Effectiveness of pharmacotherapies for diabetes on nicotine, food, and water intake in insulin-resistant rats.

The intersectionality between diabetes medications and nicotine consumption was assessed in female and male rats. Briefly, the rats were fed a high-fat diet (HFD) or regular diet (RD) for 4 weeks. Then separate groups received vehicle or a low dose of streptozotocin (STZ; 25 mg/kg). Three days later, insulin resistance was assessed by measuring plasma glucose levels for 180 min following an injection of insulin (0.75 U/kg). The rats were then prepared with jugular catheters, and they were given 23 h access to nicotine intravenous self-administration (IVSA) in 4 days cycles with 3 days of forced abstinence in their home cages where they consumed their respective diet. During the IVSA sessions, operant responses for food and water and changes in body weight were recorded. Prior to administration of the pharmacotherapies, the rats were given access to two doses of nicotine (0.015 then 0.03 mg/kg for the remainder of the study). Then, daily injections of the pharmacotherapies were given at the onset of dark cycle (6 p.m.) in the following order: 1) dapagliflozin (3.0 then 10.0 mg/kg), 2) insulin (0.75 U/kg twice), and 3) bromocriptine (3.0 then 10.0 mg/kg). The results suggest that our HFD+STZ regiment induced insulin resistance in female and male rats. Also, the HFD-fed rats displayed higher nicotine intake than RD controls, regardless of sex. Administration of insulin, but not dapagliflozin or bromocriptine, normalized nicotine intake in HFD-fed rats to control levels. These results have clinical implications regarding the potential efficacy of insulin to control excessive nicotine intake in persons with diabetes.

Sex and age differences in approach behavior toward a port that delivers nicotine vapor.

The goal of our laboratory is to study the mechanisms that promote nicotine use, particularly in vulnerable populations. To more closely mimic human use patterns, the present study employed nicotine vapor methods involving passive exposure for 14 days in adolescent and adult female and male rats. Age and sex differences in approach behavior (nosepokes) were assessed in a port that delivered nicotine plumes on Day 1 and 14 of our exposure regimen. Controls received ambient air in exposure chambers. After the final session, rats received a nicotinic receptor antagonist to precipitate withdrawal. Then, physical signs, anxiety-like behavior, and plasma levels of cotinine (a nicotine metabolite) were assessed. Over time, females displayed a larger increase in approach behavior to the nicotine port than males, an effect that was larger in adolescents. Nosepoke responses in adolescent females were correlated with anxiety-like behavior, but not physical signs of withdrawal. Adolescents gained more weight than adults regardless of treatment, and the weight gain was larger in male adolescents. Female adolescents also displayed the highest levels of cotinine than all other groups. These findings suggest that nicotine vapor produces greater motivational effects in adolescent females as compared to their adult and male counterparts.

Increased Risky Choice and Reduced CHRNB2 Expression in Adult Male Rats Exposed to Nicotine Vapor.

While the cognitive enhancing effects of nicotine use have been well documented, it has also been shown to impair decision making. The goal of this study was to determine if exposure to nicotine vapor increases risky decision making. The study also aims to investigate possible long-term effects of nicotine vapor exposure on the expression of genes coding for cholinergic and dopaminergic receptors in brain. Thirty-two adult male Sprague Dawley rats were exposed to 24 mg/mL nicotine vapor or vehicle control, immediately followed by testing in the probability discounting task for 10 consecutive days. Fifty-four days after the 10-day vapor exposure, animals were sacrificed and expression of genes coding for the α4 and ß2 cholinergic receptor subunits, and dopamine D1 and D2 receptors, were analyzed using RT-PCR. Exposure to nicotine vapor caused an immediate and transient increase in risky choice. Analyses of gene expression identified significant reductions in CHRNB2 and DRD1 in the nucleus accumbens core and CHRNB2 and DRD2 in the medial prefrontal cortex of rats previously exposed to nicotine vapor, relative to vehicle controls. Results provide data on the negative cognitive effects of nicotine vapor exposure and identify cholinergic and dopaminergic mechanisms that may affected with repeated use.

Exposure to Nicotine Vapor Produced by an Electronic Nicotine Delivery System Causes Short-Term Increases in Impulsive Choice in Adult Male Rats.

INTRODUCTION: Traditional cigarette use influences cost-benefit decision making by promoting impulsive choice. However, the impact of nicotine exposure via electronic nicotine delivery systems on impulsivity remains unclear. Hence, the present study examined the short- and long-term effects of nicotine vapor on impulsive choice. METHODS: Twenty-four adult male rats were trained in the delay discounting task to choose between small immediate food rewards and large delayed food rewards. After 24 days of training in the task rats were exposed to vapor containing either 0, 12, or 24 mg/mL of nicotine for 10 days. To validate inhalation of nicotine vapor serum cotinine levels were analyzed on exposure days 1, 5, and 10 using enzyme-linked immunosorbent assay. Following vapor exposure, rats were retrained in the discounting task until rats displayed stable responding and the effects of nicotine vapor on choice preference were assessed. RESULTS: Rats exposed to 12 and 24 mg/mL nicotine vapor displayed higher serum cotinine levels than control rats exposed to 0 mg/mL vapor. There were no differences in impulsive choice between any vapor exposure groups when tested 15 days after exposure, across 6 days of stable responding, suggesting that nicotine vapor does not have long lasting effects on impulsive choice. Interestingly, a subsequent nicotine vapor challenge revealed short-term increases in impulsive choice immediately following a single exposure to 24 mg/mL nicotine vapor, relative to choice preference immediately following exposure to 0 mg/mL vapor. CONCLUSIONS: These results suggest that exposure to nicotine vapor causes immediate, short-term increases in impulsive choice. IMPLICATIONS: E-cigarette use is increasing at an alarming rate, particularly among adolescents and young adults. This is concerning given the lack of research into the effects of nicotine vapor exposure on the brain and behavior. The present study describes a viable rodent model of human e-cigarette use and suggests that exposure to nicotine vapor produces short-term increases in impulsive choice.

The emergence of insulin resistance following a chronic high-fat diet regimen coincides with an increase in the reinforcing effects of nicotine in a sex-dependent manner.

The present study assessed the sex-dependent effects of insulin resistance on the reinforcing effects of nicotine. Female and male rats received a chronic high-fat diet (HFD) or regular diet (RD) for 8 weeks. A subset of rats then received vehicle or a dose of streptozotocin (STZ; 25 mg/kg) that induces insulin resistance. To assess insulin resistance, glucose levels were measured 15, 30, 60, 120, and 180 min after an insulin injection (0.75 U/kg). Nine days later, the rats were given extended access to intravenous self-administration (IVSA) of nicotine (0.015, 0.03, 0.06 mg/kg) in an operant box where they consumed their respective diet ad libitum and performed responses for water deliveries. Each nicotine dose was delivered for 4 days with 3 intermittent days of abstinence in their home cage. The day after the last IVSA session, physical signs were compared following administration of mecamylamine (3.0 mg/kg) to precipitate nicotine withdrawal. The results revealed that there were no changes in insulin resistance or nicotine intake in HFD alone rats regardless of sex. Insulin resistance was observed in HFD-fed rats that received STZ, and the magnitude of this effect was greater in males versus females. Our major finding was that nicotine intake was greater among HFD + STZ female rats as compared to males. Lastly, the physical signs of withdrawal were similar across all groups. Our results suggest that females diagnosed with disorders that disrupt insulin signaling, such as diabetes may be at risk of greater vulnerability to nicotine use due to enhanced reinforcing effects of this drug.