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| 2. |
- Karlsson, Camilla, et al.
(författare)
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The melanin-concentrating hormone-1 receptor modulates alcohol-induced reward and DARPP-32 phosphorylation
- 2016
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Ingår i: Psychopharmacology. - : SPRINGER. - 0033-3158 .- 1432-2072. ; 233:12, s. 2355-2363
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Tidskriftsartikel (refereegranskat)abstract
- Melanin-concentrating hormone (MCH) is involved in the regulation of food intake and has recently been associated with alcohol-related behaviors. Blockade of MCH-1 receptors (MCH1-Rs) attenuates operant alcohol self-administration and decreases cue-induced reinstatement, but the mechanism through which the MCH1-R influences these behaviors remains unknown. MCH1-Rs are highly expressed in the nucleus accumbens shell (NAcSh) where they are co-expressed with dopamine (DA) receptors. MCH has been shown to potentiate responses to dopamine and to increase phosphorylation of DARPP-32, an intracellular marker of DA receptor activation, in the NAcSh. In the present study, we investigated the role of the MCH1-R in alcohol reward using the conditioned place preference (CPP) paradigm. We then used immunohistochemistry (IHC) to assess activation of downstream signaling after administration of a rewarding dose of alcohol. We found that alcohol-induced CPP was markedly decreased in mice with a genetic deletion of the MCH1-R as well as after pharmacological treatment with an MCH1-R antagonist, GW803430. In contrast, an isocaloric dose of dextrose did not produce CPP. The increase in DARPP-32 phosphorylation seen in wildtype (WT) mice after acute alcohol administration in the NAcSh was markedly reduced in MCH1-R knock-out (KO) mice. Our results suggest that MCH1-Rs regulate the rewarding properties of alcohol through interactions with signaling cascades downstream of DA receptors in the NAcSh.
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| 3. |
- Ciccocioppo, Roberto, et al.
(författare)
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Stress-related neuropeptides and alcoholism : CRH, NPY, and beyond
- 2009
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Ingår i: Alcohol. - : Elsevier. - 0741-8329 .- 1873-6823. ; 43:7, s. 491-498
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Tidskriftsartikel (refereegranskat)abstract
- This article summarizes the proceedings of a symposium held at the conference on "Alcoholism and Stress: A Framework for Future Treatment Strategies" in Volterra, Italy, May 6-9, 2008. Chaired by Markus Heilig and Roberto Ciccocioppo, this symposium offered a forum for the presentation of recent data linking neuropetidergic neurotransmission to the regulation of different alcohol-related behaviors in animals and in humans. Dr. Donald Gehlert described the development of a new corticotrophin-releasing factor receptor 1 antagonist and showed its efficacy in reducing alcohol consumption and stress-induced relapse in different animal models of alcohol abuse. Dr. Andrey Ryabinin reviewed recent findings in his laboratory, indicating a role of the urocortin 1 receptor system in the regulation of alcohol intake. Dr. Annika Thorsell showed data supporting the significance of the neuropeptide Y receptor system in the modulation of behaviors associated with a history of ethanol intoxication. Dr. Roberto Ciccocioppo focused his presentation on the nociceptin/orphanin FQ (N/OFQ) receptors as treatment targets for alcoholism. Finally, Dr. Markus Heilig showed recent preclinical and clinical evidence suggesting that neurokinin 1 antagonism may represent a promising new treatment for alcoholism. Collectively, these investigators highlighted the significance of neuropeptidergic neurotransmission in the regulation of neurobiological mechanisms of alcohol addiction. Data also revealed the importance of these systems as treatment targets for the development of new medication for alcoholism.
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- Cippitelli, Andrea, et al.
(författare)
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Suppression of alcohol self-administration and reinstatement of alcohol seeking by melanin-concentrating hormone receptor 1 (MCH1-R) antagonism in Wistar rats
- 2010
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Ingår i: Psychopharmacology. - : Springer. - 0033-3158 .- 1432-2072. ; 211:4, s. 367-375
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE: Melanin-concentrating hormone (MCH) is involved in regulation of appetitive behaviors as well as emotional reactivity and reward, behavioral domains relevant to alcohol addiction.MATERIALS AND METHODS: We evaluated the effects of the non-peptide MCH1 receptor antagonist, GW803430 [6-(4-chloro-phenyl)-3-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-thieno[3,2-d]pyrimidin-4-one; 3-30 mg/kg, i.p.] on alcohol-related behaviors in Wistar rats.RESULTS: Ex vivo binding experiments demonstrated that the GW803430 dose range used resulted in high central MCH1 receptor occupancy. Alcohol self-administration was dose-dependently and potently suppressed, by approximately 80% at the highest dose. Reinstatement of alcohol-seeking induced by alcohol-associated cues was essentially eliminated. In contrast, reinstatement induced by footshock stress was not significantly altered. Taste preference for a quinine/saccharin solution, locomotor activity, and alcohol elimination were unaffected.CONCLUSION: Together, these observations support a specific involvement of the MCH system in mediating alcohol reward and cue-induced relapse to alcohol seeking. MCH1-R antagonism may constitute an attractive treatment target for alcohol use disorders.
