Sıçanlarda nikotin tercihinin oluşturulması ve araştırılması

Sigara tüketimi toplum için zararlı sonuçları olan bir bagımlılıktır. Nikotin tütündeki bagımlılık yapıcı madde olup tütün bagımlılıgının temelini teskil etmektedir. Gelismis ülkelerde eriskinlerde tütün kullanımı azalmakta iken adölesanlarda, özellikle de kızlarda sigara tüketimi artmaktadır. Adolesan tütün kulanımı bu boyutu ile halk saglıgı üzerinde önemli bir sorundur. Tütün ve sigara kullanımı ile ilgili literatür genellikle eriskinleri içermektedir. Ayrıca hamilelikte fötal maruziyet ile de ilgili yayınlar bulunmaktadır. Ancak, adölesans dönemindeki çalısmalar sadece son zamanlarda ivme kazanıstır. Bu oldukça talihsiz bir durumdur, çünkü genellikle adölesans sigara kullanımına tipik olarak baslanan dönemdir. Hayvan odelleri nikotin etkilerini arastırmak açısından önemli avantajlar saglar. Adölesan dönemde kronik nikotin maruziyeti beynin yapısını, biyokimyasını ve bilissel fonksiyonları etkiler; bu etki eriskinliktekinden daha önemlidir. Sunulan çalısmada 90 sıçana oral yolla nikotin tercihi sunulmus, hayvanların kendi tercihleri ile nikotin tüketimi saglanmıstır; sıçanlar dogumlarından itibaren 4 aylık oluncaya kadar izlenmis, adölesans ve eriskinlik dönemlerinde altısar hafta nikotine maruz bırakılmıslardır. Bu dönemler içinde 24 saat serbest erisimli olarak nikotine ulasmalarını mümkün kılan bir düzen içinde, kontrollerle karsılastırmalı olarak nikotin tüketimleri kaydedilmistir. Nikotinin tadı sakkarin ile maskelenmis ve sakkarin hem su hem de nikotin çözeltilerine uygulanmıstır. Bu uygulama sırasında sıçanlar her iki yas döneminde de nikotini sudan ayırdetmislerve bireysel farklılık göstererek tüketmislerdir. Grup ortalamaları nikotin tüketiminin adölesan dönemde eriskinliktekinden anlamlı derecelerde daha fazla oldugunu ortaya koymustur. Ayrıca disi sıçanlar eriskinlik döneminde nikotini daha fazla tercih etmislerdir. Adölesans ve eriskinlik dönemlerinde tüketilen nikotin arasında disilerde anlamlı bir korelasyon bulundugu halde, erkeklerde böyle bir korelasyon gözlenmemistir. Çalısmanın ikinci bölümünde nikotinin dikkat üzerindeki etkileri, tarafımızdan gelistirilmis olan dikkat ipuçlu, su tankında yer bulma deneyi le degerlendirilmistir. Dikkat testinde niotin disilerde performansı iyilestirdigi halde erkeklerde bu anlamlı bir etki görülmemistir. Sonuçta, disilerin adölesans döneminde nikotine daha duyarlı oldukları ve disilerde bu dönemde nikotin maruziyetinin eriskinlikte nikotin tüketimini belirledigi söylenebilir. Kronik nikotin disi sıçanlarda dikkati arttırdıgı halde erkeklerde anlamlı bir etki olusturmamıstır. Sonuçlarımız nikotine maruz kalınmasının cinsel dimorfik etkiler olusturdugunu ortaya koymaktadır

