한국중독정신의학회 춘계학술대회 건국대학교 의전원 및 충주병원 정신건강의학과 서정석

Presentation on theme: "한국중독정신의학회 춘계학술대회 건국대학교 의전원 및 충주병원 정신건강의학과 서정석"— Presentation transcript:

1 2017. 3. 31. 한국중독정신의학회 춘계학술대회 건국대학교 의전원 및 충주병원 정신건강의학과 서정석
중독에서 본 식이, 식이에서 본 중독 식이와 알코올 갈망감의 관계 한국중독정신의학회 춘계학술대회 건국대학교 의전원 및 충주병원 정신건강의학과 서정석

2 배경 배부르면 Leptin이 분비되어 포만감을 유발하고
배고프면(fasting, negative energy balance) ghrelin이 분비된다. Ghrelin은 시상하부와 중뇌변연계를 동시에 자극하여 음식을 섭취하게 한다. 이러한 food-motivated behavior와 중독은 측좌핵으로 투사하는 복측피개영역의 도파민 세포와 밀접한 연관이 있다. 그렇다면 ghrelin과 물질 및 행위 중독도 관련 있지 않을까?

3 Endostatic energy-homeostatic system
intrinsic sensation, Endostatic energy-homeostatic system rewarding, positive reinforcement, Exostatic system Bidrectional control of energy expenditure and appetite 보상, 과거의 경험, 음식의 hedonic properties 등이 작용한 exostatic system 렙틴 (2001) – 알코올 갈망과 관련 있다는 연구부터 식욕과 중독이 관련된 연구의 시작 LH = lateral hypothalamus VTA = ventral tegmental area NAC = nucleus accumbens. Kiefer, 2014

4 0. Ghrelin을 소개합니다.

5 Ghrelin a 28-amino acid peptide, a circulating hormone produced primarily in the stomach (Kojima et al., 1999; Date et al., 2000), is a potent orexigenic agent with a well-established role in homeostatic feeding (Kojima et al., 1999; Wren et al., 2000). highly correlated with meal initiation and increase during fasting (Cummings et al., 2001). Conversely, blockade of ghrelin receptors (growth hormone secretagogue receptor, GHS-R1A) decreases food intake (Salomé et al., 2009). Only the acetylated form of ghrelin is able to cross the BBB and activate central GHS-R1A in the hypothalamus, (Cummings et al., 2001; Wren et al., 2000). Ghrelin receptors are abundantly expressed in CNS areas associated with homeostatic feeding, including the hypothalamus and brainstem (Guan et al., 1997; Katayama et al., 2000) GHS-R1A are expressed throughout the reward systems raised the hypothesis that ghrelin may have a role in reward regulation.

6 Roles of ghrelin ghrelin increases adiposity by a mechanism that includes decreased fat utilization regulating glucose levels stimulating prolactin secretion influencing sleep and acts on the cardiovascular system influencing memory formation via hippocampal GHS-R1A stimulating gastric motility in rodents increasing anxiety- and depression-like behavior in rodents Engel and Jerlhag CNS Drugs (2014) 28:875–886

7 Neuropeptides regulating appetite
GI tract Brain Fat Ghrelin Peptide YY Oxyntomodulin Cholecystokinin Glucagon-like peptide-1 (GLP-1) Galanin Orexin neuropeptide Y (NPY) Adiponectin Leptin interleukin-6 혈당

8 1. Ghrelin and food intake via VTA, NAc

9 increasing reducing systemic and central
(ventricular) ghrelin injection (Skibicka et al., 2011). operant behavior for a food reward ↑ suppression of central ghrelin signaling by peripheral administration of a GHS-R1A antagonist (Skibicka et al., 2011). for a food reward ↓ GHS-R1A antagonist and also in GHS-R1A knockout mice (Egecioglu et al., 2010; Perello et al., 2010). Preference for a food reward-paired environment↓ ghrelin ↑dopamine activity in the VTA (Abizaid et al., 2006) and NAc with an associated locomotor response (Jerlhag et al., 2006, 2007). ghrelin microinjection directly into the VTA and the NAcc ↑food intake (Naleid et al., 2005) ghrelin microinjection directly into VTA preference for high calorie food (Egecioglu et al., 2010). ghrelin receptor (GHS-R1A) blockade in the VTA (Skibicka et al., 2011). the motivation to work for a sugar reward.

