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The Role of the Melanocortin System in Linking Energy Homeostasis with Reward Mechanisms
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There is evidence of a link between peripheral signals of energy homeostasis and reward mechanisms. A hypothesis was formulated that the melanocortin (MC) system is part of this link. The hypothesis was tested by a series of receptor expression and neurochemical studies in rats.

A novel autoradiographical method was developed for quantification of MC3 and MC4 receptors in the rat brain. MC receptor levels were studied in three rat models combining underweight with an increased susceptibility for alcohol and drug consumption: alcohol preferring AA rats, nandrolone treated rats and food restricted rats. The results showed that MC receptors were differentially regulated in different brain regions in the three models. Interestingly, in all models the MC3 receptor was down-regulated in the nucleus accumbens (ACB), a region involved in the reward system, thus possibly linking the MC3 receptor to reward mechanisms.

In vivo microdialysis indicated that the MC peptide α-MSH stimulates transmission of dopamine (DA), an important mediator of reward, in the ACB via an MC receptor mediated mechanism. Moreover, chronic treatment with an MC receptor agonist resulted in increased dopamine D2 receptor levels in the VTA and decreased D1 receptor levels in the ACB. The results show that melanocortins may have an important role for both acute and long term regulation of DA transmission.

These results support the hypothesis that the melanocortins may serve as an important link between reward and body weight homeostasis. The results add to the understanding of the frequent co-morbidity of eating disorders and substance abuse, and the similarities between eating disorders and addiction. The more detailed understanding of the relationship between metabolic status and reward may also generate novel possibilities to treat eating disorders as well as addictive conditions.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2002. , p. 55
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 268
Keyword [en]
Pharmaceutical biosciences
Keyword [sv]
Farmaceutisk biovetenskap
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Pharmacology
Identifiers
URN: urn:nbn:se:uu:diva-1860ISBN: 91-554-5252-3 (print)OAI: oai:DiVA.org:uu-1860DiVA, id: diva2:161436
Public defence
2002-04-05, B22, BMC, Uppsala, 09:15
Opponent
Available from: 2002-03-15 Created: 2002-03-15 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Autoradiographic discrimination of melanocortin receptors indicates that the MC3 subtype dominates in the medial rat brain
Open this publication in new window or tab >>Autoradiographic discrimination of melanocortin receptors indicates that the MC3 subtype dominates in the medial rat brain
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1998 In: Brain Research, Vol. 810, no 1-2, p. 161-171Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-89720 (URN)
Available from: 2002-03-15 Created: 2002-03-15Bibliographically approved
2. Alcohol preferring AA rats show a derangement in their melanocortin signalling system
Open this publication in new window or tab >>Alcohol preferring AA rats show a derangement in their melanocortin signalling system
2002 In: Pharmacology Biochemistry Behavior, Vol. 72, no 1-2, p. 491-496Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-89721 (URN)
Available from: 2002-03-15 Created: 2002-03-15Bibliographically approved
3. Anabolic androgenic steroid nandrolone decanoate reduces hypothalamic proopiomelanocortin mRNA levels
Open this publication in new window or tab >>Anabolic androgenic steroid nandrolone decanoate reduces hypothalamic proopiomelanocortin mRNA levels
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2003 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 986, no 1-2, p. 139-147Article in journal (Refereed) Published
Abstract [en]

Supratherapeutical doses of anabolic androgenic steroids (AASs) have dramatic effects on metabolism in humans, and also inhibit feeding and reduce the rate of body weight gain in rats. In order to test the hypothesis that the AAS metabolic syndrome is accompanied by alterations in the central melanocortin system, we evaluated body weight, food intake and hypothalamic agouti-related protein (AgRP) and proopiomelanocortin (POMC) mRNA levels following administration of different doses of the anabolic androgenic steroid nandrolone decanoate. In order to distinguish changes induced by the steroid treatment per se from those resulting from the reduced food intake and growth rate, we also compared the effect of nandrolone decanoate on AgRP and POMC mRNA expression with both normally fed, and food restricted control groups. We here report that administration of nandrolone specifically reduces arcuate nucleus POMC mRNA levels while not affecting the expression level of AgRP. The effect on POMC expression was not observed in the food restricted controls, excluding the possibility that the observed effect was a mere response to the reduced food intake and body weight. These results raise the possibility that some of the metabolic and behavioural consequences of AAS abuse may be the result of alterations in the melanocortin system.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-89722 (URN)10.1016/S0006-8993(03)03223-2 (DOI)12965238 (PubMedID)
Available from: 2002-03-15 Created: 2002-03-15 Last updated: 2017-12-14Bibliographically approved
4. The MC4 receptor mediates alpha-MSH induced release of nucleus accumbens dopamine
Open this publication in new window or tab >>The MC4 receptor mediates alpha-MSH induced release of nucleus accumbens dopamine
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2001 In: Neuroreport, Vol. 12, p. 2155-2158Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-89723 (URN)
Available from: 2002-03-15 Created: 2002-03-15Bibliographically approved
5. Chronic infusion of a melanocortin receptor agonist modulates dopamine receptor binding in the rat brain
Open this publication in new window or tab >>Chronic infusion of a melanocortin receptor agonist modulates dopamine receptor binding in the rat brain
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2002 In: Pharmacological Research, Vol. 45, p. 119-124Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-89724 (URN)
Available from: 2002-03-15 Created: 2002-03-15Bibliographically approved

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