Raina D. Pang

Sex differences in negative affect and lapse behavior during acute tobacco abstinence: a laboratory study.

Heightened negative affect during acute tobacco abstinence in women relative to men could be an important factor underlying sex differences in smoking motivation. However, little controlled experimental work addresses this hypothesis. The current study investigated sex differences in withdrawal-related negative affect, time to start smoking on a lab analogue smoking lapse task, and the interrelation between sex, withdrawal-related negative affect, and smoking lapse behavior. Following a baseline session, current smokers (women: n = 68, men: n = 131) attended two counterbalanced lab sessions (16 hours smoking abstinence and ad libitum smoking) during which they completed self-report measures of mood and withdrawal symptoms followed by a laboratory analogue smoking lapse task. In this task participants are monetarily rewarded for delaying smoking. Performance on this task serves as an analogue model of smoking lapse behavior by measuring smokers capability to resist temptation to smoke under conditions where abstinence is advantageous. Females showed greater abstinence induced increases in composite negative affect as well as several particular negative affect states (i.e., POMS Anger, Anxiety, Depression, and Confusion, ps < .05) but no differences in abstinence induced changes in other forms of affect or craving. Females also exhibited marginally greater abstinence induced decreases in their willingness to delay smoking for money (p = .10), which was mediated by abstinence induced increases in anger (p < .05). These results suggest that differential sensitivity to abstinence induced negative affect, particularly anger, could underlie sex specific smoking patterns. Negative affect during tobacco abstinence may be an important factor for understanding and treating nicotine addiction in women.

Mapping functional brain activation using [14C]-iodoantipyrine in male serotonin transporter knockout mice.

Background Serotonin transporter knockout mice have been a powerful tool in understanding the role played by the serotonin transporter in modulating physiological function and behavior. However, little work has examined brain function in this mouse model. We tested the hypothesis that male knockout mice show exaggerated limbic activation during exposure to an emotional stressor, similar to human subjects with genetically reduced transcription of the serotonin transporter. Methodology/Principal Findings Functional brain mapping using [14C]-iodoantipyrine was performed during recall of a fear conditioned tone. Regional cerebral blood flow was analyzed by statistical parametric mapping from autoradiographs of the three-dimensionally reconstructed brains. During recall, knockout mice compared to wild-type mice showed increased freezing, increased regional cerebral blood flow of the amygdala, insula, and barrel field somatosensory cortex, decreased regional cerebral blood flow of the ventral hippocampus, and conditioning-dependent alterations in regional cerebral blood flow in the medial prefrontal cortex (prelimbic, infralimbic, and cingulate). Anxiety tests relying on sensorimotor exploration showed a small (open field) or paradoxical effect (marble burying) of loss of the serotonin transporter on anxiety behavior, which may reflect known abnormalities in the knockout animals sensory system. Experiments evaluating whisker function showed that knockout mice displayed impaired whisker sensation in the spontaneous gap crossing task and appetitive gap cross training. Conclusions This study is the first to demonstrate altered functional activation in the serotonin transporter knockout mice of critical nodes of the fear conditioning circuit. Alterations in whisker sensation and functional activation of barrel field somatosensory cortex extend earlier reports of barrel field abnormalities, which may confound behavioral measures relying on sensorimotor exploration.

Depressive symptoms, negative urgency and substance use initiation in adolescents

BACKGROUND Studies show depressive symptoms are associated with substance use in adolescents, but the mechanism underlying this association is still unclear. This study investigated negative urgency - the disposition to rash action during emotional states - as a factor explaining relations between depressive symptoms and use of several substances. METHODS In this cross-sectional study, 476 adolescents (mean age 14.5 years) completed self-report surveys. Regression models and products of coefficient analyses examined the overall relation of depressive symptoms to substance use and negative urgency as a statistical mediator of this association. RESULTS Depression levels associated with increased likelihood of lifetime use of cigarettes, other forms of tobacco, marijuana, alcohol, inhalants, prescription painkillers, and any substance. Relations between depression levels and lifetime use of alcohol, inhalants, and any substance were accounted for (i.e., statistically mediated) by negative urgency. In adolescents endorsing lifetime use, depression levels associated with younger age of first use of other forms of tobacco and alcohol as well as use frequency of cigarette, alcohol, and composite frequency. Negative urgency accounted for the covariance between depression level and age of first use of alcohol, but did not for other forms of tobacco or frequency of use of any substances. CONCLUSIONS Depression levels are associated with lifetime use of a variety of substances in early adolescence and targeting this risk factor with preventive efforts may be useful in reducing risk. Negative urgency may be an important target for interventions aimed at alcohol and inhalant use.

