Modulation of Hippocampus-Dependent Learning and Synaptic Plasticity by Nicotine

A long-standing relationship between nicotinic acetylcholine receptors (nAChRs) and cognition exists. Drugs that act at nAChRs can have cognitive-enhancing effects and diseases that disrupt cognition such as Alzheimer's disease and schizophrenia are associated with altered nAChR function. Specifically, hippocampus-dependent learning is particularly sensitive to the effects of nicotine. However, the effects of nicotine on hippocampus-dependent learning vary not only with the doses of nicotine used and whether nicotine is administered acutely, chronically, or withdrawn after chronic nicotine treatment but also vary across different hippocampus-dependent tasks such as the Morris water maze, the radial arm maze, and contextual fear conditioning. In addition, nicotine has variable effects across different types of hippocampal long-term potentiation (LTP). Because different types of hippocampus-dependent learning and LTP involve different neural and molecular substrates, comparing the effects of nicotine across these paradigms can yield insights into the mechanisms that may underlie the effects of nicotine on learning and memory and aid in understanding the variable effects of nicotine on cognitive processes. This review compares and contrasts the effects of nicotine on hippocampus-dependent learning and LTP and briefly discusses how the effects of nicotine on learning could contribute to nicotine addiction.     

Systems genetic analysis of nicotine withdrawal deficits in hippocampus-dependent learning

Cognitive deficits, such as disrupted learning, are a major symptom of nicotine withdrawal. These deficits are heritable, yet their genetic basis is largely unknown. Our lab has developed a mouse model of nicotine withdrawal deficits in learning, using chronic nicotine exposure via osmotic minipumps and fear conditioning. Here, we utilized the BXD genetic reference panel to identify genetic variants underlying nicotine withdrawal deficits in learning. Male and female mice (n = 6–11 per sex per strain, 31 strains) received either chronic saline or nicotine (6.3 mg/kg per day for 12 days), and were then tested for hippocampus-dependent learning deficits using contextual fear conditioning. Quantitative trait locus (QTL) mapping analyses using GeneNetwork identified a significant QTL on Chromosome 4 (82.13 Mb, LRS = 20.03, p < 0.05). Publicly available hippocampal gene expression data were used to identify eight positional candidates (Snacpc3, Mysm1, Rps6, Plaa, Lurap1l, Slc24a2, Hacd4, Ptprd) that overlapped with our behavioral QTL and correlated with our behavioral data. Overall, this study demonstrates that genetic factors impact cognitive deficits during nicotine withdrawal in the BXD recombinant inbred panel and identifies candidate genes for future research.     

Pathways and Networks-Based Analysis of Candidate Genes Associated with Nicotine Addiction

Nicotine is the addictive substance in tobacco and it has a broad impact on both the central and peripheral nervous systems. Over the past decades, an increasing number of genes potentially involved in nicotine addiction have been identified by different technical approaches. However, the molecular mechanisms underlying nicotine addiction remain largely unclear. Under such situation, a comprehensive analysis focusing on the overall functional characteristics of these genes, as well as how they interact with each other will provide us valuable information to understand nicotine addiction. In this study, we presented a systematic analysis on nicotine addiction-related genes to identify the major underlying biological themes. Functional analysis revealed that biological processes and biochemical pathways related to neurodevelopment, immune system and metabolism were significantly enriched in the nicotine addiction-related genes. By extracting the nicotine addiction-specific subnetwork, a number of novel genes associated with addiction were identified. Moreover, we constructed a schematic molecular network for nicotine addiction via integrating the pathways and network, providing an intuitional view to understand the development of nicotine addiction. Pathway and network analysis indicated that the biological processes related to nicotine addiction were complex. Results from our work may have important implications for understanding the molecular mechanism underlying nicotine addiction.     

