Effects of peptides, with emphasis on feeding, pain, and behavior A 5-year (1999-2003) review of publications in Peptides

Novel effects of naturally occurring peptides are continuing to be discovered, and their mechanisms of actions as well as interactions with other substances, organs, and systems have been elucidated. Synthetic analogs may have actions similar or antagonistic to the endogenous peptides, and both the native peptides and analogs have potential as drugs or drug targets. The journal Peptides publishes many leading articles on the structure–activity relationship of peptides as well as outstanding reviews on some families of peptides. Complementary to the reviews, here we extract information from the original papers published during the past five years in Peptides (1999–2003) to summarize the effects of different classes of peptides, their modulation by other chemicals and various pathophysiological states, and the mechanisms by which the effects are exerted. Special attention is given to peptides related to feeding, pain, and other behaviors. By presenting in condensed form the effects of peptides which are essential for systems biology, we hope that this summary of existing knowledge will encourage additional novel research to be presented in Peptides.     

Chronobiology of alcohol: from chronokinetics to alcohol-related alterations of the circadian system

The development of concepts in chronobiology is intimately linked to studies on alcohol, as a number of these are based on chronobiological variations observed in the metabolism of ethanol. This concerns circadian differences in its metabolism (chronokinetics) and effects (chronoefficacy and chronotoxicity) and also inherent circadian rhythmicity in the sensitivity of target organs to its effects (chronesthesy). Chronobiologic discoveries are also fertile grounds for understanding the biological and psychotropic effects of alcohol. Confusing effects, which are difficult to explain by conventional homeostatic theory, are easy to understand when considered in the context of the concepts of chronopharmacology, and thereby uncovering new pathways of investigation. Beyond the studies that have elucidated the rhythm-dependent variation in ethanol, chronobiology is opening new explanatory pathways concerning the attributes of the alcohol withdrawal syndrome and effects of alcohol on the development of the central nervous system, particularly the development of the internal clock, and on the alcohol-dependency syndrome. The concepts of chronopharmacology and chronotoxicology are of equal importance to the fields of occupational medicine and industry medicine.     

阿片成瘾机制研究进展及治疗展望

关于阿片类药物成瘾机制的研究是药物成瘾研究中的一个热点,本文从参与阿片成瘾的神经递质系统及其相互作用、不同阿片受体在成瘾过程中的作用、学习记忆与阿片成瘾的关系、成瘾性药物的细胞内信号转导机制等几个方面介绍了近年来的研究进展,并对阿片类药物成瘾治疗和预防和新方法进行了展望。     

MicroRNAs regulate synaptic plasticity underlying drug addiction

Chronic use of drugs of abuse results in neurochemical, morphological and behavioral plasticity that underlies the emergence of compulsive drug seeking and vulnerability to relapse during periods of attempted abstinence. Identifying and reversing addiction‐relevant plasticity is seen as a potential point of pharmacotherapeutic intervention in drug‐addicted individuals. Despite considerable advances in our understanding of the actions of drugs of abuse in the brain, this information has thus far yielded few novel treatment options addicted individuals. MicroRNAs are small noncoding RNAs that can each regulate the translation of hundreds to thousands of messenger RNAs. The highly pleiotropic nature of miRNAs has focused attention on their contribution to addiction‐relevant structural and functional plasticity in the brain and their potential utility as targets for medications development. In this review, we discuss the roles of miRNAs in synaptic plasticity underlying the development of addiction and then briefly discuss the possibility of using circulating miRNA as biomarkers for addiction.     

Alcohol resistance in Drosophila is modulated by the Toll innate immune pathway

A growing body of evidence has shown that alcohol alters the activity of the innate immune system and that changes in innate immune system activity can influence alcohol‐related behaviors. Here, we show that the Toll innate immune signaling pathway modulates the level of alcohol resistance in Drosophila. In humans, a low level of response to alcohol is correlated with increased risk of developing an alcohol use disorder. The Toll signaling pathway was originally discovered in, and has been extensively studied in Drosophila. The Toll pathway is a major regulator of innate immunity in Drosophila, and mammalian Toll‐like receptor signaling has been implicated in alcohol responses. Here, we use Drosophila‐specific genetic tools to test eight genes in the Toll signaling pathway for effects on the level of response to ethanol. We show that increasing the activity of the pathway increases ethanol resistance whereas decreasing the pathway activity reduces ethanol resistance. Furthermore, we show that gene products known to be outputs of innate immune signaling are rapidly induced following ethanol exposure. The interaction between the Toll signaling pathway and ethanol is rooted in the natural history of Drosophila melanogaster.     

Life-Long Hippocampal Neurogenesis: Environmental,Pharmacological and Neurochemical Modulations

It is now well documented that active neurogenesis does exist throughout the life span in the brain of various species including human. Two discrete brain regions contain progenitor cells that are capable of differentiating into neurons or glia, the subventricular zone and the dentate gyrus of the hippocampal formation. Recent studies have shown that neurogenesis can be modulated by a variety of factors, including stress and neurohormones, growth factors, neurotransmitters, drugs of abuse, and also strokes and traumatic brain injuries. In particular, the hippocampal neurogenesis may play a role in neuroadaptation associated with pathologies, such as cognitive disorders and depression. The increased neurogenesis at sites of injury may represent an attempt by the central nervous system to regenerate after damage. We herein review the most significant data on hippocampal neurogenesis in brain under various pathological conditions, with a special attention to mood disorders including depression and addiction. Special issue dedicated to Dr. Moussa Youdim.     