Examination of Anxiety Sensitivity and Distress Tolerance as Transdiagnostic Mechanisms Linking Multiple Anxiety Pathologies to Alcohol Use Problems in Adolescents

BACKGROUND Multiple forms of anxiety psychopathology are associated with alcohol use problems in adolescents. Yet, the mechanisms underlying this association are unclear. Anxiety sensitivity (AS) and distress tolerance (DT) represent 2 distinct, conceptually relevant transdiagnostic constructs implicated in multiple manifestations of anxiety that may also underlie alcohol use problems and thereby explain why people with anxiety are more likely to have alcohol problems. METHODS The current cross-sectional study examined whether AS and DT accounted for (i.e., statistically mediated) the relationship between manifest indicators of the 3 common anxiety phenotypes (generalized anxiety, social anxiety, and panic disorders) and alcohol problems in a sample of 534 high school students (14 to 15 years old). RESULTS Multiple manifestations of anxiety were associated with greater alcohol use problems. AS statistically mediated multiple anxiety-alcohol associations, but DT did not. CONCLUSIONS These findings provide preliminary evidence suggesting AS may be an important transdiagnostic target for alcohol prevention programs for those in early adolescence that experience elevated anxiety symptoms.

Functional Brain Activation during Retrieval of Visceral Pain-Conditioned Passive Avoidance in the Rat

Summary Expectation of visceral pain in rats recruits brain areas implicated in acute pain processing and passive avoidance, homologous to findings in humans during pain anticipation. ABSTRACT This study assessed functional brain activation in rats during expectation of visceral pain. Male rats were trained in step‐down passive avoidance (PA) for 2 days. Upon stepping down from a platform, conditioned animals received noxious colorectal distension delivered through a colorectal balloon, whereas the balloon in control rats remained uninflated. On day 3, PA behavior was assessed while [14C]‐iodoantipyrine was infused intravenously, followed by immediate euthanasia. Regional cerebral blood flow‐related tissue radioactivity (rCBF) was analyzed by statistical parametric mapping using 3‐dimensional brains reconstructed from autoradiographic brain slice images. Associated with retrieved PA behavior, conditioned rats compared with control subjects showed increases in rCBF in sensory (anterior insula, somatosensory cortex), limbic/paralimbic regions (anterior cingulate, prelimbic cortex, amygdala), all regions previously reported to show activation during acute visceral pain. Increases in rCBF were also noted in the dorsal hippocampus, nucleus accumbens, and caudate putamen, regions associated with retrieval of PA. Organization of the underlying brain network was further delineated by functional connectivity analysis. This revealed in conditioned rats a strongly and positively connected corticostriatal cluster (cingulate, prelimbic cortex, caudate putamen). The amygdala and cerebellar hemispheres formed another positively connected cluster, which was negatively connected with the corticostriatal cluster, suggesting corticolimbic modulation. Prelimbic cortex, nucleus accumbens, and anterior insula emerged in conditioned animals as hubs. Our results show that during retrieval of PA, brain areas implicated in PA expression as well as those implicated in acute visceral pain processing were recruited, in line with findings from human brain imaging studies on pain expectation.

Functional reorganization of motor and limbic circuits after exercise training in a rat model of bilateral parkinsonism.

