- Email: [email protected]
Poster Abstracts
332
Conference Abstracts / Alcohol 42 (2008) 303-341
P100
P102
Alcohol use, stress, and psychiatric symptoms among traumaexposed college students James G. Murphy & Meghan E. McDevitt-Murphy, Department of Psychology, University of Memphis, Memphis, TN, USA
Role of Neuropeptide Y (NPY) in relapse to alcohol-seeking Cippitelli A, Damadzic R, Hansson AC, Sommer WH, Thorsell A, Heilig M, NIAAA/NIH, Bethesda, MD, USA
Although psychiatric symptoms, and in particular PTSD, are associated with alcohol abuse in community and clinical samples (Ouimette & Brown, 2003), the role of psychopathology in college student substance abuse has not been thoroughly investigated. The present study examined the relations between psychopathology and alcohol abuse in a sample of college students who reported lifetime exposure to a DSM-IV defined traumatic event (N = 136, 82% female, 83% Caucasian). Participants were screened from psychology courses and completed a graduated frequency measure of alcohol consumption, the Rutgers Alcohol Problem Inventory (RAPI; White & Labouvie, 1989), the Clinician Administered PTSD Scale (CAPS; Blake et al., 1995), and the Personality Assessment Inventory (PAI; Morey, 1991). The PAI is a comprehensive self-report measure of personality and psychopathology that includes 11 clinical scales. The PAI depression, stress, antisocial, and borderline personality scales showed significant, positive correlations with alcohol consumption. Hierarchical regression models indicated that the PAI antisocial personality scale predicted alcohol problems even after controlling for alcohol consumption. This is consistent with numerous other studies indicating that the closely related construct of sensation seeking predicts alcohol use and abuse. A second series of regression models that controlled for alcohol consumption and antisocial personality features indicated that the PAI stress, depression, PTSD, and borderline personality scales accounted for unique variance in alcohol-problems among women, but not among men. These results suggest that, among college students exposed to trauma, depression, anxiety and emotion dysregulation confer unique risk for alcohol related problems.
Stress and alcohol-associated cues are two of the main factors triggering relapse to alcohol-seeking. Reinstatement of responding on a previously alcohol-associated lever following extinction is a commonly used model of relapse-like behavior. Studies by our group over many years showed NPY to be a potent endogenous anti-stress system, counteracting behavioral stress responses mediated by corticotrophin-releasing hormone (CRH). Here, we tested the hypothesis that NPY modifies ethanol-seeking induced by a pharmacological stressor, yohimbine. Yohimbine is an alpha2-adrenergic antagonist that exerts anxiety and stress-like responses in human and animals, and reinstates alcoholseeking in a CRH-dependent manner. In Wistar rats, NPY (5.0, 10.0 μg/rat, icv) dose dependently blocked the reinstatement of extinguished ethanol-seeking induced by yohimbine (1.25 mg/kg, ip), but failed to suppress the reinstatement of lever pressing induced by cues previously paired with alcohol reinforcement. Suppression of reinstatement by NPY was not due to motor impairment or sedation, as demonstrated when NPY was tested on alcohol self–administration. With the aim to identify the neuronal substrates involved on this behavioral effect, NPY modulation of c-fos expression in animals pretreated with yohimbine was also evaluated. These results suggest that NPY, acting through its anxiolytic properties, suppresses relapse to alcohol-seeking selectively when it is provoked by stressful events, and point to NPY system as an attractive target for the treatment of alcohol addiction.
P101
P103
Alcohol-induced modulation of neuroendocrine responses to injury Patricia E. Molina, K. Mathis, K. Zambell, P. Greiffenstein, Department of Physiology, LSUHSC, New Orleans, LA, USA
The interaction between corticotrophin-releasing factor, ethanol and spontaneous GABA release M.K. Kelm, H.E. Criswell, G.R. Breese, Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Alcohol intoxication (AI) as well as chronic abuse has been reported to modulate noradrenergic (NA), sympatho-adrenal (SA), and hypothalamic-pituitary-adrenal (HPA) axis activation. Reports in the literature conflict as to whether the overall effects of AI are inhibitory or excitatory of neuroendocrine activation and do not provide consistent insight on the interaction of AI with the integrated response to a physical stressor. We examined the impact of AI on the neuroendocrine response to hemorrhagic shock alone (HEM) or in combination with soft tissue injury (TxHEM). Chronically catheterized, male Sprague-Dawley rats received alcohol as a single intra-gastric bolus, a continuous 15 h infusion, or a 3-day alcohol binge prior to HEM or TxHEM. Blood alcohol levels averaged 150-175 mg% at the time of HEM or TxHEM in the 3 groups. AI from alcohol bolus, did not alter resting or HEMinduced neuroendocrine response. AI from 15 h infusion or 3d binge resulted in a moderate (50%) NA activation, without significant alteration of SA or HPA systems. Prolonged (15 h) AI enhanced SA and HPA, and suppressed NA responses to HEM. 3-day alcohol binge suppressed NA and SA activation, but markedly enhanced the HPA activation in response to TxHEM. These results indicate that AI produces differential modulation of the neuroendocrine milieu during basal and following stimulation by physical stressors, which is more marked with increasing duration of alcohol intoxication. Furthermore, these results suggest stressor-specific patterns of AI interaction with the NA, SA, and HPA pathways. (Supported by DOD PR-054196, AA7577, and AA009803).
