy subjects, divided according to gender and smoking status. Moreover, the distribution of genotypes and allele of polymorphism rs2186305 has been investigated in group of alcoholics subdivided according to age of onset of alcohol abuse, suicidal and aggressive behavior, as well as the type of alcoholism according to Cloninger classification. Haplotype analysis of the polymorphism rs2186305 in combination with polymorphism rs2832407 has been conducted in healthy individuals, as well as in subjects addicted to alcohol. The results should contribute to a better understanding of the role of the GRIK1 gene, encoding subunit GluR5 kainate glutamate receptors, in the development of alcoholism, as well as to the research of new potential targets for the therapy of this chronic disease.

Postoje brojni dokazi o uključenosti glutamata u akutne i kronične učinke alkohola, te pojavu ovisnosti i sindroma ustezanja, a glutamatni sustav predstavlja potencijalni cilj u liječenju alkoholizma. Nedavna istraživanja uputila su na povezanost alkoholizma i gena koji kodiraju podjedinice ionotropnih glutamatnih receptora. Cilj istraživanja bio je utvrditi postoji li u ispitanika hrvatskog podrijetla povezanost funkcionalnog polimorfizma Ser310Ala (rs6691840) smještenog u genu GRIK3, koji kodira za GluR7 podjedinicu glutamatnih kainatnih receptora, s rizikom razvoja ovisnosti o alkoholu. U tu svrhu u istraživanje je uključeno 275 ispitanika ovisnih o alkoholu, te 208 zdravih dobrovoljaca. U sklopu istraživanja željeli smo istražiti i moguće razlike u raspodjeli GRIK3 genotipova i alela između skupina ispitanika različitog spola i pušačkog statusa, te u ispitanika ovisnih o alkoholu podijeljenih s obzirom na suicidalno i agresivno ponašanje, početak zlouporabe alkohola, kao i na tip alkoholizma prema Cloningerovoj klasifikaciji. Rezultati pokazuju manju učestalost homozigotnog CC genotipa u ispitanika koji su počeli zloupotrebljavati alkohol prije 25. godine života, u odnosu na alkoholičare s kasnijim početkom zlouporabe alkohola. Daljnja istraživanja potrebna su daljnja istraživanja kako bi se razjasnila uloga gena GRIK3 u alkoholizmu. There is accumulating data suggesting an involvement of glutamate in the acute and chronic effects of alcohol, including dependence and withdrawal, and glutamatergic system is emerging as potential target for alcoholism treatment. Recent studies have suggested an association of ionotropic glutamate receptor genes with alcohol dependence. The aim of this study was to examine the association of Ser310Ala functional polymorphism (rs6691840) in the GluR7 glutamate kainate receptor subunit gene (GRIK3) with the development of alcoholism. The study included 275 alcohol-dependent patients and 208 healthy subjects. Possible differences in the frequency of GRIK3 genotypes and alleles between subjects of different gender and smoking status, as well as between alcohol-dependent patients stratified according to aggressive and suicidal behavior, age of drinking onset, and type of alcoholism according to Cloninger’s classification were also studied. The results demonstrated lower frequency of homozygous CC genotype in patients who started abusing alcohol before 25. years of age in relation to alcohol-dependent subjects with the late onset of alcohol abuse. Further studies are needed to elucidate the role of GRIK3 gene in the development of alcohol dependence.

Dugotrajna primjena alkohola izaziva promjene GABAA receptora koje se povezuju sa razvojem alkoholizma. Gabapentin pokazuje pozitivne učinke u liječenju alkoholizma. Mehanizmi djelovanja gabapentina, kao i alkohola nisu jasni. Citotoksični učinak dugotrajnog izlaganja stanica HEK 293, transficiranih receptorima α1β2γ2s GABAA tipa, 100 mM alkoholu smanjen je ustezanjem alkohola, kao i dugotrajnom primjenom 1 μM gabapentina. Produljeni tretman alkoholom povećao je broj benzodiazepinskih veznih mjesta i smanjio alosteričku povezanost receptorskih veznih mjesta, koji se ustezanjem alkohola vraćaju na kontrolne razine. Gabapentin nije utjecao na broj benzodiazepinskih veznih mjesta, ali je poništio slabljenje funkcionalnih interakcija receptorskih veznih mjesta izazvano alkoholom. Rezultati upućuju da dugotrajna primjena alkohola izaziva slične promjene receptora GABAA tipa kao i produljeno izlaganje benzodiazepinima, koji također izazivaju ovisnost. Rezultati podržavaju pretpostavku o uključenosti receptora GABAA tipa u djelovanje gabapentina. Daljnja istraživanja trebala bi utvrditi da li se protektivno djelovanje gabapentina protiv citotoksičnog učinka alkohola ostvaruje putem jačanja funkcionalne alosteričke povezanosti receptorskih veznih mjesta. Prolonged exposure of GABAA receptors to alcohol triggers changes associated with the development of alcoholism. Gabapentin shows positive effects in alcoholism treatment. The mechanisms of action of both, gabapentin and alcohol, are not clear. Cytotoxic effect of prolonged exposure of HEK 293 cells, expressing α1β2γ2s GABAA receptors, to 100 mM alcohol was reduced by alcohol withdrawal and 1 μM gabapentin treatment. Chronic alcohol treatment induced an increase in the number of benzodiazepine binding sites and allosteric uncoupling, which were counteracted by alcohol withdrawal. Gabapentin did not affect the number of benzodiazepine binding sites, but restored their normal functional interactions. The results suggest that prolonged alcohol treatment induces similar changes of GABAA receptors as prolonged exposure to benzodiazepines, which also produce dependence. Results support the hypothesis of involvement of GABAA receptors in the actions of gabapentin. Further studies should investigate whether receptor functional coupling underlies the protective effect of gabapentin against the alcohol cytotoxic effects.