Exercise training is widely used for neurorehabilitation of Parkinson’s disease (PD). However, little is known about the functional reorganization of the injured brain after long-term aerobic exercise. We examined the effects of 4 weeks of forced running wheel exercise in a rat model of dopaminergic deafferentation (bilateral, dorsal striatal 6-hydroxydopamine lesions). One week after training, cerebral perfusion was mapped during treadmill walking or at rest using [14C]-iodoantipyrine autoradiography. Regional cerebral blood flow-related tissue radioactivity (rCBF) was analyzed in three-dimensionally reconstructed brains by statistical parametric mapping. In non-exercised rats, lesions resulted in persistent motor deficits. Compared to sham-lesioned rats, lesioned rats showed altered functional brain activation during walking, including: 1. hypoactivation of the striatum and motor cortex; 2. hyperactivation of non-lesioned areas in the basal ganglia-thalamocortical circuit; 3. functional recruitment of the red nucleus, superior colliculus and somatosensory cortex; 4. hyperactivation of the ventrolateral thalamus, cerebellar vermis and deep nuclei, suggesting recruitment of the cerebellar-thalamocortical circuit; 5. hyperactivation of limbic areas (amygdala, hippocampus, ventral striatum, septum, raphe, insula). These findings show remarkable similarities to imaging findings reported in PD patients. Exercise progressively improved motor deficits in lesioned rats, while increasing activation in dorsal striatum and rostral secondary motor cortex, attenuating a hyperemia of the zona incerta and eliciting a functional reorganization of regions participating in the cerebellar-thalamocortical circuit. Both lesions and exercise increased activation in mesolimbic areas (amygdala, hippocampus, ventral striatum, laterodorsal tegmental n., ventral pallidum), as well as in related paralimbic regions (septum, raphe, insula). Exercise, but not lesioning, resulted in decreases in rCBF in the medial prefrontal cortex (cingulate, prelimbic, infralimbic). Our results in this PD rat model uniquely highlight the breadth of functional reorganizations in motor and limbic circuits following lesion and long-term, aerobic exercise, and provide a framework for understanding the neural substrates underlying exercise-based neurorehabilitation.

Alterations in Prefrontal-Limbic Functional Activation and Connectivity in Chronic Stress-Induced Visceral Hyperalgesia

Repeated water avoidance stress (WAS) induces sustained visceral hyperalgesia (VH) in rats measured as enhanced visceromotor response to colorectal distension (CRD). This model incorporates two characteristic features of human irritable bowel syndrome (IBS), VH and a prominent role of stress in the onset and exacerbation of IBS symptoms. Little is known regarding central mechanisms underlying the stress-induced VH. Here, we applied an autoradiographic perfusion method to map regional and network-level neural correlates of VH. Adult male rats were exposed to WAS or sham treatment for 1 hour/day for 10 days. The visceromotor response was measured before and after the treatment. Cerebral blood flow (CBF) mapping was performed by intravenous injection of radiotracer ([14C]-iodoantipyrine) while the rat was receiving a 60-mmHg CRD or no distension. Regional CBF-related tissue radioactivity was quantified in autoradiographic images of brain slices and analyzed in 3-dimensionally reconstructed brains with statistical parametric mapping. Compared to sham rats, stressed rats showed VH in association with greater CRD-evoked activation in the insular cortex, amygdala, and hypothalamus, but reduced activation in the prelimbic area (PrL) of prefrontal cortex. We constrained results of seed correlation analysis by known structural connectivity of the PrL to generate structurally linked functional connectivity (SLFC) of the PrL. Dramatic differences in the SLFC of PrL were noted between stressed and sham rats under distension. In particular, sham rats showed negative correlation between the PrL and amygdala, which was absent in stressed rats. The altered pattern of functional brain activation is in general agreement with that observed in IBS patients in human brain imaging studies, providing further support for the face and construct validity of the WAS model for IBS. The absence of prefrontal cortex-amygdala anticorrelation in stressed rats is consistent with the notion that impaired corticolimbic modulation acts as a central mechanism underlying stress-induced VH.

