No / Rationale: Weight gain caused by some antipsychotics is not only confined to adults but can also adversely affect both children and adolescents. Indeed, olanzapine and risperidone have been associated with extreme weight gain in adolescents even greater than that reported in adults. We have recently shown substantial weight gain in adult female rats following treatment with olanzapine and risperidone but not ziprasidone. Objectives: The aim of the present study was to compare the effects of several antipsychotics on weight gain and reproductive function in juvenile (aged 7 weeks) female hooded Lister rats. Methods: Olanzapine (4 mg/kg), risperidone (0.5 mg/kg), ziprasidone (2.5 mg/kg), sulpiride (10 mg/kg), haloperidol (0.5 mg/kg) or vehicle was administered i.p. once per day for 21 days. Body weight, food and water intake were measured daily, in addition to the determination of stage of the oestrous cycle. Results: Sub-chronic administration of olanzapine, risperidone, sulpiride and haloperidol, but not ziprasidone, significantly increased body weight compared to vehicle-treated animals during weeks 1-3. Sulpiride significantly increased food and water intake. Significantly increased percentage intra-abdominal fat weight was observed in olanzapine, risperidone, sulpiride and haloperidol, but not ziprasidone-treated animals. Marked disruption of the oestrous cycle was observed in all but the ziprasidone-treated group, which continued to have regular 4-day oestrous cycles. Conclusions: Weight gain observed in these juvenile animals was 1.5-2 times greater than that previously observed in adult rats. These findings have important implications for the use of antipsychotics in children and adolescent patients.

<p>Akrilamid (CASR No. 79-06-1) predstavlja veoma reaktivni, hidrosolubilni&nbsp;monomer za koji se smatra da ima toksične i potencijalno kancerogene efekte po&nbsp;zdravlje ljudi. &Scaron;tetne posledice akrilamida i njegovog jo&scaron; reaktivnijeg metabolita,&nbsp;glicidamida, su dokazane kod eksperimentalnih životinja i podrazumevale su&nbsp;neurotoksičnost, genotoksičnost i kancerogenost. Epidemiolo&scaron;ke studije rađene na&nbsp;ljudima pokazale su da akrilamid izaziva neurotoksične efekte, dok se genotoksičnost i&nbsp;kancerogenost jo&scaron; smatraju potencijalnim efektima, a zasnivaju se na podacima koji su&nbsp;dobijeni u okviru istraživanja na laboratorijskim životinjama. Njegove &scaron;tetne posledice&nbsp;na jetru, posebno kod mladog organizma, jo&scaron; uvek nisu dovoljno istražene.</p><p>Akrilamid se spontano formira u hrani koja je bogata ugljenim hidratima, tokom&nbsp;termičke obrade namirnica na visokim temperaturama. Ovaj monomer se formira&nbsp;tokom tzv. neenzimatske Mallard-ove reakcije, kojom se dobijaju smeđe komponente&nbsp;u hrani. U namirnicama ovaj monomer se formira reakcijom između redukujućih&nbsp;&scaron;ećera (uglavnom glukoze ili fruktoze) i aminokiseline (dominantno asparagina).</p><p>Imajući na umu da je jetra centralni organ za metabolizam akrilamida, ovo&nbsp;istraživanje &nbsp;je imalo za cilj da ispita glavne histolo&scaron;ke i biohemijske promene na jetri&nbsp;juvenilnog organizma pacova, nakon njegove subhronične ekspozicije akrilamidu.&nbsp;Istraživanje je &nbsp;rađeno na 3 eksperimentalne grupe peripubertalnih/juvenilnih mužjaka&nbsp;Wistar pacova, od kojih su dve bile tretirane vodenim rastvorom akrilamida u dozi od&nbsp;25 ili 50 &nbsp;mg/kg telesne mase, dok je treća grupa služila kao kontrola i primala&nbsp;destilovanu vodu. Životinje su bile tretirane oralno, putem gavaže, 5 dana nedeljno,&nbsp;tokom 3 nedelje. Nakon 24 h od poslednjeg tretmana, životinje su uvedene u etarsku &nbsp;anesteziju i dekapitovane, a zatim su prikupljeni krv i uzorci tkiva jetre.</p><p>Tkivo jetre je uzeto iz srednjeg lobusa, fiksirano u 10% neutralnom puferisanom &nbsp;formalinu tokom 24 h i obrađeno prema standardnom protokolu za parafinsko kalupljenje. Ukalupljeni uzorci jetre su zatim isečeni na serijske preseke tkiva debljine&nbsp;5 &micro;m, a zatim bojeni histohemijskim i imunohistohemijskim metodama. Uzorci krvi su&nbsp;pripremljeni za serolo&scaron;ku analizu.