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Altered voluntary alcohol intake after induction and relief of chronic pain symptoms in rats
Abstracts / Alcohol 60 (2017) 203e243
Ascending nociceptive circuitry alters the function of central brain stress and reinforcement systems, and excessive alcohol exposure also produces neuroadaptations within nociceptive-terminal brain regions, including the central amygdala and cingulate cortex. We have discovered the emergence of a significant nociceptive hypersensitivity (or hyperalgesia) in alcoholdependent rats, and our current aim is to employ this model toward the development of novel neuropharmacological targets to reduce both excessive drinking and hyperalgesia. Our data describe three new promising stress-regulated targets representing three distinct intracellular signaling mechanisms. One such target is the pro-stress neuropeptide vasopressin, which has implicated in the transition to dependence in male rats via its actions on V1b receptors (V1bRs). Similarly, our most recent data describe a role for the stress-regulated metabolic enzyme soluble epoxide hydrolase (sEH) in the manifestation of excessive drinking. Finally, our lab and others have described a functional potentiation of central brain glucocorticoid receptors in association with chronic alcohol exposure and escalated drinking. A better understanding of the central brain mechanisms of excessive drinking and hyperalgesia will provide substantial insight into neurobiological mechanisms of dependence and may reveal novel treatment opportunities for AUD and pain in the context of AUD. This work is generously supported by NIAAA grant R00AA020839 and by the LSUHSC Alcohol & Drug Abuse Center of Excellence. S26 SOCIAL TRANSFER OF ALCOHOL WITHDRAWAL INDUCED HYPERALGESIA Monique L. Smith, Andre Walcott, Caroline Hostetler, Andrey E. Ryabinin, Mary M. Heinricher. Stanford University, Stanford, CA, USA Chronic pain often manifests in the absence of tissue damage, and is greatly impacted by social and environmental factors. Because chronic pain and alcohol dependence are interrelated, we examined pain during withdrawal from voluntary alcohol drinking in male C57BL/6J mice. Our findings reveal hyperalgesia not only in “primary” alcohol-withdrawn mice, but also in water-drinking “bystander” control mice housed in the same room. This phenomenon generalizes to other pain states, as evidenced by the social transfer of morphine withdrawal-induced and inflammatory hyperalgesia. Communication of this hyperalgesia occurs via olfactory cues and does not co-occur with a state of anxiety or sensory reactivity. Bystander mice demonstrate activation of cortical brain regions important for empathy and pain processing in humans, including the anterior cingulate (ACC), and anterior insula (AI). Chemogenetic inactivation of the ACC, but not the somatosensory cortex reverses the expression of hyperalgesia in both primary and bystander mice. Together, these studies further our understanding of the social communication of pain, and demonstrate that an abnormal pain state can result from voluntary alcohol drinking in the mouse. This research also suggests that the common practice of housing control animals in the same room with experimental animals may not be appropriate because of the possibility of social transfer of physiological states. S27 ALTERED VOLUNTARY ALCOHOL INTAKE AFTER INDUCTION AND RELIEF OF CHRONIC PAIN SYMPTOMS IN RATS ~ a, Kha Igor Spigelman, Yatendra Mulpuri, David H. Terry, Marijo L. Pempen Nguyen, Vincent N. Marty. University of California, Los Angeles, CA, USA Purpose: Chronic pain states affect alcohol use patterns and promote the development of alcoholism, while long-term alcohol dependence induces symptoms of hyperalgesia and may exacerbate chronic pain arising from other sources. To study the complex relationship between chronic pain and alcohol dependence we sought to develop rodent models that combine chronic pain with alcohol dependence. Methods: Model 1: we induced unilateral neuropathy symptoms of mechanical allodynia by sciatic nerve entrapment (SNE) in male Sprague Dawley rats. Two weeks after surgery, SNE and Sham surgery control rats were placed on an intermittent 2-bottle choice (2-BC) 20% alcohol (ethanol, EtOH) regimen for 48 days (21 EtOH presentations) to determine their voluntary EtOH intake. Model 2: we placed male Wistar rats on the 10% EtOH 2-BC regimen and after achieving stable levels of EtOH intake rats were injected with
209
paclitaxel (2 mg/kg, 4 doses every other day) to induce a bilateral chronic hypersensitivity to mechanical and cold stimuli. Results: There were no differences in either the rate of escalation or the steady-state EtOH intake levels between the Sham and SNE groups (two-way RM ANOVA). Paclitaxel treatment significantly increased voluntary EtOH intake and this intake was significantly suppressed by a novel synthetic peripherally-restricted cannabinoid analgesic (PrNMI, 0.6 mg/kg, i.p., administered on the EtOH presentation days), whereas vehicle administration had no effect. Conclusions: These findings suggest that certain chronic pain states may promote increases in alcohol consumption, while suppression of chronic pain symptoms may decrease voluntary alcohol intake. Supported by NIH grants AA022408 and AA022707.