Anxiety Sensitivity and Negative Urgency: A Pathway to Negative Reinforcement-Related Smoking Expectancies

Objectives:Anxiety sensitivity—fear of anxiety symptoms—may increase motivation to smoke by influencing the development of cognitive expectations regarding smokings negative reinforcing effects; yet, the nature and mechanisms of this pathway are unclear. We hypothesized that relations between anxiety sensitivity and negative reinforcement-related smoking expectancies would be mediated by negative urgency, that is, a trait tendency to act impulsively during negative affect. Methods:In a cross-sectional design, we administered self-report measures of anxiety sensitivity, negative urgency, and negative reinforcement-related smoking outcome and abstinence expectancies to 205 smokers (≥10 cigarettes/d, 34% female, M age = 44.4 years). Results:Anxiety sensitivity was associated with stronger expectancies that smoking alleviates negative affect (&bgr; = 0.30; P < 0.0001) and smoking abstinence exacerbates aversive withdrawal symptoms (&bgr; = 0.24; P = 0.0004). Negative urgency partially mediated the relation between anxiety sensitivity and both types of negative reinforcement-related smoking expectancies (&bgr;s ≥ 0.057; Ps ⩽ 0.007). Results remained significant after statistically controlling for anxiety and nicotine dependence symptoms. Conclusions:Smokers high in anxiety sensitivity tend to display negative urgency, which in turn is related to greater expectations of negative reinforcement consequences of smoking and smoking abstinence. Treatments that mitigate fear of anxiety symptoms and the tendency to act impulsively in response to negative affect (eg, interoceptive exposure, distress tolerance skills training, and mindfulness training) may be particularly useful in assisting with smoking cessation for high-anxiety sensitivity smokers.

Gender differences in negative reinforcement smoking expectancies

BACKGROUND Previous research suggests that females may be more motivated to smoke for negative reinforcement (NR) than males. However, it remains unclear whether gender differences in smoking outcome expectancies for negative smoking reinforcement-an important theoretical and clinical target defined as beliefs that smoking alleviates negative affect-exist above and beyond gender differences in depression and/or other outcome expectancies. METHODS Relations between gender and negative smoking reinforcement expectancies were examined in two independent samples. Sample 1 consisted of non-treatment seeking daily smokers (Male n = 188; Female n = 91) recruited from Southern California (49.5% Black, 32.2% Caucasian, and 18.3% other race/ethnicity). Sample 2 consisted of treatment seeking daily smokers (Male n = 257; Female n = 237) in Northern Florida and Vermont (10.7% Black, 82.9% Caucasian, and 6.4% other). RESULTS Females (vs. males) reported stronger NR smoking expectancies with and without statistically controlling for nicotine dependence, other smoking expectancies, and anxiety and depression in both samples (βs = .06 to .14, ps = .06 to < .001). CONCLUSIONS Beliefs that smoking alleviates negative affect may reflect a gender-specific etiological process disproportionately prominent in women. Enhancing ability to cope with negative affect without smoking or challenge NR expectancies may be particularly important for cessation treatment in women.

Positive and negative affect as predictors of urge to smoke: temporal factors and mediational pathways.

Elucidating interrelations between prior affective experience, current affective state, and acute urge to smoke could inform affective models of addiction motivation and smoking cessation treatment development. This study tested the hypothesis that prior levels of positive (PA) and negative (NA) affect predict current smoking urge via a mediational pathway involving current state affect. We also explored if tobacco deprivation moderated affect-urge relations and compared the effects of PA and NA on smoking urge to one another. At a baseline session, smokers reported affect experienced over the preceding few weeks. At a subsequent experimental session, participants were randomly assigned to 12-hr tobacco deprived (n = 51) or nondeprived (n = 69) conditions and reported state affect and current urge. Results revealed a mediational pathway whereby prior NA reported at baseline predicted state NA at the experimental session, which in turn predicted current urge. This mediational pathway was found primarily for an urge subtype indicative of urgent need to smoke and desire to smoke for NA relief, was stronger in the deprived (vs. nondeprived) condition, and remained significant after controlling for PA. Prior PA and current state PA were inversely associated with current urge; however, these associations were eliminated after controlling for NA. These results cohere with negative reinforcement models of addiction and with prior research and suggest that: (a) NA plays a stronger role in smoking motivation than PA; (b) state affect is an important mechanism linking prior affective experience to current urge; and (c) affect management interventions may attenuate smoking urge in individuals with a history of affective disturbance.