Genes and Pathways Co-associated with the Exposure to Multiple Drugs of Abuse,Including Alcohol,Amphetamine/Methamphetamine,Cocaine, Marijuana,Morphine, and/or Nicotine: a Review of Proteomics Analyses

Drug addiction is a chronic neuronal disease. In recent years, proteomics technology has been widely used to assess the protein expression in the brain tissues of both animals and humans exposed to addictive drugs. Through this approach, a large number of proteins potentially involved in the etiology of drug addictions have been identified, which provide a valuable resource to study protein function, biochemical pathways, and networks related to the molecular mechanisms underlying drug dependence. In this article, we summarize the recent application of proteomics to profiling protein expression patterns in animal or human brain tissues after the administration of alcohol, amphetamine/methamphetamine, cocaine, marijuana, morphine/heroin/butorphanol, or nicotine. From available reports, we compiled a list of 497 proteins associated with exposure to one or more addictive drugs, with 160 being related to exposure to at least two abused drugs. A number of biochemical pathways and biological processes appear to be enriched among these proteins, including synaptic transmission and signaling pathways related to neuronal functions. The data included in this work provide a summary and extension of the proteomics studies on drug addiction. Furthermore, the proteins and biological processes highlighted here may provide valuable insight into the cellular activities and biological processes in neurons in the development of drug addiction.     

Reinforcement processes in opiate addiction: A homeostatic model

The development of tolerance and dependence has traditionally been considered an integral aspect of the drug addiction process, and opiate dependence has been studied extensively as a model system in this regard. However, recent emphasis on the positive reinforcing properties of drugs has led to the suggestion that tolerance, dependence, and withdrawal may be of secondary or even negligible importance in motivating compulsive drug use. The current article argues for an integrated view of addiction in the form of a homeostatic neuroadaptation model which emphasizes the motivational significance of both the positive affective state produced by opiates and the negative affective state characteristic of drug withdrawal. The model is supported by evidence at both the behavioral and neural systems levels of analysis. Understanding the important distinction between somatic and affective components of opiate withdrawal is key to recognizing the factors which contribute to the motivational significance of opiate dependence and withdrawal. In addition, the critical role of conditioning processes in the maintenance of compulsive drug use and relapse after periods of abstention is discussed. Finally, it is argued that both the positive reinforcement produced by acute administration of a drug and the negative affective state produced by withdrawal are common to multiple classes of abused drugs, suggesting that an understanding of homeostatic neuroadaptation within motivational systems provides a key to the etiology, treatment and prevention of drug addiction. Special issue dedicated to Dr. Eric J. Simon.     

Cellular events in nicotine addiction

In the 25 years since the observation that chronic exposure to nicotine could regulate the number and function of high affinity nicotine binding sites in the brain there has been a major effort to link alterations in nicotinic acetylcholine receptors (nAChRs) to nicotine-induced behaviors that drive the addiction to tobacco products. Here we review the proposed roles of various nAChR subtypes in the addiction process, with emphasis on how they are regulated by nicotine and the implications for understanding the cellular neurobiology of addiction to this drug.     

In search of predictive endophenotypes in addiction: insights from preclinical research

Drug addiction is widely recognized to afflict some but not all individuals by virtue of underlying risk markers and traits involving multifaceted interactions between polygenic and external factors. Remarkably, only a small proportion of individuals exposed to licit and illicit drugs develop compulsive drug‐seeking behavior, maintained in the face of adverse consequences and associated detrimental patterns of drug intake involving extended and repeated bouts of binge intoxication, withdrawal and relapse. As a consequence, research has increasingly endeavored to identify distinctive neurobehavioral mechanisms and endophenotypes that predispose individuals to compulsive drug use. However, research in active drug users is hampered by the difficulty in categorizing putatively causal behavioral traits prior to the initiation of drug use. By contrast, research in experimental animals is often hindered by the validity of approaches used to investigate the neural and psychological mechanisms of compulsive drug‐seeking habits in humans. Herein, we survey and discuss the principal findings emanating from preclinical animal research on addiction and highlight how specific behavioral endophenotypes of presumed genetic origin (e.g. trait anxiety, novelty preference and impulsivity) differentially contribute to compulsive forms of drug seeking and taking and, in particular, how these differentiate between different classes of stimulant and non‐stimulant drugs of abuse.     