Stress can contribute to relapse in alcoholics, and corticotrophinreleasing factor (CRF) and changes in GABAergic transmission may play a role in this response to stress. Through analysis of miniature inhibitory postsynaptic currents (mIPSCs), we confirmed that CRF (200 nM) increases (59.9±11%, p<.05, n=7) GABA release in the central nucleus of the amygdala (CeA). Interestingly, application of CRF onto cerebellar Purkinje neurons decreased (p<.05, n=10) baseline mIPSC frequency (24.9±5.8%) and amplitude (12.2±5.9%). These results demonstrate that CRF has brain region-specific effects on GABA release. The CRF1 receptor antagonist, NBI-27914 (1 µM), blocked CRF from decreasing mIPSC frequency and amplitude; therefore, the CRF effect on spontaneous GABA release in the cerebellum at least partially involves a CRF1 receptor-dependent mechanism. It has been shown previously that ethanol increases GABA release in the CeA and cerebellum. While it has been concluded that CRF1 receptor activation is necessary for ethanol to enhance GABA release in the CeA, the involvement of CRF in ethanol-enhanced GABA release in the cerebellum had not been investigated. Unexpectedly, CRF prevented 100 mM ethanol from increasing mIPSC frequency (-0.6±3.7%, p<.05, n=5) compared to control (29.7±4.1%, n=9). In addition, NBI-27914 had no significant effect on the ability of ethanol to increase the mIPSC frequency (24.1±7.3%) of cerebellar Purkinje neurons. These data suggest that CRF is also having a brain region-specific effect on ethanolenhanced GABA release. Future efforts will focus on the mechanisms behind these brain-region specific effects of CRF and their behavioral relevance to alcohol/stress interactions. Support: AA14949 & AA11605.
Conference Abstracts / Alcohol 42 (2008) 303-341
P100
P102
Alcohol use, stress, and psychiatric symptoms among traumaexposed college students James G. Murphy & Meghan E. McDevitt-Murphy, Department of Psychology, University of Memphis, Memphis, TN, USA
Role of Neuropeptide Y (NPY) in relapse to alcohol-seeking Cippitelli A, Damadzic R, Hansson AC, Sommer WH, Thorsell A, Heilig M, NIAAA/NIH, Bethesda, MD, USA
Although psychiatric symptoms, and in particular PTSD, are associated with alcohol abuse in community and clinical samples (Ouimette & Brown, 2003), the role of psychopathology in college student substance abuse has not been thoroughly investigated. The present study examined the relations between psychopathology and alcohol abuse in a sample of college students who reported lifetime exposure to a DSM-IV defined traumatic event (N = 136, 82% female, 83% Caucasian). Participants were screened from psychology courses and completed a graduated frequency measure of alcohol consumption, the Rutgers Alcohol Problem Inventory (RAPI; White & Labouvie, 1989), the Clinician Administered PTSD Scale (CAPS; Blake et al., 1995), and the Personality Assessment Inventory (PAI; Morey, 1991). The PAI is a comprehensive self-report measure of personality and psychopathology that includes 11 clinical scales. The PAI depression, stress, antisocial, and borderline personality scales showed significant, positive correlations with alcohol consumption. Hierarchical regression models indicated that the PAI antisocial personality scale predicted alcohol problems even after controlling for alcohol consumption. This is consistent with numerous other studies indicating that the closely related construct of sensation seeking predicts alcohol use and abuse. A second series of regression models that controlled for alcohol consumption and antisocial personality features indicated that the PAI stress, depression, PTSD, and borderline personality scales accounted for unique variance in alcohol-problems among women, but not among men. These results suggest that, among college students exposed to trauma, depression, anxiety and emotion dysregulation confer unique risk for alcohol related problems.
