Ethanol consumption and resistance are inversely related to neuropeptide Y levels

Thiele, Todd E.; Marsh, Donald J.; Marie, Linda Ste.; Bernstein, Ilene L.; Palmiter, Richard D.

doi:10.1038/24614

Cited by 446 publications

(349 citation statements)

References 27 publications

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Section: Neural Substrates Of Motivational Withdrawalmentioning

confidence: 99%

“…Roberts, personal communication). Also, one hypothesis to explain the increased drinking in NPY knockout mice and alcohol-preferring rats is drinking to suppress a compensatory increase in a brain stress system such as CRF (Richter et al 2000;Thiele et al 1998). How the combined dysregulation of circulating corticosteroids and central nervous system CRF and NPY systems interact during protracted abstinence to different drugs of abuse contribute to allostasis and increase vulnerability to relapse remains a challenge for future studies.…”

Section: Brain Stress Systems and Vulnerability To Relapsementioning

confidence: 99%

“…Furthermore, the electrophysiological response to intracerebroventricular NPY differs between P and NP rats (Ehlers et al 1999). A causal relation between NPY expression and alcohol intake has been suggested by the inverse relationship between NPY-expression and alcohol intake in NPY-transgenic and NPY-mutant mice, respectively (Thiele et al 1998).NPY also may be involved in dependence on drugs other than alcohol. NPY expression in the ventral striatum is suppressed following prolonged treatment with cocaine, possibly related to the anhedonic state present during cocaine withdrawal (Wahlestedt et al 1991).…”

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confidence: 99%

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Drug Addiction, Dysregulation of Reward, and Allostasis

Koob

Moal

2001

Neuropsychopharmacology

2,541

1,962

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This paper reviews recent developments in the neurocircuitry and neurobiology of addiction from a perspective of allostasis. A model is proposed for brain changes that occur during the development of addiction that explain the persistent vulnerability to relapse long after drug-taking has ceased. Addiction is presented as a cycle of spiralling dysregulation of brain reward systems that progressively increases, resulting in the compulsive use and loss of control over drug-taking. The development of addiction recruits different sources of reinforcement, different neuroadaptive mechanisms, and different neurochemical changes to dysregulate the brain reward system. Counteradaptive processes such as opponent-process that are part of normal homeostatic limitation of reward function fail to return within the normal homeostatic range and are hypothesized to form an allostatic state. Allostasis from the addiction perspective is defined as the process of maintaining apparent reward function stability by changes in brain reward mechanisms. The allostatic state represents a chronic deviation of reward set point and is fueled not only by dysregulation of reward circuits per se, but also by the activation of brain and hormonal stress responses. The manifestation of this allostatic state as compulsive drugtaking and loss of control over drug-taking is hypothesized to be expressed through activation of brain circuits involved in compulsive behavior such as the cortico-striatal-thalamic loop. The view that addiction is the pathology that results from an allostatic mechanism using the circuits established for natural rewards provides a realistic approach to BACKGROUNDDrug addiction is a chronically relapsing disorder that is defined by two major characteristics: a compulsion to take the drug with a narrowing of the behavioral repertoire toward excessive drug intake, and a loss of control in limiting intake (American Psychiatric Association 1994; World Health Organization 1992). An important challenge for neurobiological research is to understand the neuroadaptive differences between controlled drug use and loss of control, and by extension, the molecular, cellular and system processes that lead to addiction (Koob and Le Moal 1997).Animal models are critical for understanding the neuropharmacological mechanisms involved in the development of addiction. While there are no complete animal models of addiction, animal models do exist for many elements of the syndrome. These elements can be derived from symptoms or diagnostic criteria for addiction or conceptual frameworks such as different sources of reinforcement (American Psychiatric Association 1994; World Health Organization 1992). Linking neu- 24 , NO . 2 ropharmacological events to animal models can occur at multiple levels of analysis -molecular, cellular and system -and it will only be the integration of these changes across dimensions of analysis that will allow a full understanding of the neurobiology of drug addiction.Advances in neuroscience research are rapidly unr...

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Section: Neural Substrates Of Motivational Withdrawalmentioning

confidence: 99%

Section: Brain Stress Systems and Vulnerability To Relapsementioning

confidence: 99%

mentioning

confidence: 99%

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Drug Addiction, Dysregulation of Reward, and Allostasis

Koob

Moal

2001

Neuropsychopharmacology

2,541

1,962

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“…NPY-deficient mice consume significantly more ethanol than do WT mice, and are less sensitive to the sedative effect. 180 In contrast, transgenic overexpression of the NPY gene in neurons results in a lower preference for ethanol in mice. 180 Moreover, Y1-R À/À mice exhibit significantly increased voluntary consumption of ethanol solutions, compared to WT control mice.…”

mentioning

confidence: 99%

“…180 In contrast, transgenic overexpression of the NPY gene in neurons results in a lower preference for ethanol in mice. 180 Moreover, Y1-R À/À mice exhibit significantly increased voluntary consumption of ethanol solutions, compared to WT control mice. 181 Evidence that implicates the dopaminergic reward system in alcoholism is also growing.…”