药物成瘾及成瘾记忆的研究现状

本文在介绍药物成瘾与学习和记忆密切相关的神经回路及共同分子机制的基础上,围绕学习和记忆在药物成瘾中的作用,综述了关联性学习与复吸,关联性学习与敏化,异常关联性学习与强迫性用药行为,关联性学习及成瘾记忆与成瘾,多重记忆系统与成瘾的发生发展等方面的研究进展,并强调了突触可塑性及成瘾记忆在药物成瘾中的重要性。在此基础上提出：作为慢性脑病的药物成瘾的形成过程的重要特征是它包含着信息的特殊学习类型。药物成瘾与依赖于多巴胺的关联性学习紊乱有密切关系。海马可能在成瘾中扮演重要角色。     

Identification of candidate genes for nicotine withdrawal in C57BL/6J × DBA/2J recombinant inbred mice

Nicotine is the reinforcing ingredient in tobacco. Following chronic exposure, sudden cessation of nicotine use produces negative symptoms of withdrawal that contribute to dependence. The molecular mechanisms underlying nicotine withdrawal behaviors, however, are poorly understood. Using recombinant inbred mice, chronic nicotine was delivered by minipump and withdrawal induced using mecamylamine. Somatic signs of withdrawal, and anxiety-like behavior using elevated plus maze, were then assessed. Interval mapping was used to identify associations between genetic variation and withdrawal behaviors, and with basal gene expression. Differential gene expression following nicotine exposure and withdrawal was also assessed in progenitor mice using microarrays. Quantitative trait loci mapping identified chromosome intervals with significant genetic associations to somatic signs of withdrawal or withdrawal-induced anxiety-like behavior. Using bioinformatics, and association with basal gene expression in nucleus accumbens, we implicated Rb1, Bnip3l, Pnma2, Itm2b, and Kif13b as candidate genes for somatic signs of withdrawal, and Galr1, which showed trans-regulation from a region of chromosome 14 that was associated with somatic signs of withdrawal. Candidate genes within the chromosome 9 region associated with anxiety-like withdrawal behavior included Dixdc1, Ncam1, and Sorl1. Bioinformatics identified six genes that were also significantly associated with nicotine or alcohol traits in recent human genome-wide association studies. Withdrawal-associated somatic signs and anxiety-like behavior had strong non-overlapping genetic associations, respectively, with regions of chromosome 14 and chromosome 9. Genetic, behavioral and gene expression correlations, and bioinformatics analysis identified several candidate genes that may represent novel molecular targets for modulating nicotine withdrawal symptoms.     

Role of Levo-tetrahydropalmatine and its metabolites for management of chronic pain and opioid use disorders

BackgroundOpioids have been prescribed to reduce suffering from pain and to enhance quality of life. Due to the addictive potential and the lack of other effective alternatives to treat severe acute and chronic pains, opioids remain a serious public health issue. While, opioids directly influence the drug-seeking behavior, tolerance and withdrawal processes, through neuroadaptation, the brain's endogenous opioid system also adapts in the presence of chronic pain and could contribute to the difficulty of treatment. Despite the seemingly obvious interaction between the presence of pain and opioid-abuse, little is known about the underlying mechanisms in the brain.PurposeTo review the current understanding of the interaction mechanisms of neurotransmitter circuitries in pain modulation and reward in the brain and the effects of L-tetrahydropalmatine (L-THP) and its metabolites in pain management and opioid use disorder and gain a better insight on the pharmacological profile and in vivo effects of L-THP and its metabolites.MethodA detailed literature search on available (preclinical and clinical) studies about the effects of L-THP and its metabolites against drug addiction and chronic pain has been performed. The data was collected using various search engines such as PubMed, ScienceDirect, Google scholar and articles in English up to December 2020 were included in this review.ResultsL-THP and its metabolites demonstrated analgesic and anti-addiction effects. Due to their dual pharmacological properties (D1 partial agonist and D2 antagonist) these compounds could be used as molecular tools to provide a better understanding of the interactions between pain and addiction.ConclusionThe available data confirms the potential of L-THP and its metabolites to treat both chronic pain and drug addiction. However, further clinical trials are needed to establish safety and efficacy.     