Group I mGluRs and Long-Term Depression: Potential Roles in Addiction?

Addiction is an enormous societal problem. A number of recent studies have focused on adaptations at glutamatergic synapses that may play a role in the behavioral responses to drugs of abuse. These studies have largely focused on NMDA receptor-dependent forms of synaptic plasticity such as NMDA receptor-dependent long-term potentiation (LTP) and long-term depression (LTD). A growing body of evidence, however, suggests that metabotropic glutamate receptors (mGluRs) also play important roles in the behavioral responses to drugs of abuse and participate in producing synaptic plasticity at glutamate synapses. In this review, we focus first on the evidence supporting a role for mGluRs in addiction and then on the properties of mGluR-dependent forms of synaptic plasticity, focusing in particular on Gq-linked receptor-induced LTD.     

p27Kip1 Mediates Addiction of Ovarian Cancer Cells to MYCC (c-MYC) and Their Dependence on MYC Paralogs

The MYCC (c-MYC) gene is amplified in 30–60% of human ovarian cancers. We assessed the functional significance of MYCC amplification by siRNA inhibition of MYCC or MYC paralogs in a panel of ovarian cancer cell lines expressing varying levels of MYCC. Inactivation of MYCC inhibited cell proliferation and induced replicative senescence only in lines with amplified MYCC, indicating that these cells are addicted to continued MYCC overexpression. In contrast, siRNA knockdown of all three MYC isoforms inhibited proliferation of MYCC non-amplified ovarian cancer cells without inducing replicative senescence, and did not inhibit the proliferation of telomerase-immortalized ovarian surface epithelial cells. The arrest induced by MYCC knockdown was accompanied by an increase in the level of the Cdk inhibitor p27^Kip1 and a decrease in cyclin A expression and Cdk2 activity, and could be reversed by RNAi knockdown of p27^Kip1 or Rb, or by overexpression of cyclin A/Cdk2. The arrest induced by knockdown of all three MYC isoforms could similarly be reversed by p27^Kip1 knockdown. Our findings indicate that the addiction of MYCC-amplified ovarian cancer cells to MYCC differs from the dependence of MYCC non-amplified cancer cells on MYC paralogs, but both are mediated, at least in part, by p27^Kip1. They also suggest that growth of ovarian cancers may be blocked by inhibition of MYCC or MYC paralogs.     

Contribution of monoamine oxidase (MAO) inhibition to tobacco and alcohol addiction

Whole-body PET-scan studies in brains of tobacco smokers have shown a decrease in monoamine oxidase (MAO) activity, which reverts to control level when they quit smoking. The observed decrease in MAO activity in smokers is presumably due to their exposure to tobacco constituents that possess MAO-inhibiting properties. The inhibition of MAO activity seems, however, not to be a unique feature of tobacco smoking as subjects with Type II alcoholism have been reported to show a similar decrease in MAO activity that reverses when they cease to use alcohol. The present review summarizes the data on MAO-inhibiting tobacco constituents and explains that the decrease in MAO activity observed in alcoholics is probably due to concomitant tobacco use. It is concluded that the inhibition of MAO by constituents contained in tobacco and tobacco smoke, enhances the addiction induced by tobacco smoking.     

α-Synuclein stimulates a dopamine transporter-dependent chloride current and modulates the activity of the transporter

Dysregulation of dopamine (DA) homeostasis is implicated in neurodegenerative diseases, drug addiction, and neuropsychiatric disorders. The neuronal plasma membrane dopamine transporter (DAT) is essential for the maintenance of DA homeostasis in the brain. α-Synuclein is a 140-amino acid protein that forms a stable complex with DAT and is linked to the pathogenesis of neurodegenerative disease. To elucidate the potential functional consequences of DAT/α-synuclein interaction, we explored α-synuclein modulation of DAT activity in midbrain dopaminergic neurons obtained from TH::RFP mice, immortalized DA neurons, and a heterologous system expressing DAT. We used dual pipette whole cell patch clamp recording to measure the DAT-mediated current before and after dialysis of recombinant α-synuclein into immortalized DA neurons. Our data suggest that intracellular α-synuclein induces a Na+ independent but Cl--sensitive inward current in DAT-expressing cells. This current is blocked by DAT blocker GBR12935 and is absent when heat-inactivated α-synuclein is dialyzed into these cells. The functional consequence of this interaction on DAT activity was further examined with real-time monitoring of transport function using a fluorescent substrate of DAT, 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP+). Overexpression of α-synuclein in DAT-positive immortalized DA neurons and CHO cells expressing DAT decreased the magnitude and rate of DAT-mediated substrate uptake without a decrease in the initial binding of the substrate at the plasma membrane. Taken together our findings are consistent with the interpretation that DAT/α-synuclein interaction at the cell surface results in a DAT-dependent, Na+-insensitive, Cl-sensitive inward current with a decrease in substrate uptake, suggesting that DAT/α-synuclein interaction can modulate dopamine transmission and thus neuronal function.