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confidence: 99%

Body weight is regulated by the brain: a link between feeding and emotion

2005

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Regulated energy homeostasis is fundamental for maintaining life. Unfortunately, this critical process is affected in a high number of mentally ill patients. Eating disorders such as anorexia nervosa are prevalent in modern societies. Impaired appetite and weight loss are common in patients with depression. In addition, the use of neuroleptics frequently produces obesity and diabetes mellitus. However, the neural mechanisms underlying the pathophysiology of these behavioral and metabolic conditions are largely unknown. In this review, we first concentrate on the established brain machinery of food intake and body weight, especially on the melanocortin and neuropeptide Y (NPY) systems as illustration. These systems play a critical role in receiving and processing critical peripheral metabolic cues such as leptin and ghrelin. It is also notable that both systems modulate emotion and motivated behavior as well. Secondly, we discuss the significance and potential promise of multidisciplinary molecular and neuroanatomic techniques that will likely increase the understanding of brain circuitries coordinating energy homeostasis and emotion. Finally, we introduce several lines of evidence suggesting a link between the melanocortin/NPY systems and several neurotransmitter systems on which many of the psychotropic agents exert their influence. Maintaining energy homeostasis is fundamental for survival. However, obesity due to over-nutrition is an increasing worldwide public health problem. 1 In psychiatric practice, on the other hand, impaired appetite is one of the crucial issues. Anorexia and weight loss are common, for example, in patients suffering from depression. Eating disorders are medically intractable and life threatening. In addition, the so-called 'atypical' antipsychotic agents, currently and widely used to treat psychoses, often induce hyperphagia, obesity, and diabetes mellitus. [2][3][4] In the past decade, fortunately, there has been remarkable progress in understanding the molecular mechanisms of food intake and body weight. This is due in large part to increased research activity towards combating the rising incidences of obesity and associated metabolic disorders. As a result, it is now established that the central nervous system (CNS) senses and processes peripheral metabolic cues including leptin 5 and ghrelin, 6,7 resulting in coordinated energy homeostasis. However, the pathophysiology of the disequilibrium between energy intake and expenditure in psychiatric disorders remains largely unknown. Nevertheless, evidence suggests that several CNS systems regulating energy balance may be dysregulated in patients with mental illnesses, for example, eating disorders, and drug addiction. [8][9][10][11][12][13][14] In the current review, we will illustrate the neuroanatomic and molecular genetic aspects of the melanocortin and neuropeptide Y (NPY) systems residing in the CNS downstream of leptin and ghrelin, to discuss the neural bases of feeding, metabolism, and emotion. Additionally, we point the reader to...

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FunctionalNPYVariation as a Factor in Stress Resilience and Alcohol Consumption in Rhesus Macaques

Lindell¹,

Schwandt²,

Sun³

et al. 2010

Arch Gen Psychiatry

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Context Neuropeptide Y (NPY) is important to countering stress and is involved in neuroadaptations that drive escalated alcohol drinking following repeated alcohol exposure in rodents. In humans, haplotype-driven diminution in NPY expression is predictive of amygdala response and emotional reactivity to stress. Genetic variation that affects the NPY system could impact resilience to stress and to developing addiction with continued alcohol use. Objective To determine whether functional NPY variation influences CSF NPY, behavioral adaptation to stress, and alcohol consumption in a nonhuman primate model of early adversity (peer rearing). Design We sequenced the rhesus macaque NPY locus (rhNPY) and performed in silico analysis to identify functional variants. We performed gel shift assays for a −1002 T>G using nuclear extract from testes, brain and hypothalamus. Levels of NPY in CSF were measured by RIA, and mRNA levels were assessed in amygdala using RT-PCR. During infancy, animals were exposed to repeated social separation stress, and tested for individual differences in alcohol consumption as young adults. Animals were genotyped for −1002 T>G, and the effects of this variant on mRNA expression, CSF NPY, behavior arousal during stress, and ethanol consumption were assessed by ANOVA. Results The G allele altered binding of regulatory proteins in all nuclear extracts tested, and −1002 T>G resulted in lower levels of NPY expression in amygdala. Macaques exposed to adversity had lower CSF NPY and exhibited higher levels of arousal during stress, but only as a function of the G allele. We also found that stress-exposed G allele carriers consumed more alcohol and exhibited an escalation in intake over cycles of alcohol availability and deprivation. Conclusions Our results suggest a role for NPY promoter variation in the susceptibility to alcohol use disorders and point to NPY as a candidate for examining GxE interactions in humans.

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Ethanol consumption and resistance are inversely related to neuropeptide Y levels

Cited by 446 publications

References 27 publications

Drug Addiction, Dysregulation of Reward, and Allostasis

Drug Addiction, Dysregulation of Reward, and Allostasis

Body weight is regulated by the brain: a link between feeding and emotion

FunctionalNPYVariation as a Factor in Stress Resilience and Alcohol Consumption in Rhesus Macaques

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