Stress and alcohol-associated cues are two of the main factors triggering relapse to alcohol-seeking. Reinstatement of responding on a previously alcohol-associated lever following extinction is a commonly used model of relapse-like behavior. Studies by our group over many years showed NPY to be a potent endogenous anti-stress system, counteracting behavioral stress responses mediated by corticotrophin-releasing hormone (CRH). Here, we tested the hypothesis that NPY modifies ethanol-seeking induced by a pharmacological stressor, yohimbine. Yohimbine is an alpha2-adrenergic antagonist that exerts anxiety and stress-like responses in human and animals, and reinstates alcoholseeking in a CRH-dependent manner. In Wistar rats, NPY (5.0, 10.0 μg/rat, icv) dose dependently blocked the reinstatement of extinguished ethanol-seeking induced by yohimbine (1.25 mg/kg, ip), but failed to suppress the reinstatement of lever pressing induced by cues previously paired with alcohol reinforcement. Suppression of reinstatement by NPY was not due to motor impairment or sedation, as demonstrated when NPY was tested on alcohol self–administration. With the aim to identify the neuronal substrates involved on this behavioral effect, NPY modulation of c-fos expression in animals pretreated with yohimbine was also evaluated. These results suggest that NPY, acting through its anxiolytic properties, suppresses relapse to alcohol-seeking selectively when it is provoked by stressful events, and point to NPY system as an attractive target for the treatment of alcohol addiction.
P101
P103
Alcohol-induced modulation of neuroendocrine responses to injury Patricia E. Molina, K. Mathis, K. Zambell, P. Greiffenstein, Department of Physiology, LSUHSC, New Orleans, LA, USA
The interaction between corticotrophin-releasing factor, ethanol and spontaneous GABA release M.K. Kelm, H.E. Criswell, G.R. Breese, Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Alcohol intoxication (AI) as well as chronic abuse has been reported to modulate noradrenergic (NA), sympatho-adrenal (SA), and hypothalamic-pituitary-adrenal (HPA) axis activation. Reports in the literature conflict as to whether the overall effects of AI are inhibitory or excitatory of neuroendocrine activation and do not provide consistent insight on the interaction of AI with the integrated response to a physical stressor. We examined the impact of AI on the neuroendocrine response to hemorrhagic shock alone (HEM) or in combination with soft tissue injury (TxHEM). Chronically catheterized, male Sprague-Dawley rats received alcohol as a single intra-gastric bolus, a continuous 15 h infusion, or a 3-day alcohol binge prior to HEM or TxHEM. Blood alcohol levels averaged 150-175 mg% at the time of HEM or TxHEM in the 3 groups. AI from alcohol bolus, did not alter resting or HEMinduced neuroendocrine response. AI from 15 h infusion or 3d binge resulted in a moderate (50%) NA activation, without significant alteration of SA or HPA systems. Prolonged (15 h) AI enhanced SA and HPA, and suppressed NA responses to HEM. 3-day alcohol binge suppressed NA and SA activation, but markedly enhanced the HPA activation in response to TxHEM. These results indicate that AI produces differential modulation of the neuroendocrine milieu during basal and following stimulation by physical stressors, which is more marked with increasing duration of alcohol intoxication. Furthermore, these results suggest stressor-specific patterns of AI interaction with the NA, SA, and HPA pathways. (Supported by DOD PR-054196, AA7577, and AA009803).
Stress can contribute to relapse in alcoholics, and corticotrophinreleasing factor (CRF) and changes in GABAergic transmission may play a role in this response to stress. Through analysis of miniature inhibitory postsynaptic currents (mIPSCs), we confirmed that CRF (200 nM) increases (59.9±11%, p<.05, n=7) GABA release in the central nucleus of the amygdala (CeA). Interestingly, application of CRF onto cerebellar Purkinje neurons decreased (p<.05, n=10) baseline mIPSC frequency (24.9±5.8%) and amplitude (12.2±5.9%). These results demonstrate that CRF has brain region-specific effects on GABA release. The CRF1 receptor antagonist, NBI-27914 (1 µM), blocked CRF from decreasing mIPSC frequency and amplitude; therefore, the CRF effect on spontaneous GABA release in the cerebellum at least partially involves a CRF1 receptor-dependent mechanism. It has been shown previously that ethanol increases GABA release in the CeA and cerebellum. While it has been concluded that CRF1 receptor activation is necessary for ethanol to enhance GABA release in the CeA, the involvement of CRF in ethanol-enhanced GABA release in the cerebellum had not been investigated. Unexpectedly, CRF prevented 100 mM ethanol from increasing mIPSC frequency (-0.6±3.7%, p<.05, n=5) compared to control (29.7±4.1%, n=9). In addition, NBI-27914 had no significant effect on the ability of ethanol to increase the mIPSC frequency (24.1±7.3%) of cerebellar Purkinje neurons. These data suggest that CRF is also having a brain region-specific effect on ethanolenhanced GABA release. Future efforts will focus on the mechanisms behind these brain-region specific effects of CRF and their behavioral relevance to alcohol/stress interactions. Support: AA14949 & AA11605.