&nbsp;</p><p>Histolo&scaron;ka analiza preseka bojenih hematoksilin-eozin (H&amp;E) metodom nije &nbsp;zabeležila prisustvo značajnih razlika u op&scaron;toj arhitekturi jetre i njenoj lobularnoj &nbsp;organizaciji među eksperimentalnim grupama. Stereolo&scaron;ka analiza je ukazala na &nbsp;<br />mikrostrukturne promene kod hepatocita i jetrinih sinusoida. Rezultati sugeri&scaron;u, na&nbsp;dozno-zavisno povećanje volumena hepatocita, njihove citoplazme i nukleusa, i doznozavsino smanjenje volumena sinusoida, u odnosu na kontrolne uzorke jetre.</p><p>Analiza glikogena je rađena na presecima jetre bojenim metodom Periodic acid&ndash;<br />Schiff-a (PAS), gde se uočilo smanjenje količine glikogena u grupi tretiranoj nižom &nbsp;dozom akrilamida, dok je u grupi tretiranoj većom dozom uočena njegova&nbsp;<br />akumulacija, u odnosu na kontrolne životinje.</p><p>Imunopozitivnost hepatocita na marker proliferacije, Ki-67, bila je smanjena u&nbsp;grupi pacova tretiranoj nižom dozom, a bila povećana u grupi tretiranoj većom dozom&nbsp;akrilamida pri komparaciji sa kontrolom. Stereolo&scaron;ki nalazi su potvrdili inicijalnu&nbsp;histolo&scaron;ku analizu.</p><p>Imunopozitivnost hepatocita na marker apoptoze, Caspase 3, je bila smanjena&nbsp;<br />kod obe grupe životinja tretiranih akrilamidom u odnosu na kontrolu. Nasuprot tome,&nbsp;<br />imunopozitivnost neparenhimskih ćelija jetre, pretežno Kupffer-ovih ćelija, je bila&nbsp;<br />uvećana u obe tretirane grupe pri komparaciji sa kontrolom.</p><p>Imunopozitivnost Kupffer-ovih ćelija na marker CD68 je bila smanjena u&nbsp;uzorcima jetre kod oba tretmana akrilamidom u odnosu na kontrolu.</p><p>Populacija mastocita, prikazana toluidine-blue (TB) metodom bojenja, bila je&nbsp;uvećana &nbsp;kod obe grupe pacova tretiranih akrilamidom u poređenju sa kontrolom.&nbsp;Povećanje brojnosti ovih ćelija je bilo posebno prominentno kod njihove degranulisane &nbsp;subpopulacije. Stereolo&scaron;ka analiza je potvrdila histolo&scaron;ke nalaze.&nbsp;</p><p>Serumska analiza je pokazala uvećanu aktivnost aspartat aminotrasferaze (AST) i&nbsp;<br />smanjenu aktivnost alanin aminotrasferaze (ALT) kod obe grupe životinja tretiranih &nbsp;<br />akrilamidom u odnosu na kontrolu. Aktivnost alkalne fosfataze (ALP) je bila uvećana&nbsp;<br />u grupi tretiranoj nižom dozom, a smanjena u grupi tretiranoj većom dozom&nbsp;<br />akrilamida, u odnosu na kontrolu. Vrednosti koncentracije ukupnih serumskih proteina&nbsp;kao i koncentracije C reaktivnog proteina (CRP) nisu pokazale značajnije promene&nbsp;među eksperimentalnim grupama.</p><p>Oba akrilamidna tretmana su izazvala gubitak telesne mase kod tretiranih&nbsp;pacova, u odnosu na kontrolne životinje.&nbsp;Postojeći podaci ukazuju prominentni hepatotoksični potencijal akrilamida koji može&nbsp;poremetiti mikrostrukturne osobine i funkcionalni status hepatocita kod jetre mladog&nbsp;organizma. Akrilamid može značajno poremetiti funkcionalnost jetre, obzirom da se&nbsp;promene na celularnom nivou mogu relativno brzo odraziti na nivo tkiva, a kasnije&nbsp;ugroziti i homeostazu celog organizma.</p> / <p>Acrylamide&nbsp; (CASR No. 79-06- 1)&nbsp; is highly reactive, water-soluble monomer which is considered as toxic and potentially cancer causing chemical to humans. Adverse health effects regarding acrylamide and its more reactive metabolite,glycidamide, were detected in experimental animals, and&nbsp; included neurotoxicity, genotoxicity, and&nbsp;&nbsp; carcinogenicity.&nbsp; Human epidemiological studies claim that acrylamide has neurotoxic effects, while&nbsp; genotoxicity and carcinogenicity are considered as&nbsp; potential human health risks only on the basis of animal studies. Its harmful effects on the liver, especially in a young organism, are still to be elucidated.</p><p>Acrylamide&nbsp; is spontaneously formed in&nbsp; carbohydrate-rich food during high-temperature&nbsp; processing. It is&nbsp; formed during heat-induced non-enzymatic reaction, also known as&nbsp; the Maillard browning reaction, between reducing sugars (glucose and fructose), and free amino acids (mainly asparagine).