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Participation of CC-chemokine ligands in reward system on methamphetamine-induced psychological dependence in mice
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Abstracts / Drug and Alcohol Dependence 171 (2017) e2–e226
Participation of CC-chemokine ligands in reward system on methamphetamine-induced psychological dependence in mice Shiroh Kishioka 1,∗ , Fumihiro Saika 1 , Shinsuke Matsuzaki 1 , Mei-Chuan Ko 2 , Norikazu Kiguchi 1,2 1 Pharmacology, Wakayama Medical University, Wakayama, Japan 2 Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
Aims: Methamphetamine (METH) elicits psychological dependence, which is considered as a chronic neurological disorder associated with plasticity due to neuroinflammation in the mesolimbic dopaminergic system. Recent findings indicate that CC Chemokine ligands (CCL) play an important role in the neuroinflammation. In this study, we examined the possibility of CCL involvement in METH-induced psychological dependence. Methods: Male C57BL/6 mice were used. METH-induced gene expression was evaluated by microarray analysis. Immunohistochemistory (IHC) and RT-PCR were analyzed by conventional methods. Psychological dependence was assessed by conditioned place preference (CPP) test. Results: By microarray analysis, gene expression of CCL2 and CCL7 were up-regulated in prefrontal cortex (PFC) after METH treatment. And the up-regulation of CCL2 and CCL7 mRNA were also observed in both nucleus accumbens (NAc) and PFC after METH (3 mg/kg) by RT-PCR. By IHC, CCL2 and CCL7 were localized on NeuN-positive neurons in NAc and/or PFC after METH. CCChemokine receptor 2 (CCR2), which is a common receptor of CCL2 and CCL7, was observed in NAc and PFC. On the other hand, METH increased phosphorylated tyrosine hydroxylase (p-TH) levels in the ventral tegmental area (VTA) evaluated by IHC, and the increments of pTH in VTA were also observed by recombinant CCL2 and CCL7 (i.c.v.). The METH- induced increase in pTH was attenuated by CCR2 antagonist (RS504393). In CPP test, METH (0.3–3 mg/kg) elicited place preference in a dose-dependent manner, indicating the development psychological dependence, and METH- induced place preference was attenuated not only by concomitant treatment with dopamine D1 receptor antagonist (SCH23390), but also by that with RS504393. Conclusions: CCL2 and CCL7 play an important role in the development of METH-induced psychological dependence through the activation of dopaminergic system in the mesolimbic reward system. Financial support: Supported by KAKENHI 26860357. http://dx.doi.org/10.1016/j.drugalcdep.2016.08.296 Kappa opioid receptor agonist 16-ethynyl salvinorin a attenuates the rewarding effects of cocaine in the progressive ratio model in rats with fewer side-effects Bronwyn Maree Kivell 1,∗ , David Young 1 , Aimee Culverhouse 1 , Thomas Prisinzano 2 1 School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand 2 Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, United States
Aims: Acute activation of kappa opioid receptors (KOPr) is known to suppress the effects of cocaine and other drugs of abuse. However, side-effects such as aversion, sedation, anxiety
and depression limit their clinical use. 16-ethynyl salvinorin A (Ethy-SalA), is a more potent analogue of salvinorin A (SalA) that has recently been shown to attenuate cocaine-prime induced drug seeking in rats without causing sedation. Here, we aim to investigate the ability of Ethy-SalA to modulate the rewarding effects of cocaine and screen for side-effects including anxiety, aversion and depression. Methods: The anti-cocaine effects of Ethy-SalA were evaluated preclinically in male Sprague Dawley rats using the progressive ratio model whereby increasing responses are required to receive each infusion of cocaine. The elevated plus maze, conditioned place aversion (CPA) and the forced swim test (FST) were used to evaluate anxiety, aversion and depression respectively (n = 6–14 per group). Results: Ethy-SalA (2 mg/kg/i.p.) pretreated rats show significant attenuation of cocaine self-administration on progressive ratio schedule compared to vehicle treated rats and SalA administered at the same dose (p < 0.05). SalA (0.3 mg/kg) caused significant anxiogenic effects with