1,721,253 research outputs found
Antagonising TLR4-TRIF signalling before or after a low-dose alcohol binge during adolescence prevents alcohol drinking but not seeking behaviour in adulthood
Full text linkAbstract not availableJonathan Henry W. Jacobsen, Femke T. Buisman-Pijlman, Sanam Mustafa, Kenner C. Rice, Mark R. Hutchinso
Role of CRF system in a model of binge eating in female rats
No full textBinge eating (BE) may be caused by a unique interaction between dieting and stress. Hence we considered interesting to evaluate the role of corticotrophin releasing factor 1 receptor (CRF-1R) mechanisms in BE.
Four groups of female rats were used: NR+NS was normally fed and not stressed on the test day (d25); NR+S was fed as NR+NS and stressed on d25; R+NS was exposed to 3 cycles of yo-yo dieting but not stressed; R+S was fed as R+NS and stressed on d25. All groups were fed with highly palatable food (HPF) for 2 h on day 5-6 and 13-14. Stress was induced by preventing access to HPF for 15 min, while rats were able to see and smell it. After the stressful procedure the rats had free access to HPF and standard chow.
BE was observed only in the R+S group and injections of R121919 (10-20 mg/kg, s.c.) significantly reduced it
Endocrinological analysis revealed marked increase of CORT levels under R+S conditions. On the other hand, metyrapone (50 and 100 mg/kg), a CORT synthesis inhibitor, did not prevent BE, neither CORT injection (2.5 and 10 mg/kg) induced it.
When CRHR1 gene expression was monitored, an up-regulation in the BNST, central (CeA) and basolateral amygdala (BLA) of R+S rats was found. Of note, bilaterally injection of the non selective CRF receptor antagonist D-Phe-CRF(12-41) (50 ng/rat) into the BNST potently and selectively reduced BE.
Altogether these findings demonstrated that extra-hypothalamic CRF-1R related mechanisms rather than the endocrine function of these receptors are involved in BE
Selective antagonism at CRF1 receptor as a novel pharmacological treatment for binge eating and other eating disorders with a compulsive component
No full textEpisodes of binge eating (BE) in humans are characterized by compulsive, non-homeostatic consumption of an unusually large quantity of highly palatable food (HPF) in a short period of time. Considerable evidence suggests that BE may be caused by a unique interaction between dieting and stress. The present study evaluated the role of the corticotrophin releasing factor 1 receptor (CRF-1R) system in female rats, in which BE for HPF was evoked by stress and repeated food restrictions (Cifani et al. (2009) Psychopharmacology 204:113-25).
Four groups of female Sprague-Dawley rats were used: NR+NS was normally fed and not stressed on the test day (d25); NR+S was fed as NR+NS and stressed on d25; R+NS was exposed to 3 cycles of yo-yo dieting (8-day cycles of food restriction/refeeding (4d 66% of the standard chow food intake, 4d food ad libitum) but not stressed; R+S was fed as R+NS and stressed on d25. All groups were fed HPF for 2 h on day 5-6 and 13-14. Stress was induced by preventing access to HPF for 15 min, while rats were able to see and smell it. After the stressful procedure the rats had free access to HPF and standard chow.
Results revealed that BE was selectively elicited in R+S, that showed a marked increase in HPF intake in comparison to NR+NS. Intake of standard chow pellets was not significantly modified. HPF intake in R+NS and NR+S was not significantly different from that of NR+NS. Systemic injections of the selective CRF-1R antagonist R121919 (10-20 mg/kg) significantly reduced HPF intake in the R+S, but had no effect in the other 3 groups.
To explore the significance of hypothalamic CRF related mechanisms in BE, HPA axis activity in the R+S and NR+NS groups was monitored by measuring serum corticosterone (CORT) levels. Data showed a marked increase of CORT levels in the R+S group that lasted for about 30 min. On the other hand, treatment with metyrapone (50 and 100 mg/kg), a CORT synthesis inhibitor, failed to prevent BE. Consistent with this finding, CORT injection (2.5 and 10 mg/kg) did not induce BE.