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| 5. |
- Gehlert, Donald R., et al.
(författare)
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3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine : a novel brain-penetrant, orally available corticotropin-releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism
- 2007
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Ingår i: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 27:10, s. 2718-2726
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Tidskriftsartikel (refereegranskat)abstract
- We describe a novel corticotropin-releasing factor receptor 1 (CRF1) antagonist with advantageous properties for clinical development, and its in vivo activity in preclinical alcoholism models. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (MTIP) inhibited 125I-sauvagine binding to rat pituitary membranes and cloned human CRF1 with subnanomolar affinities, with no detectable activity at the CRF2 receptor or other common drug targets. After oral administration to rats, MTIP inhibited 125I-sauvagine binding to rat cerebellar membranes ex vivo with an ED50 of approximately 1.3 mg/kg and an oral bioavailability of 91.1%. Compared with R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino-pyrazolo[1,5-a]pyrimidine) and CP154526 (N-butyl-N-ethyl-4,9-dimethyl-7-(2,4,6-trimethylphenyl)-3,5,7-triazabicyclo[4.3.0]nona-2,4,8,10-tetraen-2-amine), MTIP had a markedly reduced volume of distribution and clearance. Neither open-field activity nor baseline exploration of an elevated plus-maze was affected by MTIP (1-10 mg/kg). In contrast, MTIP dose-dependently reversed anxiogenic effects of withdrawal from a 3 g/kg alcohol dose. Similarly, MTIP blocked excessive alcohol self-administration in Wistar rats with a history of dependence, and in a genetic model of high alcohol preference, the msP rat, at doses that had no effect in nondependent Wistar rats. Also, MTIP blocked reinstatement of stress-induced alcohol seeking both in postdependent and in genetically selected msP animals, again at doses that were ineffective in nondependent Wistar rats. Based on these findings, MTIP is a promising candidate for treatment of alcohol dependence.
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| 6. |
- George, David T., et al.
(författare)
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Neurokinin 1 receptor antagonism as a possible therapy for alcoholism
- 2008
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Ingår i: Science. - : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 319:5869, s. 1536-1539
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol dependence is a major public health challenge in need of new treatments. As alcoholism evolves, stress systems in the brain play an increasing role in motivating continued alcohol use and relapse. We investigated the role of the neurokinin 1 receptor (NK1R), a mediator of behavioral stress responses, in alcohol dependence and treatment. In preclinical studies, mice genetically deficient in NK1R showed a marked decrease in voluntary alcohol consumption and had an increased sensitivity to the sedative effects of alcohol. In a randomized controlled experimental study, we treated recently detoxified alcoholic inpatients with an NK1R antagonist (LY686017; n = 25) or placebo (n = 25). LY686017 suppressed spontaneous alcohol cravings, improved overall well-being, blunted cravings induced by a challenge procedure, and attenuated concomitant cortisol responses. Brain functional magnetic resonance imaging responses to affective stimuli likewise suggested beneficial LY686017 effects. Thus, as assessed by these surrogate markers of efficacy, NK1R antagonism warrants further investigation as a treatment in alcoholism.
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| 7. |
- Karlsson, Camilla, et al.
(författare)
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Melanin-concentrating hormone receptor 1 (MCH1-R) antagonism : reduced appetite for calories and suppression of addictive-like behaviors
- 2012
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Ingår i: Pharmacology, Biochemistry and Behavior. - : Elsevier. - 0091-3057 .- 1873-5177. ; 102:3, s. 400-406
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE: The hypothalamic neuropeptide melanin-concentrating hormone and its MCH1 receptor have been implicated in regulation of feeding and energy homeostasis, as well as modulation of reward-related behaviors. Here, we examined whether the MCH system plays a role both in caloric and motivational aspects of sugar intake.MATERIALS AND METHODS: The non-peptide MCH1-R antagonist GW803430 (3, 10, 30 mg/kg, i.p.) was first tested on self-administration under a fixed ratio schedule of reinforcement of both a caloric (10% w/v sucrose) and a non-caloric (0.06% w/v saccharin) sweet solution. GW803430 was then tested for its ability to alter motivational properties and seeking of sucrose. Lastly, the drug was tested to concurrently examine its effects on the escalated consumption of both sugar and food in animals following intermittent sugar access.RESULTS: The MCH1-R antagonist reduced sucrose- but not saccharin-reinforced lever pressing, likely reflecting a decreased appetite for calories in GW803430-treated rats. GW803430 reduced sucrose self-administration under a progressive ratio schedule, and suppressed cue-induced reinstatement of sucrose seeking, suggesting effects on rewarding properties of sucrose. GW803430 attenuated food intake in rats on intermittent access to sucrose at all doses examined (3, 10, 30 mg/kg), while reduction of sugar intake was weaker in magnitude.CONCLUSION: Together, these observations support an involvement of the MCH system in regulation of energy balance as well as mediation of sucrose reward. MCH may be an important regulator of sugar intake by acting on both caloric and rewarding components.
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