Modulation of Anxiety and Neuropeptide Y-Y1 Receptors by Antisense Oligodeoxynucleotides

Wahlestedt, Claes; Pich, Emilio Merlo; Koob, George F.; Yee, Frances; Heilig, Markus

doi:10.1126/science.8380941

Cited by 522 publications

(189 citation statements)

References 32 publications

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“…As demonstrated earlier, specific inhibition of neurotransmitter receptor expression in the living brain can be accomplished by the use of antisense oligodeoxynucleotides (Wahlestedt et al, 1993). For local administration of the antisense oligodeoxynucleotide to glucocorticoid receptor mRNA, scrambled sequence, sense or vehicle, cannulae were placed (under ether anaesthesia) bilaterally into the dentate gyrus of the hippocampus; AP = -3.6 mm from the bregma; L = + 1.4; DV = -3.3 from the dura mater (according to the Paxinos stereotaxic rat brain map).…”

Section: Methodsmentioning

confidence: 99%

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Antisense to the glucocorticoid receptor in hippocampal dentate gyrus reduces immobility in forced swim test

Korte

Kloet

Buwalda

et al. 1996

European Journal of Pharmacology

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Section: Methodsmentioning

confidence: 99%

“…Antisense to the glucocorticoid receptor mRNA was administered locally into the dentate gyrus to prevent translation. It is assumed that antisense oligodeoxynucleotides to specific mRNAs block the translation and thereby the synthesis of proteins (Wahlestedt et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Antisense to the glucocorticoid receptor in hippocampal dentate gyrus reduces immobility in forced swim test

Korte

Kloet

Buwalda

et al. 1996

European Journal of Pharmacology

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“…167 When administered centrally, an antisense oligodeoxynucleotide for the Y1-R produces behavioral signs of anxiety measured with plus maze testing. 207 Transgenic overexpression of NPY in the rat markedly attenuated behavioral sensitivity to restraint stress and decreased NPY-Y1-R binding in the hippocampus. 208 Thus, Y1-R-mediated hippocampal NPY signaling may be involved in anxiety and related disorders.…”

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confidence: 98%

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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“…2), and there are also published reports of asODN inhibition of target gene expression in animal models of cancer, [3][4][5] cardiovascular disease, 6 and several central nervous system applications. [7][8][9] There are currently at least 12 clinical trials using asODN to treat diseases such as Crohn's disease and non-Hodgkin's lymphoma, as well as viral infections such as human immunodeficiency virus and cytomegalovirus. 10 Throughout this period of development, liposomes have played an important role as carriers for asODN.…”

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confidence: 99%

A novel, long-circulating, and functional liposomal formulation of antisense oligodeoxynucleotides targeted against MDR1

2000

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The goal of this study was to develop a small, stable liposomal carrier for antisense oligodeoxynucleotides (asODN) that would have high trapping efficiencies and long circulation times in vivo. Traditional cationic liposomes aggregate to large complexes and, when injected intravenously, rapidly accumulate in the liver and lung. We produced charge-neutralized liposome-asODN particles by optimizing the charge interaction between a cationic lipid and negatively charged asODN, followed by a procedure in which a layer of neutral lipids coated the exterior of the cationic lipid-asODN particle. The coated cationic liposomes had an average diameter of 188 nm and entrapped 85-95% of the asODN. The biodistribution and pharmacokinetics of an 18-mer 125 I-labeled phosphorothioate ODN formulated by this method were determined after tail vein injection in mice. The majority of the asODN was cleared from blood, with a half-life of Ͼ10 hours compared with Ͻ1 hour for free asODN. When coupled with an anti-CD19 targeted antibody, this formulation was also effective at delivering an MDR1 asODN to a multidrug-resistant human B-lymphoma cell line in vitro, decreasing the activity of P-glycoprotein. No inhibition was found for nontargeted formulations or for free asODN. A number of therapeutic opportunities exist for the use of small, stable, long-circulating, and targetable liposomal carriers such as this, with high trapping efficiencies for asODN. Cancer Gene Therapy (2000) 7, 466 -475

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Modulation of Anxiety and Neuropeptide Y-Y1 Receptors by Antisense Oligodeoxynucleotides

Cited by 522 publications

References 32 publications

Antisense to the glucocorticoid receptor in hippocampal dentate gyrus reduces immobility in forced swim test

Antisense to the glucocorticoid receptor in hippocampal dentate gyrus reduces immobility in forced swim test

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

A novel, long-circulating, and functional liposomal formulation of antisense oligodeoxynucleotides targeted against MDR1

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