In a subsequent in situ hybridization experiment the expression of CRHR1 transcript in the R+S and NR+NS groups was monitored. Results revealed an up regulation of CRHR1 mRNA signal in the BNST, central (CeA) and basolateral amygdala (BLA) of R+S rats. No significant differences were observed in the other regions examined (ventral tegmental area, medial amygdala, hypothalamic arcuate nucleus, lateral hypothalamus, dorsomedial hypothalamic nucleus, paraventricular thalamic nucleus). Of note, when the non selective CRF receptor antagonist D-Phe-CRF (50 ng/rat) was bilaterally injected into the BNST it significantly and selectively reduced BE in the R+S group thus replicating the results obtained following systemic administration of R121919
Altogether these findings demonstrated that extra-hypothalamic CRF-1R mechanisms rather than the endocrine function of these receptors are involved in BE. Selective antagonism at CRF1 receptor could represent a novel pharmacological treatment for binge eating and other eating disorders with a compulsive component
Dissociation between opioid and CRF1 antagonist sensitive drinking in Sardinian Alcohol Preferring Rats
No full textRationale The role of positive vs negative ethanol reinforcement in ethanol intake of Sardinian alcohol-preferring (sP) rats is unclear.
Objectives To test the hypothesis that spontaneous ethanol self-administration of sP rats was sensitive to the opioid receptor antagonist naltrexone, whereas withdrawal-induced, but not spontaneous, ethanol self-administration would be sensitive to corticotropin-releasing factor(1) (CRF1) antagonists, implicating differential roles for positive and negative reinforcement, respectively.
Methods Male sP rats operantly (FR1, 30 min/day) self-administered ethanol (10% v/v) until responding stabilized. One group (n=11) was made ethanol dependent through intermittent ethanol vapor exposure. Both nondependent (n=10) and dependent rats received the CRF1 antagonist LWH-63 (5, 10, and 20 mg/kg, s.c.). Separate nondependent sP rats (n=10) received the opioid antagonist naltrexone (16, 50, 150, and 450 mu g/kg, s.c.). Finally, CRF1 antagonists (MJL-1-109-2, LWH-63, and R121919) were studied for their actions on home-cage ethanol drinking in nondependent sP rats (n=6-8/group) under continuous, limited-access, or stressed conditions.
Results Naltrexone potently reduced ethanol self-administration in nondependent sP rats. LWH-63 reduced heightened ethanol self-administration of vapor-sensitive, dependent sP rats. CRF1 antagonists did not reduce ethanol intake in nondependent sP rats. R121919 (10 mg/kg, s.c.) retained antistress activity in sP rats, blunting novelty stress-induced suppression of ethanol intake.
Conclusions Spontaneous ethanol self-administration of sP rats was opioid dependent with CRF1 receptors implicated in withdrawal-induced drinking. Opioid and CRF1 receptors play different roles in ethanol reinforcement and perhaps the ethanol addiction cycle. Such distinctions may apply to subtypes of alcoholic patients who differ in their motivation to drink and ultimately treatment response
Supplemental_Table_S2 – Supplemental material for Metabolites of the ring-substituted stimulants MDMA, methylone and MDPV differentially affect human monoaminergic systems
No full textSupplemental material, Supplemental_Table_S2 for Metabolites of the ring-substituted stimulants MDMA, methylone and MDPV differentially affect human monoaminergic systems by Dino Luethi, Karolina E Kolaczynska, Melanie Walter, Masaki Suzuki, Kenner C Rice, Bruce E Blough, Marius C Hoener, Michael H Baumann and Matthias E Liechti in Journal of Psychopharmacology</p
Supplemental_Figure_S1 – Supplemental material for Metabolites of the ring-substituted stimulants MDMA, methylone and MDPV differentially affect human monoaminergic systems
No full textSupplemental material, Supplemental_Figure_S1 for Metabolites of the ring-substituted stimulants MDMA, methylone and MDPV differentially affect human monoaminergic systems by Dino Luethi, Karolina E Kolaczynska, Melanie Walter, Masaki Suzuki, Kenner C Rice, Bruce E Blough, Marius C Hoener, Michael H Baumann and Matthias E Liechti in Journal of Psychopharmacology</p
Supplemental_Table_S1 – Supplemental material for Metabolites of the ring-substituted stimulants MDMA, methylone and MDPV differentially affect human monoaminergic systems
No full textSupplemental material, Supplemental_Table_S1 for Metabolites of the ring-substituted stimulants MDMA, methylone and MDPV differentially affect human monoaminergic systems by Dino Luethi, Karolina E Kolaczynska, Melanie Walter, Masaki Suzuki, Kenner C Rice, Bruce E Blough, Marius C Hoener, Michael H Baumann and Matthias E Liechti in Journal of Psychopharmacology</p
Supplemental_Table_S3 – Supplemental material for Metabolites of the ring-substituted stimulants MDMA, methylone and MDPV differentially affect human monoaminergic systems
