Moran-Santa Maria MM, McRae-Clark A, Baker NL, Ramakrishnan V, Brady KT. Yohimbine administration and cue-reactivity in cocaine-dependent individuals. Psychopharmacology (Berl). 2014 Oct;231(21):4157-65. PubMed PMID: 24710621; PubMed Central PMCID: PMC4190106.
RATIONALE:Preclinical studies suggest that stress potentiates cue-induced cocaine seeking and that this effect is more pronounced in females. These findings have not been characterized in clinical populations.
OBJECTIVES:The objectives of this study were to examine the impact a pharmacological stressor, alpha-2 adrenergic receptor antagonist yohimbine, on the subjective, endocrine, and physiologic responses to drug-paired cues cocaine-dependent men and women.
METHODS:In a double-blind placebo-controlled cross-over study, cocaine-dependent men (n = 32), cocaine-dependent women (n = 30), control men (n = 32), and control women (n = 25) received either yohimbine or placebo prior to two cocaine cue exposure sessions.
RESULTS:Yohimbine increased ratings of anxiety both before (p < 0.001) and after (p = 0.035) cues, and the post-cue increase in anxiety was more pronounced in women (p = 0.001). Yohimbine also significantly increased craving, compared with placebo (p < 0.05), following the cue presentation, and this effect was greater in women than men (gender by treatment interaction; p = 0.006). Yohimbine also increased salivary cortisol (p < 0.001) and dehydroepiandrosterone (p = 0.003) levels, regardless of diagnostic group. Women had a significantly greater heart rate response following yohimbine as compared with men (p < 0.001).
CONCLUSIONS: Stress may increase the salience of cocaine cues for cocaine-dependent women as compared with men. This suggests gender differences in vulnerability to craving and relapse under stressful conditions.
Cason AM, Aston-Jones G. Role of orexin/hypocretin in conditioned sucrose-seeking in female rats. Neuropharmacology. 2014 Nov;86:97-102. PubMed PMID: 25036612; PubMed Central PMCID: PMC4188723.
The orexin/hypocretin system has recently been implicated in reward-seeking, especially for highly salient food and drug rewards. Given that eating disorders affect women more than men, we reasoned that the orexin system may be strongly engaged in female rats, and during periods of food restriction as we recently reported in male rats. Therefore, the present study examined the involvement of the orexin system in operant responding for sucrose, and in cue-induced reinstatement of extinguished sucrose-seeking, in ad libitum fed vs. food-restricted female subjects. Female Sprague Dawley rats were trained to self-administer sucrose pellets, and we determined the effects of pretreatment with the OxR1 receptor antagonist SB 334867 (SB; 10-30 mg/kg) on fixed ratio (FR) sucrose self-administration, and on cue-induced reinstatement of extinguished sucrose-seeking. SB decreased sucrose self-administration in food-restricted but not in ad libitum-fed females. SB did not alter active lever responding during cue-induced reinstatement of sucrose-seeking in either feeding group. These results confirm our previous results in male rats that signaling at the OxR1 receptor is involved in the sucrose reinforcement and self-administration in food-restricted subjects. However, the finding that SB is ineffective at attenuating cue-induced reinstatement in females, but was effective in food-restricted males, leads us to conclude that food seeking induced by conditioned stimuli engages the orexin system differentially in males and females.
Saladin ME, McClure EA, Baker NL, Carpenter MJ, Ramakrishnan V, Hartwell KJ, Gray KM. Increasing progesterone levels are associated with smoking abstinence among free-cycling women smokers who receive brief pharmacotherapy. Nicotine Tob Res.
2015 Apr;17(4):398-406. PubMed PMID: 25762749.
INTRODUCTION: Preclinical and human laboratory research suggests that (a) progesterone may decrease drug reward, craving, and smoking behavior, and (b) estradiol may enhance drug reward and smoking behavior. A modest majority of treatment research examining the relationship between menstrual cycle phase and outcomes suggests that the luteal menstrual phase, with its uniquely higher progesterone levels, is associated with better cessation outcomes. However, no studies to date have examined the effects of naturally occurring variation in progesterone and estradiol levels on medication-assisted smoking cessation. The present study sought to fill this notable gap in the treatment literature.
METHODS: Weekly plasma progesterone and estradiol levels were obtained from nicotine-dependent female smokers enrolled in a 4-week cessation trial. Participants (N = 108) were randomized to receive a 4-week course of either varenicline (VAR) tablets and placebo patches or placebo tablets and nicotine patches. Plasma samples were obtained 1 week before their cessation attempt and weekly during medication administration. Abstinence was assessed weekly.