an increase in time spent in the open arm in the elevated plus maze; whereas, Ethy-SalA (0.3 mg/kg) displayed no anxiogenic effects. Ethy-SalA (0.3 mg/kg, i.p) also showed no significant aversive effects unlike SalA (0.3 mg/kg, i.p). SalA displays pro-depressive effects in the FST, however, Ethy-SalA (0.3 mg/kg) showed no change in immobility in the FST. Conclusions: Ethy-SalA is potent analogue of SalA showing significant improvements over SalA. Ethy-SalA significantly attenuates self-administration of cocaine in rats in progressive ratio experiments without causing anxiogenic, aversive or prodepressive side effects. Financial support: Neurological Foundation of New Zealand (BK). http://dx.doi.org/10.1016/j.drugalcdep.2016.08.297 HCV incidence and treatment in aging Latino injectors Michelle R. Klawans ∗ , Yolanda Villarreal, T. Northrup, Angela Stotts McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States Aims: HCV incidence is about 2% in the general US population; however, it is much higher among aging (45 and older), Latino, heroin injectors. High HCV incidence is concerning as this generally hidden population rarely presents for treatment and has unique treatment barriers. This study aimed to investigate risk factors for HCV infection and factors related to receipt of treatment among an aging Latino injectors. Methods: The sample of male Latino heroin injectors (n = 227) had a mean age of 55, most (82%) did not complete high school, half (50%) were married, and all had a history of incarcerated. Field intensive outreach methodology was used for data collection. Chi-square and logistic regression investigated relations among sociodemographic, drug use, incarceration, and co-occurring diseases on HCV infection and treatment. Results: Fifty-seven percent of aging injectors reported ever testing positive for HCV; of which only 31% received treatment. Duration of heroin use (OR = 1.03, p < 0.05), years incarcerated (OR = 1.04, p < 0.05), use of shooting galleries (OR = 2.5, p < 0.01), and poverty (OR = 2.13, p < 0.05) were risks for HCV. Receiving HCV treatment was positively associated with duration of heroin use (OR = 1.05, p < 0.05) and seeking treatment for sexually transmitted infections (STIs; OR = 2.6, p < 0.05).
Abstracts / Drug and Alcohol Dependence 171 (2017) e2–e226
Participation of CC-chemokine ligands in reward system on methamphetamine-induced psychological dependence in mice Shiroh Kishioka 1,∗ , Fumihiro Saika 1 , Shinsuke Matsuzaki 1 , Mei-Chuan Ko 2 , Norikazu Kiguchi 1,2 1 Pharmacology, Wakayama Medical University, Wakayama, Japan 2 Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
Aims: Methamphetamine (METH) elicits psychological dependence, which is considered as a chronic neurological disorder associated with plasticity due to neuroinflammation in the mesolimbic dopaminergic system. Recent findings indicate that CC Chemokine ligands (CCL) play an important role in the neuroinflammation. In this study, we examined the possibility of CCL involvement in METH-induced psychological dependence. Methods: Male C57BL/6 mice were used. METH-induced gene expression was evaluated by microarray analysis. Immunohistochemistory (IHC) and RT-PCR were analyzed by conventional methods. Psychological dependence was assessed by conditioned place preference (CPP) test. Results: By microarray analysis, gene expression of CCL2 and CCL7 were up-regulated in prefrontal cortex (PFC) after METH treatment. And the up-regulation of CCL2 and CCL7 mRNA were also observed in both nucleus accumbens (NAc) and PFC after METH (3 mg/kg) by RT-PCR. By IHC, CCL2 and CCL7 were localized on NeuN-positive neurons in NAc and/or PFC after METH. CCChemokine receptor 2 (CCR2), which is a common receptor of CCL2 and CCL7, was observed in NAc and PFC. On the other hand, METH increased phosphorylated tyrosine hydroxylase (p-TH) levels in the ventral tegmental area (VTA) evaluated by IHC, and the increments of pTH in VTA were also observed by recombinant CCL2 and CCL7 (i.c.v.). The METH- induced increase in pTH was attenuated by CCR2 antagonist (RS504393). In CPP test, METH (0.3–3 mg/kg) elicited place preference in a dose-dependent manner, indicating the development psychological dependence, and METH- induced place preference was attenuated not only