Chronic exposure to cigarette smoke extract increases nicotine withdrawal symptoms in adult and adolescent male rats.

The aim of the current study was to determine whether non-nicotine constituents of cigarette smoke contribute to nicotine dependence in adolescent and adult male Sprague Dawley rats. For 10 days animals were given three times daily intravenous injections of nicotine (1.5 mg/kg/day) or cigarette smoke extract (CSE) containing an equivalent dose of nicotine. Both spontaneous and mecamylamine-precipitated withdrawal were then measured. Chronic treatment with CSE induced significantly greater somatic and affective withdrawal signs than nicotine in both adolescents and adults. Mecamylamine-precipitated somatic signs were similar at both ages. In contrast, animals spontaneously withdrawn from chronic drug treatment exhibited significant age differences: whereas adolescents chronically treated with nicotine did not show somatic signs, those treated with CSE showed similar physical withdrawal to those of adults. Mecamylamine did not precipitate anxiety-like behavior at either age. However, both adolescents and adults showed significant anxiety in a light-dark box test 18 h after spontaneous withdrawal. Anxiety-like behavior was still evident in an open field test 1 month after termination of drug treatment, with adolescents showing significantly greater affective symptoms than adults. Our findings indicate that non-nicotine constituents of cigarette smoke do contribute to dependence in both adolescents and adults and emphasize the importance of including smoke constituents with nicotine in animal models of tobacco dependence.

Chronic exposure to cigarette smoke extract upregulates nicotinic receptor binding in adult and adolescent rats.

Heavy smokers display increased radioligand binding of nicotinic acetylcholine receptors (nAChRs). This "upregulation" is thought to be a contributing factor to tobacco dependence. Although cigarette smoke contains thousands of constituents that can contribute to nicotine dependence, it is not well understood whether non-nicotine constituents contribute to nAChR upregulation. In this study, we used an aqueous cigarette smoke extract (CSE), which contains nicotine and soluble constituents of cigarette smoke, to induce nAChR upregulation in adult and adolescent rats. To do this, male rats were exposed to nicotine or CSE (1.5 mg/kg/day nicotine equivalent, intravenously) daily for ten days. This experimental procedure produces equivalent levels of brain and plasma nicotine in nicotine- and CSE-treated animals. We then assessed nAChR upregulation using quantitative autoradiography to measure changes in three nAChR types. Adolescents were found to have consistently greater α4ß2 nAChR binding than adults in many brain regions. Chronic nicotine exposure did not significantly increase nAChR binding in any brain region at either age. Chronic CSE exposure selectively increased α4ß2 nAChR binding in adolescent medial amygdala and α7 binding in adolescent central amygdala and lateral hypothalamus. CSE also increased α3ß4 nAChR binding in the medial habenula and interpeduncular nucleus, and α7 binding in the medial amygdala, independent of age. Overall, this work provides evidence that cigarette smoke constituents influence nAChR upregulation in an age-, nAChR type- and region-dependent manner.

Trends and associated characteristics for Chagas disease among women of reproductive age in the United States, 2002 to 2017.

BACKGROUND: American trypanosomiasis, commonly referred to as Chagas disease, is caused by a single cell protozoan known as Trypanosoma cruzi (T. cruzi). Although those affected are mainly in Latin America, Chagas has been detected in the United States (US), Canada and in many European countries due to migration. Few studies have explored the epidemiology of Chagas within the US or changes in disease burden over the past decade. The objective of this study was to explore the trends and associated characteristics for Chagas disease among hospitalized women of reproductive age in the US. METHODS: We analyzed admissions data including socio-demographic and hospital characteristics for inpatient hospitalization for women of reproductive age (15-49 years) in the US from 2002 through 2017. We employed Joinpoint regression analysis to determine trends in the prevalence of Chagas disease over this period. RESULTS: A total of 487 hospitalizations of Chagas disease were identified, corresponding to 3.7 per million hospitalizations over the study period. The rate statistically increased from 1.6 per million in 2002 to 7.6 per million hospitalizations in 2017. Chagas was most prevalent among older women, Hispanics and those in the highest zip income bracket. The in-hospital mortality rate was about 10 times greater among women with Chagas compared to those without the condition (3.1% versus 0.3%), and the condition tended to be clustered in women treated at large, urban teaching hospitals in the Northeastern region of the US. CONCLUSION: Chagas disease diagnosis appears to be increasing among hospitalized women of reproductive age in the US with a 10-fold elevated risk of mortality.

Differences in mechanisms underlying reinstatement of cigarette smoke extract- and nicotine-seeking behavior in rats.

Despite extensive research, current therapies for smoking cessation are largely ineffective at maintaining abstinence for more than a year. Whereas most preclinical studies use nicotine alone, the goal of the present study was to evaluate whether inclusion of non-nicotine tobacco constituents provides better face validity for the development of new pharmacological therapies for smoking cessation. Here, we trained adult male rats to self-administer nicotine alone or cigarette smoke extract (CSE), which contains nicotine and other aqueous constituents of cigarette smoke. After stable self-administration behavior was established, animals underwent extinction training followed by drug and cue primed reinstatement testing. We show that animals that self-administered CSE had significant reinstatement in all drug and drug + cue stimulus conditions whereas animals that self-administered nicotine only showed significant reinstatement in the drug + cue conditions. AT-1001, an α3ß4 nicotinic acetylcholine receptor (nAChR) functional antagonist, attenuated drug + cue-primed reinstatement of both CSE- and nicotine-seeking behavior. However, AT-1001 was less potent in blocking drug-primed reinstatement in animals that had self-administered CSE than in those that had self-administered nicotine alone. This was the case even when nicotine was used to prime reinstatement in animals that had self-administered CSE, suggesting that prior CSE exposure had altered the functional role of α3ß4-containing nAChRs in drug-seeking behavior. These findings confirm the importance of non-nicotine tobacco constituents and α3ß4* nAChRs in cue- and nicotine-primed craving. They also suggest that tests using CSE may be more valid models to study tobacco dependence than use of nicotine alone.