Abstract Clinical and animal studies have indicated that propofol has potential for abuse, but the specific neurobi- ological mechanism underlying propofol reward is not fully understood. The purpose of this study was...Abstract Clinical and animal studies have indicated that propofol has potential for abuse, but the specific neurobi- ological mechanism underlying propofol reward is not fully understood. The purpose of this study was to inves- tigate the role of extracellular signal-regulated kinase （ERK） signal transduction pathways in the nucleus accumbens （NAc） in propofol self-administration. We tested the expression of p-ERK in the NAc following the maintenance of propofol self-administration in rats. We also assessed the effect of administration of SCH23390, an antagonist of the D1 dopamine receptor, on the expression of p-ERK in the NAc in propofol self-administering rats, and examined the effects of intra-NAc injection of U0126, an MEK inhibitor, on propofol reinforcement in rats. The results showed that the expression of p-ERK in the NAc increased significantly in rats maintained on propofol, and pre-treatment with SCH23390 inhibited the propofol self- administration and diminished the expression of p-ERK in the NAc. Moreover, intra-NAc injection of U0126 （4 μg/ side） attenuated the propofol self-administration. The data suggest that ERK signal transduction pathways coupledwith D1 dopamine receptors in the NAc may be involved in the maintenance of propofol self-administration and its rewarding effects.展开更多
Melatonin is a pleiotropic signalling molecule that regulates several physiological functions, and synchronises biological rhythms. Recent evidences are beginning to reveal that a dysregulation of endogenous melatonin...Melatonin is a pleiotropic signalling molecule that regulates several physiological functions, and synchronises biological rhythms. Recent evidences are beginning to reveal that a dysregulation of endogenous melatonin rhythm or action may play a larger role in the aetiology and behavioural expression of drug addiction, than was previously considered. Also, the findings from a number of animal studies suggest that exogenous melatonin supplementation and therapeutic manipulation of melatonin/melatonin receptor interactions may be beneficial in the management of behavioural manifestations of drug addiction. However, repeated exogenous melatonin administration may cause a disruption of its endogenous rhythm and be associated with potential drawbacks that might limit its usefulness. In this review, we examine the roles of melatonin and its receptors in addictive behaviours; discussing how our understanding of melatonin's modulatory effects on the brain rewards system and crucial neurotransmitters such as dopamine has evolved over the years. Possible indications(s) for melatonergic agents in addiction management, and how manipulations of the endogenous melatonin system may be of benefit are also discussed. Finally, the potential impediments to application of melatonin in the management of addictive behaviours are considered.展开更多
<b>Aim:</b> Δ<sup>9</sup>-Tetrahydrocannabinol (Δ<sup>9</sup>-THC) is a potentially addictive cannabinoid. Its impact on the activity of liver arylamine N-Acetyltransferase (NAT) ...<b>Aim:</b> Δ<sup>9</sup>-Tetrahydrocannabinol (Δ<sup>9</sup>-THC) is a potentially addictive cannabinoid. Its impact on the activity of liver arylamine N-Acetyltransferase (NAT) has not been reported. This study investigated the rewarding effects of Δ<sup>9</sup>-THC in mice and whether Δ<sup>9</sup>-THC had any impact <i>ex-vivo</i> and <i>in-vitro</i> on NAT activity. <b>Methods:</b> Thirty-six Swiss albinomice randomly assigned to six groups (n = 6) completed a biased, 8-week Conditioned Place Preference (CPP) paradigm. Mice exhibiting ~80% preference for the black chamber at pre-conditioning were selected. Treatment groups were administered Δ<sup>9</sup>-THC (0.10, 0.50 or 2.0 mg/kg/mL, <i>ip</i>) or amphetamine (AMP, 5.0 mg/kg/mL, <i>ip</i>);while untreated groups (controls) received vehicle solutions (coconut oil or 0.9% saline). Entries and time spent in the white, drug-paired chamber during a 15-min post-conditioning exploration of the CPP apparatus were compared with the pre-conditioning exploratory scores. Livers from Δ<sup>9</sup>-THC treated and untreated mice were excised and NAT enzyme activity determined <i>ex-vivo</i> using a spectrophotometric assay with p-anisidine as substrate. The impact of varying concentrations of Δ<sup>9</sup>-THC (0.00 - 162 μM) on the activities of NAT from untreated mice livers were also investigated <i>in-vitro</i>. <b>Results:</b> Δ<sup>9</sup>-THC treated mice entered and spent significantly more time in the drug-paired CPP chamber (p ≤ 0.05) at post-conditioning vs pre-conditioning (F = 11.22). Mice treated with 2.0 mg/kg Δ<sup>9</sup>-THC made significantly more entries into the drug-paired chamber (p ≤ 0.05) as compared with their vehicle controls. AMP-treated mice displayed significant (p < 0.001) increases in both entries and time spent in the drug-paired chamber at post-conditioning (positive place preference). <i>In-vitro</i> NAT evaluations revealed a dose-dependent inhibitory impact of Δ<sup>9</sup>-THC on NAT activity with an IC50 value of 34展开更多