10 Intra-VTA ghrelin 1. Ghrelin injection into the VTA increases motivated as well as free feeding. Intra-VTA ghrelin increases motivation to work for sugar as expressed by increased number of rewards earned in a progressive ratio schedule (A). 1 h free feeding of chow is also increased by intra-VTA ghrelin (B). 24 h chow intake remains unchanged (C). Only data from rats with verified VTA injection placement were included in the analysis, included placements are indicated here on coronal rat brain sections (D). Histograms represent meansSEM. * P0.05; ** P0.005; *** P Skibicka et al. Neuroscience 180 (2011) 129–137

11 1. (A) Intra-VTA JMV2959 decreases the motivation to work for food, as expressed by the decreased number of sugar pellets earned in a progressive ratio schedule in rats receiving the antagonist (A). Skibicka et al. Neuroscience 180 (2011) 129–137

12 mechanisms regulating the ability of ghrelin to active the cholinergic–dopaminergic reward link
specific subtypes (a3b2, b3 and a6) of the nicotinic acetylcholine receptor expressed within the VTA are crucial for ghrelin-induced reward antagonists to these subtypes also attenuate the reinforcing properties of alcohol in rodents and reduce alcohol intake in heavy drinking smokers NMDA antagonist attenuates ghrelin’s ability to increase accumbal dopamine release, condition a place preference and cause a locomotor stimulation in mice

13 LDT: laterodorsal tegmental area
Laterodorsal tegmental area (cholinergic) LDT: laterodorsal tegmental area

14 Alcohol and all other addictive drugs as well as food
central ghrelin regulates alcohol reward and consumption. ghrelin Mesolimbic area animal/human to focus on relevant environmental signals like food and water Nicotinic /NMDA ? GHS-R1A ↑ dopamine release Alcohol and all other addictive drugs as well as food

15 Food consumption vs substance use disorders as a useful model for motivational behaviour (Kiefer, 2014) Ghrelin and AUD

16 동물 실험, The role of ghrelin and alcohol or drug addiction
GLP-1 : glucagon-like peptide 1 Engel and Jerlhag CNS Drugs (2014) 28:875–886

17

18 Summary, findings from a variety of animal studies: ghrelin is crucially involved in the pathogenesis of addiction Activates the mesolimbic dopamine system, specifically the cholinergic–dopaminergic reward link, in rodents Ghrelin receptor antagonism reduced operant self-administration of alcohol and high alcohol consumption in rats ghrelin KO-mice displayed significantly less voluntary alcohol consumption than wild type mice Ghrelin antagonism in wild type mice reduced alcohol consumption and locomotor activity ghrelin antagonism reduced alcohol consumption in rats after 2, 5 and 10 months of voluntary alcohol consumption and reduced alcohol deprivation effects as well as rebound drinking Rats showed enhanced locomotor activity and conditioned place preference after systemic administration of ghrelin and cocaine compared to cocaine alone. Central infusion of ghrelin led to an enhanced self-administration of heroin and enhanced heroin-seeking behavior and increased dopaminergic transmission caused by nicotine Wittekind and Kluge Psychoneuroendocrinology (2015) 52, 176—194

19 인간 대상 연구, ghrelin and alcohol or drug addiction
Engel and Jerlhag CNS Drugs (2014) 28:875–886

20

21 Findings from humans studies
그렐린을 투여하면 동물 연구에서는 알코올 섭취를 증가시킨다. 그러나 인간 연구에서는 명확하지 않다. 금주 중인 AUD 환자에서는 금주 초기에 공복 그렐린이 건강 대조군에 비해 유의하게 증가한다 . 금주 후의 그렐린 농도는 금주 전 알코올 섭취량과 반비례, 금주 기간에 비례한다 (Kim et al., 2005) 2가지가 궁금합니다. 인간에게 그렐린을 주면 음주가 증가할 것인가? 만성적으로 음주하면 그렐린 농도는 어떻게 될 것인가? 오랜기간 금주하면 그렐린 농도는 어떻게 될 것인가?