Bitter taste and nicotine preference: evidence for sex differences in rats

WOS: 000346073600008PubMed ID: 25490608Background: Nicotine affects sensory pathways and an interaction between taste and nicotine preference is likely. In addition to pharmacologic effects, orosensory factors are important in nicotine dependence. Recent evidence suggests a link between taste (notably bitter) receptor genes and nicotine addiction. Objectives: To explore the possible interaction between taste and nicotine preference in rats, including sex as a factor. Methods: Adult male and female Sprague Dawley rats (n = 82) were used in free choice oral intake experiments. In Experiment 1 rats received water from one bottle and one of the taste substances (quinine, sucrose, or saccharine) from the other bottle for 12 days. Following a wash-out period, Experiment 2a was initiated in the same rats. Rats received water from one bottle and nicotine (10 and 20 mg/l) from the other for 12 days. In Experiment 2b, nicotine exposure was continued for four more weeks. Liquid intake and weight were measured at four-day (Experiments 1 and 2a) and one week (Experiment 2b) periods. Results: In female rats, quinine and subsequent nicotine intake were positively correlated and quinine intake and weight gain were negatively correlated. No association was depicted between nicotine consumption and sweet tastants in either female or male animals. Conclusion: The results suggest that bitter taste and nicotine preference are related, but only in female rats. This finding is parallel to observations in human smokers. Our study may be a preliminary step in the search for common genes that underlie nicotine dependence and taste preference.Ege UniversityEge University [2010 BAM 003]This study was supported by Ege University Research Fund Grant 2010 BAM 003. The authors thank Professor Allan C. Collins for helpful comments in the preparation of this manuscript

Nicotine withdrawal in selectively bred high and low nicotine preferring rat lines

WOS: 000352173200015PubMed ID: 25687373Background: We have generated high- and low-nicotine preferring (high-NP, low-NP) rat lines using voluntary oral nicotine intake as the selection criterion. After nine generations, the estimated realized heritability for high intake was 0.26. The aim of the current study is to compare how nicotine withdrawal varies between these two lines. This new analysis would help elucidate if nicotine withdrawal and intake share common genetic mechanisms. Methods: After exposing male and female Sprague Dawley rats (F-8 generation) to six weeks of nicotine exposure, nicotine was withdrawn. Somatic signs of withdrawal, locomotor activity, and weight were measured at 16 and 40 h. One week after withdrawal, resumption of nicotine intake was determined. Results: The High-NP line had higher nicotine intake before and after withdrawal than the Low-NP line. High-NP rats were more active than Low-NP rats, and locomotor activity decreased during withdrawal; this decrease was more pronounced in the High-NP line. High-NP rats gained more weight during withdrawal than Low-NP rats. Escape attempts decreased during withdrawal in all groups, but overall females demonstrated more escape attempts than males. The other somatic signs of withdrawal were higher during withdrawal compared to baseline and more pronounced in females. Conclusions: Selection for nicotine preference affected nicotine intake, locomotion and weight, suggesting the heritability of these traits. However, despite differences in nicotine preference and intake, high-NP and low-NP rats showed similar withdrawal responses: escape attempts decreased and somatic signs increased. Withdrawal responses of females were more pronounced than males suggesting sex differences in the negative affect induced by nicotine withdrawal. The major finding of this novel analysis is showing that nicotine preference does not predict withdrawal symptoms. This finding, together with sex differences observed during withdrawal, may contribute to a better understanding of nicotine dependence and have translational value in developing more effective strategies for smoking cessation. (C) 2015 Elsevier Inc All rights reserved

Previous chronic exposure eliminates the conditioning effect of nicotine in rats

WOS: 000293719700004PubMed ID: 21640169Smoking continues to be a major health problem and unfortunately smoking cessation interventions have limited success; the conditioning effects of nicotine and individual differences in tobacco addiction are important factors that underlie this setback. The aim of the current study was to investigate nicotine-induced conditioned place preference (CPP) in male and female rats which were previously exposed to a free choice of oral nicotine or water and showed different preferences for nicotine; subsequently nicotine intake also varied between subjects. Exposure patterns were varied in three experiments to allow for assessing the effect of adult v.s. adolescent exposure. The design of CPP testing enabled testing for the possible confounding effects of withdrawal or tolerance. A total of 150 male and female rats were used in three experiments. The oral nicotine choice was provided for at least six weeks in all experiments. Our results replicate our previous findings that nicotine induces CPP in male, but not female rats not pre-exposed to nicotine. Previous nicotine exposure, irrespective of the amount of nicotine consumed, eliminated the conditioning effects of nicotine in a new context. The diminished CPP response was more pronounced in rats exposed to nicotine as adolescents than those exposed as adults. This reduced responsiveness cannot be explained by tolerance. The neuroplastic changes caused by chronic nicotine administration or the strong conditioning to receiving nicotine in the home cage before CPP testing may underlie the weakened responsiveness. These findings support the well known clinical notion that smoking cessation attempts are more successful in a novel environment, not previously connected with smoking. (C) 2011 Elsevier Inc. All rights reserved.Ege UniversityEge University [001 BAM 2006-02]This work was supported by Ege University Research Fund (Grant 001 BAM 2006-02)

