Nicotine withdrawal in adolescent and adult rats.

Department of Neuropharmacology, CVN-7, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037, USA.
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 07/2004; 1021:167-74. DOI:10.1196/annals.1308.022
Source: PubMed

ABSTRACT Previous research with animal models has demonstrated that adolescent rats display heightened sensitivity to the reinforcing and stimulant effects of nicotine relative to adult rats. Little work has focused on the response of adolescent rats to measures of nicotine withdrawal. To test the hypothesis that adolescent rats may be differentially sensitive to withdrawal relative to their adult counterparts, the present study was designed to compare precipitated withdrawal in adolescent and adult rats following chronic nicotine administration. Adult and adolescent rats were prepared with subcutaneous osmotic minipumps that delivered either saline or nicotine (9 mg/kg per day, salt; N =12 per group). All rats were challenged with the nicotinic receptor antagonist mecamylamine (1.5 mg/kg) on day 7 of chronic nicotine treatment. Twenty minutes after the injection, overt somatic signs of withdrawal (i.e., eye blinks, writhes, body shakes, teeth chatter, gasps, and ptosis) were recorded for 10 min. Adult rats were observed on postnatal day 73-77, and adolescent rats were tested on postnatal day 36-40. The results revealed a robust increase in mecamylamine-induced withdrawal signs in adult rats receiving chronic nicotine relative to adult rats receiving saline. In contrast, mecamylamine did not precipitate withdrawal signs in adolescent rats receiving chronic nicotine. These results indicate that there is decreased sensitivity to the somatic aspects of nicotine withdrawal in adolescent rats that may maximize the reinforcing effects of nicotine during adolescence by minimizing the aversive effects of abstinence.

0 0
  • [show abstract] [hide abstract]
    ABSTRACT: Women are particularly more vulnerable to tobacco use than men. This review proposes a unifying hypothesis that females experience greater rewarding effects of nicotine and more intense stress produced by withdrawal than males. We also provide a neural framework whereby estrogen promotes greater rewarding effects of nicotine in females via enhanced dopamine release in the nucleus accumbens (NAcc). During withdrawal, we suggest that corticotropin-releasing factor (CRF) stress systems are sensitized and promote a greater suppression of dopamine release in the NAcc of females versus males. Taken together, females display enhanced nicotine reward via estrogen and amplified effects of withdrawal via stress systems. Although this framework focuses on sex differences in adult rats, it is also applied to adolescent females who display enhanced rewarding effects of nicotine, but reduced effects of withdrawal from this drug. Since females experience strong rewarding effects of nicotine, a clinical implication of our hypothesis is that specific strategies to prevent smoking initiation among females are critical. Also, anxiolytic medications may be more effective in females that experience intense stress during withdrawal. Furthermore, medications that target withdrawal should not be applied in a unilateral manner across age and sex, given that nicotine withdrawal is lower during adolescence. This review highlights key factors that promote nicotine use in females, and future studies on sex-dependent interactions of stress and reward systems are needed to test our mechanistic hypotheses. Future studies in this area will have important translational value toward reducing health disparities produced by nicotine use in females.
    Neuropharmacology 05/2013; · 4.11 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Stress is a major factor that promotes tobacco use and relapse during withdrawal. Although women are more vulnerable to tobacco use than men, the manner in which stress contributes to tobacco use in women versus men is unclear. Thus, the goal of this study was to compare behavioral and biological indices of stress in male and female rats during nicotine withdrawal. Since the effects of nicotine withdrawal are age-dependent, this study also included adolescent rats. An initial study was conducted to provide comparable nicotine doses across age and sex during nicotine exposure and withdrawal. Rats received sham surgery or an osmotic pump that delivered nicotine. After 14 days of nicotine, the pumps were removed and controls received a sham surgery. Twenty-four hours later, anxiety-like behavior and plasma corticosterone were assessed. The nucleus accumbens (NAcc), amygdala, and hypothalamus were examined for changes in corticotropin-releasing factor (CRF) gene expression. In order to differentiate the effects of nicotine withdrawal from exposure to nicotine, a cohort of rats did not have their pumps removed. The major finding is that during nicotine withdrawal, adult females display higher levels of anxiety-like behavior, plasma corticosterone, and CRF mRNA expression in the NAcc relative to adult males. However, during nicotine exposure, adult males exhibited higher levels of corticosterone and CRF mRNA in the amygdala relative to females. Adolescents displayed less nicotine withdrawal than adults. Moreover, adolescent males displayed an increase in anxiety-like behavior and an up-regulation of CRF mRNA in the amygdala during nicotine exposure and withdrawal. These findings are likely related to stress produced by the high doses of nicotine that were administered to adolescents to produce equivalent levels of cotinine as adults. In conclusion, these findings suggest that intense stress produced by nicotine withdrawal may contribute to tobacco use in women.
    Frontiers in Psychiatry 01/2013; 4:38.
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Much evidence indicates that individuals use tobacco primarily to experience the psychopharmacological properties of nicotine and that a large proportion of smokers eventually become dependent on nicotine. In humans, nicotine acutely produces positive reinforcing effects, including mild euphoria, whereas a nicotine abstinence syndrome with both somatic and affective components is observed after chronic nicotine exposure. Animal models of nicotine self-administration and chronic exposure to nicotine have been critical in unveiling the neurobiological substrates that mediate the acute reinforcing effects of nicotine and emergence of a withdrawal syndrome during abstinence. However, important aspects of the transition from nicotine abuse to nicotine dependence, such as the emergence of increased motivation and compulsive nicotine intake following repeated exposure to the drug, have only recently begun to be modeled in animals. Thus, the neurobiological mechanisms that are involved in these important aspects of nicotine addiction remain largely unknown. In this review, we describe the different animal models available to date and discuss recent advances in animal models of nicotine exposure and nicotine dependence. This review demonstrates that novel animal models of nicotine vapor exposure and escalation of nicotine intake provide a unique opportunity to investigate the neurobiological effects of second-hand nicotine exposure, electronic cigarette use, and the mechanisms that underlie the transition from nicotine use to compulsive nicotine intake.
    Frontiers in Psychiatry 01/2013; 4:41.


1 Download
Available from