22 INCREASED FASTING PLASMA GHRELIN LEVELS DURING ALCOHOL ABSTINENCE
N= 47, control =50 대상순: 춘천 국정에 알코올 6개월 입원 프로그램 참가자중에서 30일 이상 금주 유지하고 있는 환자를 대상 즉, 30일 이상 6개월 미만 금주자를 대상 Kim et al, Alcohol & Alcoholism Vol. 40, No. 1, pp. 76–79, 2005

23 3가지가 궁금합니다. 1. 인간에게 그렐린을 주면 음주가 증가할 것인가. 2
3가지가 궁금합니다. 1. 인간에게 그렐린을 주면 음주가 증가할 것인가? 2. 만성적으로 음주하면 그렐린 농도는 어떻게 될 것인가? 3. 오랜기간 금주하면 그렐린 농도는 어떻게 될 것인가?

24 ghrelin in dependent patients

25 만성 음주와 그렐린 알코올은 급성과 만성 사용 모두 그렐린 농도를 낮춘다. (Calissendorff et al.,2005, 2006; Kraus et al., 2005; Zimmermann et al., 2007;Badaoui et al., 2008) In abstinent alcoholics several studies have shown that the levels of ghrelin are increased (Engel and Jerlhag, 2014)) 장기간 금주 유지 환자의 그렐린 농도는 ?? 낮아졌던 그렐린이 오래 금주하면 정상수준으로 돌아온다(증가)한다는 것인지, 정상보다 더 증가한다는 것인지는 불명확하다.

26 Ghrelin and alcohol consumption
Acute intake Dependent patients reduces the secretion of ghrelin in healthy volunteers acute IV of alcohol in healthy nonsmoking social drinkers suppresses fasting-induced increase in ghrelin, but does not alter circulating ghrelin levels In abstinent alcoholics, the levels of ghrelin are increased significantly during early abstinence In abstinent alcoholics several studies have shown that the levels of ghrelin are increased/decreased Engel and Jerlhag CNS Drugs (2014) 28:875–886

27 정리, Ghrelin and alcohol consumption
The majority of human studies showed that acute oral alcohol ingestion reduced ghrelin plasma concentrations, while chronic alcohol consumption seem not to be associated with lower ghrelin plasma concentrations. 향후 대규모, 장기간의 연구가 필요하다.

28 ghrelin increases alcohol craving. (Leggio et al., 2014)
Ghrelin levels were positively associated with alcohol craving in abstinent patients (Addolorato et al., 2006; Koopmannet al., 2012; Leggio et al., 2012). -> Higher ghrelin levels correlate with higher craving levels in patients with alcohol use disorder 동물에서는 그렐린이 음줄ㄹ 증가시켰는데 사람에서는 어떨까? Ghrelin and craving

29 Intravenous Ghrelin Administration Increases Alcohol Craving in Alcohol-Dependent Heavy Drinkers: A Preliminary Investigation Leggio et al, BIOL PSYCHIATRY 2014;76:734–741

30 Increase in alcohol urge by dose, expressed as its increase compared with the baseline (predrug) value of the Alcohol-Visual Analogue Scale (dA-VAS). F2,40=3.36, p = .045 * Leggio et al, 2014 그렐린 용량별로 투여 후 쥬스와 알코올 사진(큐)를 주고 갈망을 측정한 이중맹검 위약-대조군 연구 그렐린 투여 후 쥬스를 컵에 따라서 냄새를 맡게 한다. (juice trial 1,2) 주스 대신 술을 따라서 냄새를 맡게 한다. (alcoholt rial 1,2) 그렐링은 갈망 증가와 유의한 차이를 보였고 (F2,40=3.36, p = .045), 특히 그렐린 3mg군과 위약간에 차이( effect size=0.94)가 있었지만 . 그러나그렐린 1mg 와 위약간, 1-3mg 간에는 차이가 없었다. Baseine 에 비해서는 알코올이나 주스 모두 유의하게 갈망이 증가했으나 군내에서 비교해서 술만 유의한 ANOVA 차이를 보임(d ¼ .94). b) F2,40=1.16, p = .32 Leggio et al, BIOL PSYCHIATRY 2014;76:734–741