Nicotinic cholinergic and dopaminergic receptor mRNA expression in male and female rats with high or low preference for nicotine

<p><i>Background</i>: Nicotine exerts its central actions through nicotinic acetylcholine receptors (nAChRs), which in turn regulate major neurotransmitter systems including dopamine. Nicotinic and dopaminergic systems play significant roles in physiological functions, neuropsychiatric disorders, and addiction. <i>Objectives</i>: To evaluate possible differences in the expression of nAChR subunit and dopamine receptor (DR) mRNAs following voluntary nicotine intake. <i>Methods</i>: Male and female rats (<i>n</i> = 67) were exposed to long-term free-choice oral nicotine (24 hours/day, 6 weeks); rats with maximum and minimum nicotine preference/intake were selected. The mRNA levels of genes encoding α4,β2,α5, and α7 nAChR subunits and DR Drd1and Drd2 subtypes were evaluated in the striatum (STR), prefrontal cortex (PFC), and hippocampus using quantitative real-time polymerase chain reaction in selected rats (<i>n</i> = 30) and their control groups (<i>n</i> = 15). <i>Results</i>: In addition to baseline differences, expression changes were observed in the mRNA levels of evaluated genes in rats exposed to voluntary oral nicotine in a brain region-, sex-, and preference-related manner. Nicotine intake is correlated negatively with <i>Chrnb2, Chrna7</i> and positively with <i>Drd1</i> expression. In the cholinergic system, regional differences in <i>Chnrb2</i> and <i>Chrna5</i>, sex differences in <i>Chrna4</i> and <i>Chrna5</i>, and nicotine preference effects in the expression of all subunits except α4 were observed. <i>Chrna5</i> was lower in maximum than in minimum preferring, and in male than female rats, supporting the inhibitory role of the α5 subunit in nicotine dependence. Nicotine increased <i>Drd2</i> mRNA expression only in minimum preferring female rats in STR and PFC. <i>Conclusion</i>: Modulation of nAChR and DR gene expression by nicotine may have clinical implications and aid drug development. Pharmaceuticals targeting the nicotinic cholinergic and dopaminergic systems might be expected to have differential efficacy that varies with the patient’s sex or smoking status.</p

RNA deep sequencing analysis reveals that nicotine restores impaired gene expression by viral proteins in the brains of HIV-1 transgenic rats.

Persons infected with HIV-1 often develop neurologic disorders despite receiving highly active anti-retroviral therapy. Although the underlying mechanism is largely undetermined, our previous RNA-seq-based study showed that the expression of many genes was altered in the central nervous system (CNS) of HIV-1 transgenic (HIV-1Tg) rats. Because nicotine, a natural agonist of nicotinic acetylcholine receptors, exhibits a neuroprotective effect, we presently tested the hypothesis that nicotine restores the expression of altered genes in the CNS of HIV-1Tg rats. Adult male HIV-1Tg and F344 control strain rats were injected with either nicotine (0.25 mg/kg) or saline subcutaneously twice a day for 17 days. Gene expression in the prefrontal cortex (PFC), dorsal hippocampus (HIP), and dorsal striatum (STR) was evaluated using the RNA deep sequencing technique. We found that about 20% of the altered genes in the HIV-1Tg rat were affected by nicotine in each brain region, with the expression of most restored. Analysis of the restored genes showed distinct pathways corrected by nicotine in different brain regions of HIV-1Tg rats. Specifically, the two most significantly restored pathways were Wnt/β-catenin signaling and ephrin B signaling in the PFC, cAMP-responsive element-binding protein (CREB) signaling and glutathione metabolism pathway in the HIP, and tricarboxylic acid (TCA) cycle and calcium signaling in the STR. Together, our findings indicate that cholinergic modulators such as nicotine have beneficial effects on HIV-1-induced neurologic deficits