GABAA receptori posreduju akutne i kronične učinke alkohola uključujući toleranciju, ovisnost, te sindrom ustezanja. Noviji rezultati upućuju na povezanost alkoholizma i gena GABRA2 koji kodira α2 podjedinicu GABAA receptora, smještenom na kromosomu 4, a posebice na polimorfizme u blizini susjednog gena GABRG1 koji kodira γ1 podjedinicu. Cilj istraživanja bio je ispitati povezanost polimorfizma rs567926, smještenog između gena GABRA2 i GABRG1 sa alkoholizmom i povezanim ponašanjima, poput pušenja, početka zlouporabe alkohola, agresivnog ponašanja i pokušaja samoubojstva. U istraživanju je genotipizirano 335 ovisnika o alkoholu i 230 kontrolnih ispitanika iz hrvatske populacije. Iako nije pronađena povezanost biljega rs567926 sa ovisnošću o alkoholu i nikotinu, niti sa ponašanjem povezanim sa alkoholizmom, utvrđena je haplotipska povezanost biljega rs567926 i rs279858, kao i povezanost pojedinih haplotipova sa specifičnim fenotipovima unutar skupine ispitanika s alkoholizmom. U svrhu razjašnjavanja uloge gena GABRA2 u razvoju ovisnosti o alkoholu i u ponašanju povezanim sa alkoholizmom, potrebna su daljnja istraživanja. GABAA receptors mediate acute and chronic effects of alcohol, including alcohol tolerance, dependence and withdrawal. The results suggested the association of alcoholism with GABRA2 gene encoding the GABAA receptor α2 subunit located on chromosome 4, especially with polymorphisms near the neighboring GABRG1 gene, which encodes the γ1 subunit. The aim of this study was to examine the association of polymorphism rs567926, located between GABRG1 and GABRA2 genes, with alcoholism and related behavior, including smoking, onset of alcohol abuse, aggressive behavior and suicide attempt. We genotyped 335 alcohol-dependent and 230 control subjects from Croatian population. Although the results demonstrated no association of marker rs567926 with alcohol and nicotine addiction or alcoholism-associated behaviour, we found haplotypic association between markers rs567926 and rs279858, and association of some haplotypes with specific phenotypes of alcohol-dependent patients. Further research is needed in order to elucidate the role of GABRA2 gene in alcohol dependence and alcoholism-associated behavior.

Alkoholizam predstavlja čest i kompleksan kronični poremećaj s brojnim genetskim i okolišnim čimbenicima rizika. Receptori za γ-amino-maslačnu kiselinu (GABA) tipa A igraju značajnu ulogu u akutnim i kroničnim učincima alkohola, uključujući pojavu tolerancije, ovisnosti i ustezanja. Dosadašnja istraživanja upućuju na povezanost gena za α2 podjedinicu GABAA receptora (GABRA2) s ovisnošću o alkoholu. Cilj ovog istraživanja bio je ispitati povezanost polimorfizma rs279858, smještenog unutar središnje regije gena GABRA2, s alkoholizmom i povezanim ponašanjima, poput pušenja, početka konzumacije alkohola, suicidalnog i agresivnog ponašanja. Istraživanje je obuhvatilo 335 osoba ovisnih o alkoholu i 230 zdravih ispitanika hrvatskog podrijetla koji su genotipizirani pomoću RT-PCR metode. Iako rezultati nisu pokazali značajnu razliku u distribuciji genotipova i alela između alkoholičara i kontrolnih ispitanika, unutar skupine alkoholičara dokazana je povećana frekvencija alela T i genotipa TT kod suicidalnih u odnosu na nesuicidalne ispitanike. Također je dokazano postojanje visoko konzerviranog haplotipskog bloka unutar 3’ regije gena GABRA2, no ne i povezanost ovog bloka s alkoholizmom. Daljnja istraživanja potrebna su da bi se razjasnila povezanost gena GABRA2 s alkoholizmom, kao i primijećena povezanost polimorfizma rs279858 sa suicidalnim ponašanjem. Alcoholism is a frequent and complex chronic disorder with a numerous genetic and environmental risk factors. γ-aminobutyric acid (GABA) A receptors play a significant role in the acute and chronic effects of alcohol, including tolerance, dependence and withdrawal. Recent studies have suggested an association of the GABAA receptor α2 subunit gene (GABRA2) with alcohol dependence. The aim of this study was to examine the association of marker rs279858, located in the central region of GABRA2 gene, with alcoholism and alcoholism-related behaviour, namely smoking, age of drinking onset, suicide attempt and aggressive bahaviour. The study included 355 alcohol-dependent patients and 230 healthy subjects, which were genotyped using the RT-PCR method. Although the results demonstrated no significant differences in the frequencies of genotypes and alleles between alcohol-dependent and control individuals, the patients with alcohol dependence who attempted suicide had significantly higher frequency of T allele, as well as TT genotype in relation to nonsuicidal alcoholics. Our results also confirmed the existence of highly conserved haplotype block within the 3’ region of GABRA2 gene, however no haplotypic association of this block and alcoholism was demonstrated. Further studies are needed to elucidate the association of GABRA2 gene with alcoholism, as well as to explore the observed association of marker rs279858 with suicidal behaviour.