</p><p>Having in mind&nbsp; that&nbsp; acrylamide&nbsp; metabolism takes place in a liver,&nbsp; the study aimed to investigate the main histological and&nbsp; biochemical changes in the liver of juvenile rat following subchronic acrylamide intoxication. Study was performed on peripubertal/juvenile male Wistar rats, divided in 3 experimental groups, two of which were treated with acrylamide in doses of 25 or 50 mg/kg of body weight, while the third group served as the control and received distilled water. Animals were treated orally, via gavage, 5 days a week, during 3 weeks. Animals&nbsp; were anesthetized by&nbsp;&nbsp; ether inhalation and decapitated 24 hrs after the last treatment.</p><p>Liver tissue was sampled from the middle lobe, fixed in&nbsp; 10% neutral&nbsp; buffered formalin for 24 hrs,&nbsp; routinely processed for paraffin&nbsp; embedding&nbsp; and cut into 5-&micro;m thick serial sections for subsequent histochemical and immunohistochemical staining.Blood samples were collected for subsequent biochemical analysis .</p><p>Histological examination of haematoxylin and eosin (H&amp;E) stained sections did not point to any major alteration in main in liver lobular architecture or organization among the experimental groups. Stereological analysis revealed a microstructural changes in hepatocytes and liver sinusoids. The analysis detected a dose-dependant increase in the volume of hepatocytes, their cytoplasm and nuclei, and dose-dependant decrease in the volume of liver sinusoids compared to the control, respectively.</p><p>Glycogen analysis was performed on Periodic acid&ndash;Schiff (PAS) stained sections which showed glycogen reduction in the low-dose group, and its accumulation in the high-dose group, compared to the control, respectively.</p><p>Imunopositivity in hepatocytes for Ki-67 protein, a known marker for proliferation, showed a decrease in low-dose group, while in high- dose group was detected its increase compared to the control, respectively. Stereological analysis confirmed initial histological observation.</p><p>Caspase 3 immunopositivity, a known marker for apoptosis, proved to be decreased in hepatocytes in both acrylamide-treated groups when compared to the control. One the other hand, immunopositivity was increased in non-parenchymal&nbsp; cell, predominantly in Kupffer cells, in comparison to the control. Immunopositivity for CD68, a marker for Kupffer cells, proved to be decreased in both acrylamide-treated groups when compared to the control.</p><p>Population of the mast cells, visualized on toluidine blue (TB) stained sections, showed its increase in both acrylamide-treated groups, in comparison to the control. The increase was especially prominent regarding a degranulated subpopulation of these cells. Subsequent stereological analysis confirmed histological findings.</p><p>Serum analysis showed increased&nbsp; activity of&nbsp; aspartate aminotransferase (AST), and decreased&nbsp; activity&nbsp; of alanine aminotransferase (ALT) in&nbsp; both AA-treated groups, while the&nbsp; activity&nbsp; of alkaline phosphatase (ALP)&nbsp; was increased in low-dose, but&nbsp;&nbsp; decreased in high- dose group compared to the control, respectively.&nbsp; The concentration of total serum proteins as well as concentration of C reactive protein (CRP) did not show any major changes among the experimental groups.</p><p>Body weight measurements showed that all acrylamide-treated rats lost their body weight as opposed to the control rats whose body mass increased.</p><p>Present results suggest a prominent hepatotoxic potential of acrylamide which might alter the microstructural features and functional status in hepatocytes of&nbsp; immature liver.&nbsp; Acrylamide may cause significant perturbation in liver functionality which may be reflected from cellular to the tissue level, thereby endangering the whole body&rsquo;s homeostasis.</p>