Symposium VII Emerging targets for alcohol addiction treatment. Co-Chairs: Roberto Ciccocioppo, Ph.D. & Koji Teshima, Ph.D. Discussant: Friedbert Weiss, Ph.D.
S28 EPIGENETIC ENZYMES AS A NOVEL CLASS OF TARGETS FOR DISEASEMODIFYING PHARMACOTHERAPIES IN ALCOHOL ADDICTION E. Barbier, A.L. Johnstone, B.B. Khomtchouk, J.D. Tapocik, C. Pitcairn, F. Rehman, E. Augier, A. Borich, J.R. Schank, C.A. Rienas, D.J. Van €tt, C. Wahlestedt, M. Heilig. Linko € ping University, Booven, H. Sun, D. Na € ping, Sweden; NIAAA/NIH, Bethesda, MD, USA; University of Linko Miami, Miami, FL, USA; The University of Georgia, Athens, GA, USA Alcohol dependence leads to escalation of alcohol intake, increased aversion-resistant alcohol taking (“compulsivity”), and increased sensitivity to stress-induced relapse. We have shown that the emergence of these traits is in part driven by a coordinated and persistent dysregulations of gene expression networks in the medial prefrontal cortex (mPFC). Recently, we identified several novel candidates that might be mechanistically related to alcohol-addiction relevant phenotypes, and offer targets for diseasemodifying pharmacotherapies. Among the candidate targets, we first selected PR-domain methyltransferase 2 (PRDM2) for functional validation. In rats with a history of dependence, PRDM2 expression was decreased in the mPFC. Alcohol-induced PRDM2 repression is reversed by the DNA methyltransferase inhibitor RG108, showing that it is driven by DNA methylation. Conversely, PRDM2 knockdown in non-dependent rats induced a set of gene expression changes that overlapped with those found following alcohol dependence. These expression changes were associated with behavioral consequences otherwise seen following a history of dependence, including escalated alcohol intake, increased resistance to quinine adulteration, and enhanced stress-induced reinstatement. Several genes that exhibited a significantly decreased enrichment for H3K9me1 (a functional consequence of PRDM2 repression) were identified using ChIPseq, including synaptotagmin 1. In summary, PRDM2 is a mediator of neuroadaptations and behaviors that are critical in alcoholism. Specifically, our findings indicate that DNA-methylation mediated repression of PRDM2 is involved in multiple aspects of alcohol dependence, including stress-induced relapse, compulsivity-like behavior and escalation in alcohol intake. Follow-up work has identified molecular pathways that are dysregulated due to PRDM2 repression, and may offer additional therapeutic targets. S29 INVOLVEMENT OF a4b2 AND a3b4 NICOTINIC RECEPTOR SUBTYPES IN ALCOHOL TAKING AND SEEKING Andrea Cippitelli, Jinhua Wu, Ginamarie Debevec, Christopher Armishaw, Greg S. Welmaker, Marc Giulianotti, Lawrence Toll. Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL, USA; Assuage Pharmaceuticals Inc, Port St. Lucie, FL, USA Preclinical and clinical evidence has indicated that nicotinic acetylcholine receptors (nAChRs) are important pharmacological targets for treatment of alcoholism. However, it is unclear which specific nAChR subtypes serve as mediators of the rewarding effects of alcohol due, in part, to the lack of potent and selective ligands for the different possible combinations of the
Ascending nociceptive circuitry alters the function of central brain stress and reinforcement systems, and excessive alcohol exposure also produces neuroadaptations within nociceptive-terminal brain regions, including the central amygdala and cingulate cortex. We have discovered the emergence of a significant nociceptive hypersensitivity (or hyperalgesia) in alcoholdependent rats, and our current aim is to employ this model toward the development of novel neuropharmacological targets to reduce both excessive drinking and hyperalgesia. Our data describe three new promising stress-regulated targets representing three distinct intracellular signaling mechanisms. One such target is the pro-stress neuropeptide vasopressin, which has implicated in the transition to dependence in male rats via its actions on V1b receptors (V1bRs). Similarly, our most recent data describe a role for the stress-regulated metabolic enzyme soluble epoxide hydrolase (sEH) in