31 Leggio et al, BIOL PSYCHIATRY 2014;76:734–741
Intravenous Ghrelin Administration Increases Alcohol Craving in Alcohol-Dependent Heavy Drinkers: A Preliminary Investigation Leggio et al, 2014 C, D; 각 trial 마다 6회의 혈액 측정에서 최고 그렐린 혈중 농도와 갈망간의 관계 Serum total ghrelin level was correlated with the increase in alcohol urge measured by the increase in the Alcohol-Visual Analogue Scale (dA-VAS) during both the (A) first (p = .008) and the (B) second (p=.005) alcohol cue trials. The maximum serum total ghrelin peak level across the six measurements was correlated with the increase in alcohol urge both in the (C) first (p = .02) and the (D) second (p= .04) alcohol cue trials. A. p = .008; B, p=0.005; C, p=0.02; D, p=0.04)

32 more increased ghrelin in early abstinent patients
Alcohol dependent patients Central area Higher ghrelin level more increased ghrelin in early abstinent patients 동물실험 Recurrence Higher craving

33 ghrelin Increased food intake
Lateral Hypothalamus Mesolimbic area animal/human to focus on relevant environmental signals like food and water Nicotinic /NMDA ? GHS-R1A ↑dopamine release ↑alcohol cravings Increased food intake

34 AUD Animal/healthy person Ghrelin Alcohol (-) calorie balance ↑
craving ↑ Acute intake Food ↑ ↓ ? Chronic intake Alcohol 쥐, 음주 ↑ 사람,갈망 동물 실험에서는 그렐린을 주면 알코올 섭취가 증가하지만, 사람에서는 불명확 ↑ Early abstinence Long-term abstinence ↓ ?

35 정상인에서 그렐린은 읍식섭취와 함께 음주 갈망을 증가시킨다 아마도 동기부여, 조건화와 강화가 작용할 것이다
정상인에서 그렐린은 읍식섭취와 함께 음주 갈망을 증가시킨다 아마도 동기부여, 조건화와 강화가 작용할 것이다. 술을 먹으면 그렐린이 저하된다. 환자에서 금주 초기엔 그렐린이 증가된다. 만성 금주 유지 시에 그렐린의 농도는 불명확하다. 만성 알코올리즘의 BMI는 감소되어 있거나 , Negative calorie balance로 인해 그렐린이 증가되고 갈망이 늘어 자꾸 술을 먹게 되는 악순환의 원인이 될 수 있다면 그렇다면 cachexic 한 환자들을 적절한 체중으로 만들어 주는 것 또는 공복을 피하게 하는 것도 치료 목표가 될 수 있지 않을까? 그렐린을 중뇌에 투여하면 음식섭취가 늘어난다. 그러나 그렐린을 투여하면 음주 증가가 일어나는지는 확실하지 않다 그러나 술을 먹으면 그렐린이 저하된다. 금주 초기엔 그렐린이 증가된다.

36 감사합니다.

37

38 peripheral or central administration of GHS-R1A antagonists (JMV2959)
reduces the intake of alcohol in mice consuming alcohol for 12 weeks reduces high alcohol consumption in high-alcohol consuming Wistar as well as in alcohol-preferring decreased alcohol intake without inducing tolerance or rebound increase in alcohol intake after treatment termination reduces the motivation to consume alcohol as measured in the operant lever pressing model Engel et al, 2014 Engel et al, 2014

39 central administration of GHS-R1A antagonists (JMV2959)
increases alcohol intake in rats alcohol-induced locomotor stimulation and dopamine release in NAc are attenuated in ghrelin knockout mice Spiegelmer NOX-B11-2, which binds and neutralizes active ghrelin in the periphery, does not attenuate alcohol-induced reward in mice nor alcohol intake in rats Engel et al, 2014 그러나 central 로 ghrelin을 주입했을때가 말초로 주었을떄보다 더 많은 알코올 섭취를 하는 것으로 보아 중추 삽입이 더 중요 Engel et al, 2014

40 Attenuating dopamine activity
Chronic alcohol intake Mesolimbic area amygdala GHS-R1A down regulation GABA ↓ ? Attenuating dopamine activity Reinforcing 동물실험 decreased (acetylated) ghrelin increased or decreased ghrelin (?) in long-term abstinent patients Alcohol dependence