RESULTS: Weekly hormone data replicated commonly observed menstrual cycle patterns of progesterone and estradiol levels. Importantly, increases in progesterone level were associated with a 23% increase in the odds for being abstinent within each week of treatment. This effect was driven primarily by nicotine patch-treated versus VAR-treated females.
CONCLUSIONS: This study was the first to identify an association between progesterone level (increasing) and abstinence outcomes in free-cycling women smokers who participated in a medication-based treatment. Furthermore, the potential benefits of progesterone may vary across different pharmacotherapies. Implications of these findings for smoking cessation intervention are discussed.
Zhou L, Ghee SM, See RE, Reichel CM. Oxytocin differentially affects sucrose taking and seeking in male and female rats. Behav Brain Res. 2015 Apr 15;283:184-90.
PubMed PMID: 25647756; PubMed Central PMCID: PMC4387851.
Oxytocin has a modulatory role in natural and drug reward processes. While the role of oxytocin in pair bonding and reproduction has been extensively studied, sex differences in conditioned and unconditioned behavioral responses to oxytocin treatment have not been fully characterized. Here, we determined whether male and female rats would show similar dose response curves in response to acute oxytocin on measures of locomotor activity, sucrose seeking, and sucrose intake. Male and freely cycling female rats received vehicle or oxytocin (0.1, 0.3, 1, 3mg/kg, IP) injections before behavioral tests designed to assess general motor activity, as well as sucrose self-administration and seeking. Lower doses of oxytocin decreased motor activity in a novel environment in females relative to males. Likewise, lower doses of oxytocin in females decreased responding for sucrose during maintenance of sucrose self-administration and reinstatement to sucrose-conditioned cues. However, sucrose seeking in response to a sucrose prime was only decreased by the highest oxytocin dose in both sexes. In general, oxytocin had similar effects in both sexes. However, females were more sensitive to lower doses of oxytocin than males. These findings are consistent with the notion that oxytocin regulates many of the same behaviors in males and females, but that the effects are typically more profound in females. Therapeutic use of oxytocin should include sex as a factor in determining dose regimens.
Gray KM, McClure EA, Baker NL, Hartwell KJ, Carpenter MJ, Saladin ME. An exploratory short-term double-blind randomized trial of varenicline versus nicotine patch for smoking cessation in women. Addiction. 2015 Jun;110(6):1027-34. PubMed PMID: 25727442; NIHMSID: 668188.
AIMS: Within a parent study examining ovarian hormone effects on smoking cessation in women, we conducted an exploratory short-term trial of varenicline versus transdermal nicotine patch.
DESIGN: Double-blind double-dummy randomized trial.
SETTING: Single-site out-patient research clinic in the United States.
PARTICIPANTS: Female smokers, ages 18-45 years and averaging ≥10 cigarettes per day for at least 6 months (n = 140).
INTERVENTIONS: Participants were randomized to receive a 4-week course of (a) varenicline tablets and placebo patches (n = 67) or (b) placebo tablets and nicotine patches (n = 73). Two brief cessation counseling sessions were provided for all participants.
MEASUREMENTS: The outcome of primary clinical interest was 2-week end-of-treatment abstinence. Secondary outcomes included 1- and 4-week end-of treatment abstinence and abstinence at a post-treatment follow-up visit occurring 4 weeks after treatment conclusion. Breath carbon monoxide (≤ 10 parts per million) was used to confirm biochemically self-reported abstinence.
FINDINGS: Two-week end-of-treatment abstinence was achieved by 37.3% (25 of 67) of varenicline participants and by 17.8% (13 of 73) of nicotine patch participants [odds ratio (OR) = 2.7, 95% confidence interval (CI) = 1.3-6.0, P = 0.011]. One-week (44.8 versus 20.6%, OR = 3.1, 95% CI = 1.5-6.6, P = 0.003) and 4-week (22.4 versus 9.6%, OR = 2.7, 95% CI = 1.0-7.2, P = 0.043) end-of-treatment abstinence similarly favored varenicline, although post-treatment follow-up Russell Standard abstinence was not significantly different between groups (23.9 versus 13.7%, OR = 2.0, 95% CI = 0.8-4.7, P = 0.126).
CONCLUSION: In an exploratory 4-week head-to-head trial in female smokers, varenicline, compared with nicotine patch, more than doubled the odds of end-of-treatment abstinence, although this diminished somewhat at post-treatment follow-up.