基金supported in part by the National Natural Science Foundation of China(81271469 and 81471350)the Natural Science Foundation of Zhejiang Province,China(Z2101211 and Y20140692)a Medical Health Project of Zhejiang Province, China(2014KYB161)
文摘Abstract Clinical and animal studies have indicated that propofol has potential for abuse, but the specific neurobi- ological mechanism underlying propofol reward is not fully understood. The purpose of this study was to inves- tigate the role of extracellular signal-regulated kinase （ERK） signal transduction pathways in the nucleus accumbens （NAc） in propofol self-administration. We tested the expression of p-ERK in the NAc following the maintenance of propofol self-administration in rats. We also assessed the effect of administration of SCH23390, an antagonist of the D1 dopamine receptor, on the expression of p-ERK in the NAc in propofol self-administering rats, and examined the effects of intra-NAc injection of U0126, an MEK inhibitor, on propofol reinforcement in rats. The results showed that the expression of p-ERK in the NAc increased significantly in rats maintained on propofol, and pre-treatment with SCH23390 inhibited the propofol self- administration and diminished the expression of p-ERK in the NAc. Moreover, intra-NAc injection of U0126 （4 μg/ side） attenuated the propofol self-administration. The data suggest that ERK signal transduction pathways coupledwith D1 dopamine receptors in the NAc may be involved in the maintenance of propofol self-administration and its rewarding effects.
文摘Melatonin is a pleiotropic signalling molecule that regulates several physiological functions, and synchronises biological rhythms. Recent evidences are beginning to reveal that a dysregulation of endogenous melatonin rhythm or action may play a larger role in the aetiology and behavioural expression of drug addiction, than was previously considered. Also, the findings from a number of animal studies suggest that exogenous melatonin supplementation and therapeutic manipulation of melatonin/melatonin receptor interactions may be beneficial in the management of behavioural manifestations of drug addiction. However, repeated exogenous melatonin administration may cause a disruption of its endogenous rhythm and be associated with potential drawbacks that might limit its usefulness. In this review, we examine the roles of melatonin and its receptors in addictive behaviours; discussing how our understanding of melatonin's modulatory effects on the brain rewards system and crucial neurotransmitters such as dopamine has evolved over the years. Possible indications(s) for melatonergic agents in addiction management, and how manipulations of the endogenous melatonin system may be of benefit are also discussed. Finally, the potential impediments to application of melatonin in the management of addictive behaviours are considered.
文摘<b>Aim:</b> Δ<sup>9</sup>-Tetrahydrocannabinol (Δ<sup>9</sup>-THC) is a potentially addictive cannabinoid. Its impact on the activity of liver arylamine N-Acetyltransferase (NAT) has not been reported. This study investigated the rewarding effects of Δ<sup>9</sup>-THC in mice and whether Δ<sup>9</sup>-THC had any impact <i>ex-vivo</i> and <i>in-vitro</i> on NAT activity. <b>Methods:</b> Thirty-six Swiss albinomice randomly assigned to six groups (n = 6) completed a biased, 8-week Conditioned Place Preference (CPP) paradigm. Mice exhibiting ~80% preference for the black chamber at pre-conditioning were selected. Treatment groups were administered Δ<sup>9</sup>-THC (0.10, 0.50 or 2.0 mg/kg/mL, <i>ip</i>) or amphetamine (AMP, 5.0 mg/kg/mL, <i>ip</i>);while untreated groups (controls) received vehicle solutions (coconut oil or 0.9% saline). Entries and time spent in the white, drug-paired chamber during a 15-min post-conditioning exploration of the CPP apparatus were compared with the pre-conditioning exploratory scores. Livers from Δ<sup>9</sup>-THC treated and untreated mice were excised and NAT enzyme activity determined <i>ex-vivo</i> using a spectrophotometric assay with p-anisidine as substrate. The impact of varying concentrations of Δ<sup>9</sup>-THC (0.00 - 162 μM) on the activities of NAT from untreated mice livers were also investigated <i>in-vitro</i>. <b>Results:</b> Δ<sup>9</sup>-THC treated mice entered and spent significantly more time in the drug-paired CPP chamber (p ≤ 0.05) at post-conditioning vs pre-conditioning (F = 11.22). Mice treated with 2.0 mg/kg Δ<sup>9</sup>-THC made significantly more entries into the drug-paired chamber (p ≤ 0.05) as compared with their vehicle controls. AMP-treated mice displayed significant (p < 0.001) increases in both entries and time spent in the drug-paired chamber at post-conditioning (positive place preference). <i>In-vitro</i> NAT evaluations revealed a dose-dependent inhibitory impact of Δ<sup>9</sup>-THC on NAT activity with an IC50 value of 34