by concomitant treatment with dopamine D1 receptor antagonist (SCH23390), but also by that with RS504393. Conclusions: CCL2 and CCL7 play an important role in the development of METH-induced psychological dependence through the activation of dopaminergic system in the mesolimbic reward system. Financial support: Supported by KAKENHI 26860357. http://dx.doi.org/10.1016/j.drugalcdep.2016.08.296 Kappa opioid receptor agonist 16-ethynyl salvinorin a attenuates the rewarding effects of cocaine in the progressive ratio model in rats with fewer side-effects Bronwyn Maree Kivell 1,∗ , David Young 1 , Aimee Culverhouse 1 , Thomas Prisinzano 2 1 School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand 2 Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, United States
Aims: Acute activation of kappa opioid receptors (KOPr) is known to suppress the effects of cocaine and other drugs of abuse. However, side-effects such as aversion, sedation, anxiety
and depression limit their clinical use. 16-ethynyl salvinorin A (Ethy-SalA), is a more potent analogue of salvinorin A (SalA) that has recently been shown to attenuate cocaine-prime induced drug seeking in rats without causing sedation. Here, we aim to investigate the ability of Ethy-SalA to modulate the rewarding effects of cocaine and screen for side-effects including anxiety, aversion and depression. Methods: The anti-cocaine effects of Ethy-SalA were evaluated preclinically in male Sprague Dawley rats using the progressive ratio model whereby increasing responses are required to receive each infusion of cocaine. The elevated plus maze, conditioned place aversion (CPA) and the forced swim test (FST) were used to evaluate anxiety, aversion and depression respectively (n = 6–14 per group). Results: Ethy-SalA (2 mg/kg/i.p.) pretreated rats show significant attenuation of cocaine self-administration on progressive ratio schedule compared to vehicle treated rats and SalA administered at the same dose (p < 0.05). SalA (0.3 mg/kg) caused significant anxiogenic effects with an increase in time spent in the open arm in the elevated plus maze; whereas, Ethy-SalA (0.3 mg/kg) displayed no anxiogenic effects. Ethy-SalA (0.3 mg/kg, i.p) also showed no significant aversive effects unlike SalA (0.3 mg/kg, i.p). SalA displays pro-depressive effects in the FST, however, Ethy-SalA (0.3 mg/kg) showed no change in immobility in the FST. Conclusions: Ethy-SalA is potent analogue of SalA showing significant improvements over SalA. Ethy-SalA significantly attenuates self-administration of cocaine in rats in progressive ratio experiments without causing anxiogenic, aversive or prodepressive side effects. Financial support: Neurological Foundation of New Zealand (BK). http://dx.doi.org/10.1016/j.drugalcdep.2016.08.297 HCV incidence and treatment in aging Latino injectors Michelle R. Klawans ∗ , Yolanda Villarreal, T. Northrup, Angela Stotts McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States Aims: HCV incidence is about 2% in the general US population; however, it is much higher among aging (45 and older), Latino, heroin injectors. High HCV incidence is concerning as this generally hidden population rarely presents for treatment and has unique treatment barriers. This study aimed to investigate risk factors for HCV infection and factors related to receipt of treatment among an aging Latino injectors. Methods: The sample of male Latino heroin injectors (n = 227) had a mean age of 55, most (82%) did not complete high school, half (50%) were married, and all had a history of incarcerated. Field intensive outreach methodology was used for data collection. Chi-square and logistic regression investigated relations among sociodemographic, drug use, incarceration, and co-occurring diseases on HCV infection and treatment. Results: Fifty-seven percent of aging injectors reported ever testing positive for HCV; of which only 31% received treatment. Duration of heroin use (OR = 1.03, p < 0.05), years incarcerated (OR = 1.04, p < 0.05), use of shooting galleries (OR = 2.5, p < 0.01), and poverty (OR = 2.13, p < 0.05) were risks for HCV. Receiving HCV treatment was positively associated with duration of heroin use (OR = 1.05, p < 0.05) and seeking treatment for sexually transmitted infections (STIs; OR = 2.6, p < 0.05).