The Brain on Drugs: From Reward to Addiction.

https://www.cell.com/trends/cognitive-sciences/pdf/S1364-6613(11)00037-4.pdf

The neural mechanisms of inter-temporal decision-making: understanding variability

The purpose of this review is to discuss ways to think about and study sex differences in preclinical animal models. We use the framework of addiction, in which animal models have excellent face and construct validity, to illustrate the importance of considering sex differences. There are four types of sex differences: qualitative, quantitative, population, and mechanistic. A better understanding of the ways males and females can differ will help scientists design experiments to characterize better the presence or absence of sex differences in new phenomena that they are investigating. We have outlined major quantitative, population, and mechanistic sex differences in the addiction domain using a heuristic framework of the three established stages of the addiction cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Female rats, in general, acquire the self-administration of drugs and alcohol more rapidly, escalate their drug taking with extended access more rapidly, show more motivational withdrawal, and (where tested in animal models of "craving") show greater reinstatement. The one exception is that female rats show less motivational withdrawal to alcohol. The bases for these quantitative sex differences appear to be both organizational, in that estradiol-treated neonatal animals show the male phenotype, and activational, in that the female phenotype depends on the effects of gonadal hormones. In animals, differences within the estrous cycle can be observed but are relatively minor. Such hormonal effects seem to be most prevalent during the acquisition of drug taking and less influential once compulsive drug taking is established and are linked largely to progesterone and estradiol. This review emphasizes not only significant differences in the phenotypes of females and males in the domain of addiction but emphasizes the paucity of data to date in our understanding of those differences.

https://pharmrev.aspetjournals.org/content/pharmrev/68/2/242.full.pdf

Sex Differences in Animal Models: Focus on Addiction

https://boerenlandvogels.nl/sites/default/files/Dwyer%20et%20al_%20Pharmacol%20Ther_2009.pdf

The Dynamic Effects of Nicotine on the Developing Brain

基因科学与亲子鉴定——国际流行病与公众健康杂志J Epidemiol Community Health

This study compared the rewarding and aversive effects of nicotine in adolescent, adult, and adult rats pre-exposed to nicotine during adolescence. Prior to conditioning, the rats were tested for their initial preference for either of 2 distinct compartments. Adolescent and adult rats then received various nicotine doses in their initially non-preferred side on one day and saline in the other side on alternate days. This 2-day procedure was repeated over 8 consecutive days. Following conditioning, rats were re-tested for their preference. Another cohort of adolescent and adult rats were conditioned with various doses of d-amphetamine. Nicotine produced CPP in an inverted U-shaped manner in both age groups. However, adolescents displayed a larger upward shift in CPP that was significant across a wider dose range relative to adults. There were no developmental differences to CPP produced by d-amphetamine. In a final study, adolescents were prepared with pumps that delivered nicotine for 14 days. These rats were conditioned later as adults using the same procedures used previously. Pre-exposure to nicotine during adolescence diminished the aversive effects produced by the highest nicotine dose in naive adults. Taken together, these studies provide a basis for enhanced vulnerability to nicotine during adolescence.

https://works.bepress.com/laura_odell/9/download/

Enhanced vulnerability to the rewarding effects of nicotine during the adolescent period of development

Introduction The objective of this study was to examine age-, hormone-, and sex-dependent differences to the behavioral effects of nicotine using place-conditioning procedures in female rats. Methods Animals received nicotine in their initially nonpreferred side and saline on alternate days in their initially preferredside.Followingfourconditioningtrials,ratswereretested for their preference. To examine developmental differences, we compared the effects of various nicotine doses in female and male adolescent and adult rats. To examine whether our developmental differences are specific to nicotine, we included adolescent and adult females that were conditioned with various amphetamine doses. To examine the influence of hormones on the behavioral effects of nicotine, we compared the effects of various nicotine doses in intact females that were tested during different phases of the estrous cycle and in separate females that were ovariectomized. Results The rewarding effects of nicotine were observed at a lower nicotine dose in adolescents versus adults. Amphetamineproducedsimilarrewardingeffectsacrossagegroupsin females. The shifts in preference produced by nicotine were similar across the different phases of estrous. Females lacking ovarian hormones did not display rewarding effects of nicotine at any dose. The rewarding effects of nicotine were enhanced in adult female versus male rats. An intermediate nicotine dose produced rewarding effects in adolescent male but not female rats, suggesting that developmental differences to nicotine may be enhanced in males. Conclusion In females, nicotine reward is enhanced during adolescence and is facilitated by the presence of ovarian hormones.

/pdf/female-rats-display-dose-dependent-differences-to-the-2bl83qwt4n.pdf

Female rats display dose-dependent differences to the rewarding and aversive effects of nicotine in an age-, hormone-, and sex-dependent manner

https://works.bepress.com/laura_odell/15/download/

Adolescent nicotine exposure produces less affective measures of withdrawal relative to adult nicotine exposure in male rats.

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.

/pdf/behavioral-biochemical-and-molecular-indices-of-stress-are-3qrrlfn6gy.pdf

Behavioral, Biochemical, and Molecular Indices of Stress are Enhanced in Female Versus Male Rats Experiencing Nicotine Withdrawal.

The behavioral effects of nicotine withdrawal are lower in adolescent versus adult rats. However, the neurochemical mechanisms that mediate these developmental differences are unknown. Previous studies have shown that extracellular levels of dopamine in the nucleus accumbens (NAcc) are reduced in adult rats experiencing withdrawal. This study compared dopamine levels in the NAcc of male adolescent and adult rats experiencing nicotine withdrawal. Animals were prepared with subcutaneous pumps that delivered an equivalent nicotine dose in these age groups. Following 13 days of nicotine exposure, rats were implanted unilaterally with microdialysis probes into the NAcc and ipsilateral ventral tegmental area (VTA). The next day, dialysate levels were collected following systemic administration of the nicotinic-receptor antagonist mecamylamine to precipitate withdrawal. Mecamylamine produced an average % decrease in NAcc dopamine that was lower in adolescents (20%) versus adults (44%). Similar developmental differences were observed with the dopaminergic (DOPAC and HVA) but not serotonergic (5-HIAA) metabolites. A follow-up study compared NAcc dopamine in adolescent and adult rats receiving intra-VTA administration of bicuculline, which reduces γ-aminobutyric acid (GABA) inhibition of dopamine transmission. The results revealed that blockade of GABAA receptors in the VTA produced a two-fold increase in NAcc dopamine of adults but not adolescents. These results provide a potential mechanism involving dopamine that mediates developmental differences in nicotine withdrawal. Specifically, they suggest that GABA systems are underdeveloped during adolescence and this reduced inhibition of dopamine neurons in the VTA may lead to reduced decreases in NAcc dopamine of young animals experiencing withdrawal. Synapse 64:136–145, 2010. © 2009 Wiley-Liss, Inc.

Nicotine withdrawal produces a decrease in extracellular levels of dopamine in the nucleus accumbens that is lower in adolescent versus adult male rats.

Luis A. Natividad

Papers

Enhanced vulnerability to the rewarding effects of nicotine during the adolescent period of development

Female rats display dose-dependent differences to the rewarding and aversive effects of nicotine in an age-, hormone-, and sex-dependent manner

Adolescent nicotine exposure produces less affective measures of withdrawal relative to adult nicotine exposure in male rats.

Behavioral, Biochemical, and Molecular Indices of Stress are Enhanced in Female Versus Male Rats Experiencing Nicotine Withdrawal.

Nicotine withdrawal produces a decrease in extracellular levels of dopamine in the nucleus accumbens that is lower in adolescent versus adult male rats.