the manifestation of excessive drinking. Finally, our lab and others have described a functional potentiation of central brain glucocorticoid receptors in association with chronic alcohol exposure and escalated drinking. A better understanding of the central brain mechanisms of excessive drinking and hyperalgesia will provide substantial insight into neurobiological mechanisms of dependence and may reveal novel treatment opportunities for AUD and pain in the context of AUD. This work is generously supported by NIAAA grant R00AA020839 and by the LSUHSC Alcohol & Drug Abuse Center of Excellence. S26 SOCIAL TRANSFER OF ALCOHOL WITHDRAWAL INDUCED HYPERALGESIA Monique L. Smith, Andre Walcott, Caroline Hostetler, Andrey E. Ryabinin, Mary M. Heinricher. Stanford University, Stanford, CA, USA Chronic pain often manifests in the absence of tissue damage, and is greatly impacted by social and environmental factors. Because chronic pain and alcohol dependence are interrelated, we examined pain during withdrawal from voluntary alcohol drinking in male C57BL/6J mice. Our findings reveal hyperalgesia not only in “primary” alcohol-withdrawn mice, but also in water-drinking “bystander” control mice housed in the same room. This phenomenon generalizes to other pain states, as evidenced by the social transfer of morphine withdrawal-induced and inflammatory hyperalgesia. Communication of this hyperalgesia occurs via olfactory cues and does not co-occur with a state of anxiety or sensory reactivity. Bystander mice demonstrate activation of cortical brain regions important for empathy and pain processing in humans, including the anterior cingulate (ACC), and anterior insula (AI). Chemogenetic inactivation of the ACC, but not the somatosensory cortex reverses the expression of hyperalgesia in both primary and bystander mice. Together, these studies further our understanding of the social communication of pain, and demonstrate that an abnormal pain state can result from voluntary alcohol drinking in the mouse. This research also suggests that the common practice of housing control animals in the same room with experimental animals may not be appropriate because of the possibility of social transfer of physiological states. S27 ALTERED VOLUNTARY ALCOHOL INTAKE AFTER INDUCTION AND RELIEF OF CHRONIC PAIN SYMPTOMS IN RATS ~ a, Kha Igor Spigelman, Yatendra Mulpuri, David H. Terry, Marijo L. Pempen Nguyen, Vincent N. Marty. University of California, Los Angeles, CA, USA Purpose: Chronic pain states affect alcohol use patterns and promote the development of alcoholism, while long-term alcohol dependence induces symptoms of hyperalgesia and may exacerbate chronic pain arising from other sources. To study the complex relationship between chronic pain and alcohol dependence we sought to develop rodent models that combine chronic pain with alcohol dependence. Methods: Model 1: we induced unilateral neuropathy symptoms of mechanical allodynia by sciatic nerve entrapment (SNE) in male Sprague Dawley rats. Two weeks after surgery, SNE and Sham surgery control rats were placed on an intermittent 2-bottle choice (2-BC) 20% alcohol (ethanol, EtOH) regimen for 48 days (21 EtOH presentations) to determine their voluntary EtOH intake. Model 2: we placed male Wistar rats on the 10% EtOH 2-BC regimen and after achieving stable levels of EtOH intake rats were injected with
209
paclitaxel (2 mg/kg, 4 doses every other day) to induce a bilateral chronic hypersensitivity to mechanical and cold stimuli. Results: There were no differences in either the rate of escalation or the steady-state EtOH intake levels between the Sham and SNE groups (two-way RM ANOVA). Paclitaxel treatment significantly increased voluntary EtOH intake and this intake was significantly suppressed by a novel synthetic peripherally-restricted cannabinoid analgesic (PrNMI, 0.6 mg/kg, i.p., administered on the EtOH presentation days), whereas vehicle administration had no effect. Conclusions: These findings suggest that certain chronic pain states may promote increases in alcohol consumption, while suppression of chronic pain symptoms may decrease voluntary alcohol intake. Supported by NIH grants AA022408 and AA022707.
