Browsing by Subject "Allopregnanolone"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Allopregnanolone during short-term smoking abstinence: associations with depressive symptoms, smoking-related symptomatology and nicotine response
    (2012-11) Allen, Alicia Marie
    Background: Allopregnanolone (ALLO) is a neuroactive steroid metabolized from progesterone and, therefore, varies by menstrual phase in premenopausal women. Previously published literature has shown that risk for relapse to smoking varies by menstrual phase. Further, recent preclinical research indicates that ALLO may protect against drug abuse behaviors. Therefore, this dissertation project aims to characterize ALLO by menstrual phase in women with and without depressive symptoms (Paper #1) and explore the effect of ALLO on smoking-related symptomatology (SRS; Paper #2) and nicotine response (NR; Paper #3) during short-term smoking abstinence. Methods: At screening, participants (n=87) were stratified by depressive symptoms status and, using a controlled cross-over study design, were randomized to testing order (i.e., follicular (F) menstrual phase followed by the luteal (L) phase or vice versa (L-F)). The six-day testing week consisted of two days of ad libitum smoking followed by four days of biochemically verified smoking abstinence. ALLO was measured twice during each testing week: during ad libitum smoking and on the fourth day of smoking abstinence. Participants completed daily forms to assess SRS during the testing week. On the fourth day of smoking abstinence, participants participated in a NR lab session. Growth curve and covariance pattern models, adjusted for menstrual phase and testing order, were used to assess the effect of ALLO on SRS and NR, respectively. Results: In the first paper (n=84), a significant menstrual phase difference was observed in the change in ALLO level during smoking cessation. Specifically, ALLO decreased by 10% in the F phase and increased by 31% in the L phase (p<0.01). There were no significant differences in ALLO levels between the depressive symptoms groups. In the second paper (n=64), the absolute level of ALLO on the day before quit was significantly associated with the following: (1) perceived stress on the day before quit (β=-2.25, p<0.01), (2) the change in perceived stress during smoking abstinence (β=0.79, p<0.01), and (3) premenstrual symptoms of pain and water retention on the day before quit (β=1.09, p<0.01; β=1.08, p<0.01; respectively). The change in ALLO during smoking abstinence was significantly associated with the following: (1) positive and negative affect on the day before quit (β=1.15, p<0.01; β=1.04, p=0.04; respectively), (2) perceived stress on the day before quit (β=-1.77, p=0.01), (3) the change in perceived stress during smoking cessation (β=0.17, p<0.01), and (4) the change in depressive symptoms on the day of quit (β=-1.52, p=0.02). Finally, in the third paper (n=77), ALLO had a significant, positive association with the following variables prior to initiation of nicotine nasal spray: systolic blood pressure (β=0.85, p=0.04), diastolic blood pressure (β=1.19, p<0.01), and subjective levels of physical symptoms (β=0.58, p<0.01), dizziness (β =0.88, p<0.01), jitteriness (β=0.90, p=0.04) and pleasantness (β=2.05, p=0.041). ALLO also had significant associations with changes in cognition from baseline to post nicotine nasal spray use: specifically, discriminability (a measure of attention; β=1.15, p=0.05), and bias (a measure of impulsivity; β=0.12, p=0.02). Conclusion: ALLO varied significantly by menstrual phase and smoking status, and had a significant effect on several measures of SRS and NR. While several of these associations were favorable (i.e., perceived stress on the day before quit and pleasantness on the fourth day of smoking abstinence), some were not (i.e., premenstrual symptoms on the day before quit and increased subjective report of physical symptoms on the fourth day of smoking abstinence). Therefore, it remains unknown whether or not ALLO is a protective factor against drug abuse behaviors. Additional research is needed to explore the role of ALLO directly on smoking cessation outcomes.
  • Thumbnail Image
    Item
    The effects of progestins on animal models of cocaine bingeing and relapse.
    (2009-10) Anker, Justin Jack
    Female gonadal hormones influence responses to stimulant drugs, and estrogen (EST) facilitates while progesterone (PROG) attenuates these responses. The PROG metabolite allopregnanolone (ALLO) also suppresses responses to cocaine, and it may be responsible for PROG's attenuating effects. The research included in this thesis is concerned with the influence of PROG and its metabolite ALLO on animal models of escalation or bingeing of cocaine of intake (Experiments 1 and 2) and reinstatement of extinguished drug seeking or relapse (Experiments 3, 4, and 5). Experiment 1 focused on the influence of PROG on the escalation of cocaine self-administration that occurs with long (6 h) daily access in ovariectomized (OVX) and gonadally intact female rats treated with either EST or VEH. Following the escalation procedure, treatment groups were compared on a progressive ratio (PR) schedule for several doses of cocaine. This research was extended to the PROG metabolite ALLO in Experiment 2a. Gonadally intact female rats were treated with ALLO or VEH and allowed to earn either i.v. cocaine infusions or sucrose deliveries under a long-access (LgA) escalation procedure. In Experiment 2b sucrose was used to determine the specificity of ALLO's effects on the escalation of cocaine self-administration, and in Experiment 2c control conditions were used to examine the effect of ALLO on locomotor activity and operant behavior reinforced by food. In Experiment 3 the effects of PROG on the reinstatement of cocaine-seeking behavior were examined in OVX and intact female rats that received EST or VEH treatment. In Experiment 4 the mechanism of PROG's effects was further studied by using finasteride, a 5-alpha reductase inhibitor that prevents the metabolism of PROG into ALLO. Finasteride (FIN) was administered concurrently with PROG to determine whether it could block the attenuating effects of PROG on cocaine-primed reinstatement, thus implicating ALLO in PROG's actions. Allopregnanolone was also tested on cocaine-primed reinstatement in male and female rats to examine possible sex-specific treatment effects. In the final experiment (Experiment 5), the effects of ALLO were examined on stress-induced reinstatement by injecting rats with yohimbine (YOH) to generate a stressful condition. Results from Experiment 1 indicated that EST facilitated while PROG attenuated the escalation of cocaine self-administration during LgA, but neither hormone affected cocaine-maintained responding under a PR schedule. Experiment 2a confirmed that ALLO also attenuated the escalation of cocaine self-administration, and 2b indicated that ALLO did not affect the escalation of intake of a nondrug reward (i.e., sucrose). Experiment 2c revealed that ALLO also had no effect on locomotor activity or operant food-reinforced behavior. Experiments 3 and 4 demonstrated that PROG and ALLO also decreased the reinstatement of cocaine-seeking behavior precipitated by i.p. injections of cocaine. Results from Experiment 4 further indicated that the attenuation of cocaine seeking by PROG may be attributed to its conversion into ALLO, as blocking this conversion with FIN prevented PROG's attenuating effects. In addition, the effects of ALLO were specific to females and did not extend to males. Finally, in Experiment 5, female rats exhibited greater reinstatement of cocaine seeking following a stressful stimulus (YOH) than males, and the attenuating effects of ALLO on this behavior were specific to females. Taken together, these results demonstrated a role for PROG and ALLO in suppressing the bingeing and relapse associated with cocaine abuse. These effects were specific to cocaine seeking in females (vs. males) and did not extend to behavior maintained by a nondrug rewards (i.e., sucrose or food) or locomotor activity.