No full textSupplemental material, Supplemental_Table_S3 for Metabolites of the ring-substituted stimulants MDMA, methylone and MDPV differentially affect human monoaminergic systems by Dino Luethi, Karolina E Kolaczynska, Melanie Walter, Masaki Suzuki, Kenner C Rice, Bruce E Blough, Marius C Hoener, Michael H Baumann and Matthias E Liechti in Journal of Psychopharmacology</p
The sigma-Receptor Antagonist BD-1063 Decreases Ethanol Intake and Reinforcement in Animal Models of Excessive Drinking
No full textsigma-Receptors (SigRs) have been implicated in behavioral and appetitive effects of psychostimulants and may also modulate the motivating properties of ethanol. This study tested the hypothesis that SigRs modulate ethanol reinforcement and contribute to excessive ethanol intake. The effects of subcutaneous treatment with the potent, selective Sig-1R antagonist BD-1063 on operant ethanol self-administration were studied in two models of excessive drinking-Sardinian alcohol-preferring (sP) rats and acutely withdrawn ethanol-dependent Wistar rats-and compared to ethanol self-administration in nondependent Wistar controls. To assess the specificity of action, the effects of BD-1063 on self-administration of an equally reinforcing saccharin solution were determined in Wistar and sP rats. Gene expression of Sig-1R in reward-related brain areas implicated in ethanol reinforcement was compared between ethanol-naive sP and Wistar rats and withdrawn ethanol-dependent Wistar rats. BD-1063 dose dependently reduced ethanol self-administration in sP rats (3.3-11 mg/kg) and withdrawn, dependent Wistar rats (4-11 mg/kg) at doses that did not modify mean ethanol self-administration in nondependent Wistar controls. BD-1063 did not reduce concurrent water self-administration and did not comparably suppress saccharin self-administration, suggesting selectivity of action. BD-1063 also reduced the breakpoints of sP rats to work for ethanol under a progressive-ratio reinforcement schedule. Ethanol-naive sP rats and 24-h withdrawn, dependent Wistar rats showed reduced Sig-1R mRNA expression in the nucleus accumbens. The results suggest that SigR systems may contribute to innate or ethanol-induced increases in susceptibility to self-administer high ethanol levels, identifying a potential neuroadaptive mechanism contributing to excessive drinking and a therapeutic target for alcohol abuse and dependence
Activation of σ-receptors induces binge-like drinking in Sardinian alcohol-preferring rats.
No full textSigma (sigma) receptors have been implicated in the behavioral and motivational effects of alcohol and psychostimulants. Sigma receptor antagonists reduce the reinforcing effects of alcohol and excessive alcohol intake in both genetic (alcohol-preferring rats) and environmental (chronic alcohol-induced) models of alcoholism. The present study tested the hypothesis that pharmacological activation of sigma-receptors facilitates ethanol reinforcement and induces excessive, binge-like ethanol intake. The effects of repeated subcutaneous treatment with the selective sigma-receptor agonist 1,3-di-(2-tolyl) guanidine (DTG; 15 mg/kg, twice a day for 7 days) on operant ethanol (10%) self-administration were studied in Sardinian alcohol-preferring (sP) rats. To confirm that the effect of DTG was mediated by sigma-receptors, the effects of pretreatment with the selective sigma-receptor antagonist BD-1063 (7 mg/kg, subcutaneously) were determined. To assess the specificity of action, the effects of DTG on the self-administration of equally reinforcing solutions of saccharin or sucrose were also determined. Finally, gene expression of opioid receptors in brain areas implicated in ethanol reinforcement was analyzed in ethanol-naive sP rats treated acutely or repeatedly with DTG, because of the well-established role of the opioid system in alcohol reinforcement and addiction. Repeatedly administered DTG progressively and dramatically increased ethanol self-administration in sP rats and increased blood alcohol levels, which reached mean values close to 100 mg% in 1 h drinking sessions. Repeated DTG treatment also increased the rats' motivation to work for alcohol under a progressive-ratio schedule of reinforcement. BD-1063 prevented the effects of DTG, confirming that sigma-receptors mediate the effects of DTG. Repeated DTG treatment also increased the self-administration of the non-drug reinforcers saccharin and sucrose. Naive sP rats repeatedly treated with DTG showed increased mRNA expression of m-and delta-opioid receptors in the ventral tegmental area. These results suggest a key facilitatory role for sigma-receptors in the reinforcing effects of alcohol and identify a potential mechanism that contributes to binge-like and excessive drinking. Neuropsychopharmacology (2011) 36, 1207-1218; doi: 10.1038/npp.2011.5; published online 23 February 201
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