Symposium VII Emerging targets for alcohol addiction treatment. Co-Chairs: Roberto Ciccocioppo, Ph.D. & Koji Teshima, Ph.D. Discussant: Friedbert Weiss, Ph.D.
S28 EPIGENETIC ENZYMES AS A NOVEL CLASS OF TARGETS FOR DISEASEMODIFYING PHARMACOTHERAPIES IN ALCOHOL ADDICTION E. Barbier, A.L. Johnstone, B.B. Khomtchouk, J.D. Tapocik, C. Pitcairn, F. Rehman, E. Augier, A. Borich, J.R. Schank, C.A. Rienas, D.J. Van €tt, C. Wahlestedt, M. Heilig. Linko € ping University, Booven, H. Sun, D. Na € ping, Sweden; NIAAA/NIH, Bethesda, MD, USA; University of Linko Miami, Miami, FL, USA; The University of Georgia, Athens, GA, USA Alcohol dependence leads to escalation of alcohol intake, increased aversion-resistant alcohol taking (“compulsivity”), and increased sensitivity to stress-induced relapse. We have shown that the emergence of these traits is in part driven by a coordinated and persistent dysregulations of gene expression networks in the medial prefrontal cortex (mPFC). Recently, we identified several novel candidates that might be mechanistically related to alcohol-addiction relevant phenotypes, and offer targets for diseasemodifying pharmacotherapies. Among the candidate targets, we first selected PR-domain methyltransferase 2 (PRDM2) for functional validation. In rats with a history of dependence, PRDM2 expression was decreased in the mPFC. Alcohol-induced PRDM2 repression is reversed by the DNA methyltransferase inhibitor RG108, showing that it is driven by DNA methylation. Conversely, PRDM2 knockdown in non-dependent rats induced a set of gene expression changes that overlapped with those found following alcohol dependence. These expression changes were associated with behavioral consequences otherwise seen following a history of dependence, including escalated alcohol intake, increased resistance to quinine adulteration, and enhanced stress-induced reinstatement. Several genes that exhibited a significantly decreased enrichment for H3K9me1 (a functional consequence of PRDM2 repression) were identified using ChIPseq, including synaptotagmin 1. In summary, PRDM2 is a mediator of neuroadaptations and behaviors that are critical in alcoholism. Specifically, our findings indicate that DNA-methylation mediated repression of PRDM2 is involved in multiple aspects of alcohol dependence, including stress-induced relapse, compulsivity-like behavior and escalation in alcohol intake. Follow-up work has identified molecular pathways that are dysregulated due to PRDM2 repression, and may offer additional therapeutic targets. S29 INVOLVEMENT OF a4b2 AND a3b4 NICOTINIC RECEPTOR SUBTYPES IN ALCOHOL TAKING AND SEEKING Andrea Cippitelli, Jinhua Wu, Ginamarie Debevec, Christopher Armishaw, Greg S. Welmaker, Marc Giulianotti, Lawrence Toll. Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL, USA; Assuage Pharmaceuticals Inc, Port St. Lucie, FL, USA Preclinical and clinical evidence has indicated that nicotinic acetylcholine receptors (nAChRs) are important pharmacological targets for treatment of alcoholism. However, it is unclear which specific nAChR subtypes serve as mediators of the rewarding effects of alcohol due, in part, to the lack of potent and selective ligands for the different possible combinations of the