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Browsing by Subject "Withdrawal"

Now showing 1 - 4 of 4
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    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.
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    Behavioral and neurobiological consequences of intermittent exposure to addictive drugs.
    (2010-02) Rothwell, Patrick Eldredge
    These studies were undertaken to better understand how repeated exposure to addictive drugs leads to adaptations in brain function and behavior related to the development of addiction. They are predicated on evidence that the mere presence of a drug in the body is not the sole determinant of adaptation - rather, the pattern of drug exposure is a key variable, with intermittent exposure making the brain reward system increasingly sensitive to drugs and leaving individuals susceptible to relapse. These experiments were designed to examine whether events occurring during the offset of drug action may contribute to the unique effects of intermittent drug exposure. The first series of experiments develops a set of behavioral measures that can be used to resolve and quantify a state of acute withdrawal caused by the offset of drug action. The second series of experiments utilizes these measures to investigate whether recurrent episodes of acute withdrawal contribute to the development of psychomotor sensitization - a specific consequence of intermittent drug exposure related to adaptations in the brain reward system. The final series of experiments describes a specific synaptic adaptation in a key component of the brain reward system (the nucleus accumbens) that is caused by intermittent drug exposure, related to the development of psychomotor sensitization, and reversed by experiences linked to relapse. The results of these studies suggests new and provocative interactions between neural circuits mediating reward and aversion, which may help identify and explain forms of neural plasticity that underlie the development of drug addiction.
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    Neural mechanisms of anxiety during opiate withdrawal:role of the ventral tegmental area and extended amygdala.
    (2011-07) Radke, Anna Kay
    Exposure to addictive drugs alters neural circuits involved in reward and motivation, executive control, habit formation, learning and memory, and negative affect, and all except the last are known to depend on changes in the mesolimbic dopamine system. Negative affective symptoms of withdrawal are common to all drugs of abuse and negatively reinforce drug taking behavior. Using potentiation of the acoustic startle reflex as a measure of anxiety during withdrawal from acute morphine exposure, the experiments detailed in this thesis tested the hypothesis that µ-opioid receptor-mediated activation of VTA dopaminergic neurons is responsible for triggering negative emotional symptoms of withdrawal via recruitment of the extended amygdala. These experiments demonstrate the emergence of a negative affective state that occurs during withdrawal from direct infusion of morphine into the ventral tegmental area (VTA), the origin of the mesolimbic dopamine system. Potentiation of startle during withdrawal from systemic morphine exposure requires a decrease in ì-opioid receptor stimulation in the VTA and can be relieved by systemic or intra-nucleus accumbens administration of a dopamine receptor agonist. Investigation of mechanisms downstream of dopaminergic signaling found a role for type 2 corticotropin-releasing factor receptors following the very first, but not subsequent, opiate exposures. Together these results suggest that transient activation of the VTA mesolimbic dopamine system triggers the expression of anxiety during opiate withdrawal, possibly via direct recruitment of the extended amygdala. This conclusion provides unique insight into the neural mechanisms responsible for negative reinforcement of drug taking during the earliest stages of dependence.
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    Psychophysiological and fMRI investigations of tobacco cue reactivity.
    (2010-06) Engelmann, Jeffrey Michael
    Development of new smoking-cessation therapies may be facilitated by identifying the neural basis of smoking-related emotional responses. In this dissertation, the affective consequences of cigarette smoking and abstinence were modeled in rats and humans using a potentiated-startle paradigm. In rats, repeated daily nicotine injections resulted in increased startle amplitude 2 h after nicotine exposure, which is consistent with the emergence of an anxiety-like withdrawal episode. In humans, startle responses to tobacco, pleasant, neutral, and unpleasant cues were measured in nonsmokers, nonabstinent smokers, and smokers who were 24 h into a 48 h abstinence period. Startle amplitude was potentiated during unpleasant cues in nonsmokers and abstinent smokers, but not in nonabstinent smokers, which suggests that smoking a cigarette reduced anxiety. Event-related brain potentials also suggested that abstinent smokers were more emotionally reactive than nonsmokers and nonabstinent smokers to both tobacco cues and unpleasant cues. An additional, functional magnetic resonance imaging study found that that two brain regions, the dorsal striatum and the anterior cingulate cortex, were involved in the expression of abstinent smokers' emotional responses to tobacco and unpleasant cues. These results suggest negative affect may be important in maintaining cigarette smoking and that the potentiated startle paradigm is an ideal model for preclinical and clinical studies of smoking-related emotional responses.