Cellular mechanisms of striatum-dependent behavioral plasticity and drug addiction

The striatum has long been known to be involved in the control of motor behavior, since disruption of dopamine-mediated function in this brain structure is directly linked to Parkinson's disease and other disorders of movement. However, it is now accepted that both dorsal and ventral striatal nuclei are also essential for a variety of cognitive processes, which depend on reward-based stimulus-response learning. Since the neuroanatomical and neurochemical organization of dorsal and ventral striatum is only partially overlapping, it is likely that both common and nucleus-specific cellular and molecular events contribute to synaptic plasticity, learning and memory processes mediated by these cerebral structures. Alterations in cell signaling in the striatum may be particularly important in the response to both acute and chronic administration of drugs of abuse, resulting in maladaptive changes in the reward-based associative learning involved in addiction, withdrawal and relapse.     

In vivo nicotine treatment regulates mesocorticolimbic CREB and ERK signaling in C57Bl/6J mice

The extracellular regulated kinase (ERK) pathway was studied to determine its role in neuronal plasticity related to the development of nicotine dependence. Levels and phosphorylation state of ERK, cAMP response element binding protein (CREB) and proline-rich/Ca2+-activated tyrosine kinase (PYK2), and levels of tyrosine hydroxylase (TH), were determined using western blotting. C57Bl/6J mice received acute or chronic nicotine (200 microg/mL) in their drinking water or were withdrawn from nicotine for 24 h following chronic exposure. CREB phosphorylation was reduced in the nucleus accumbens following chronic nicotine, consistent with previous reports that decreased accumbens CREB activity increases drug reinforcement. In contrast, CREB phosphorylation was increased in the prefrontal cortex following chronic nicotine exposure and in the ventral tegmental area during nicotine withdrawal. In addition, total and phosphorylated ERK decreased in the amygdala following chronic nicotine exposure, but ERK phosphorylation increased in the prefrontal cortex. TH levels increased in both the amygdala and prefrontal cortex, supporting the hypothesis that increased catecholaminergic tone contributes to nicotine reinforcement. Overall, these results support a role for ERK and CREB activity in neural plasticity associated with nicotine dependence.     

Corticotropin releasing factor and neuroplasticity in cocaine addiction

Corticotropin releasing factor (CRF), one of the major effectors of stress, plays a major role in the natural course of drug addiction by accelerating the acquisition of psychostimulant self-administration and increasing incentive motivation for the drug itself and for drug-associated stimuli. Stress-induced CRF is also considered a predictor of relapse and is responsible for feelings of anxiety and distress during cocaine withdrawal. Despite this knowledge, the role of CRF has not been explored in the context of recent research on reward-related learning, built on the hypothesis that neuroplastic changes in the mesocorticolimbic circuitry underlie addiction. The present review explores the effects of stress on the pattern of interaction between CRF, dopamine and glutamate in distinct structures of the mesocorticolimbic circuitry, including the ventral tegmental area (VTA), amygdala, bed nucleus of stria terminalis (BNST) and the prefrontal cortex (PFC), after acute and chronic cocaine consumption as well as in early withdrawal and protracted abstinence. A better knowledge of the neurochemical and cellular mechanisms involved in these interactions would be useful to elucidate the role of CRF in cocaine-induced neuronal plasticity, which could be useful in developing new pharmacological strategies for the treatment of cocaine addiction.     

miRNAs与药物成瘾

药物成瘾是一种慢性复发性脑病,主要表现为不可控制的对药物持续渴求和戒断后的高复吸。目前观点认为,成瘾是中脑腹侧被盖（ventral tegmental area,VTA）到伏隔核（nucleus accumbens,NAc）脑区多巴胺能奖赏通路中神经可塑性发生改变而导致的一种神经精神疾病。基因表达变化在神经可塑性中发挥着重要作用,但成瘾药物导致相关脑区结构和功能改变的机制还不甚清楚。微小RNAs（microRNAs,miRNAs）是一类非编码RNA,主要通过结合靶基因mRNA 3′非翻译区（3′untranslated region,3′UTR）,在转录后水平阻断其翻译成蛋白质或触发其不稳定而降解。越来越多的研究证实,miRNAs参与调节成瘾相关神经可塑性的变化。本文较系统地阐述miRNAs在药物成瘾中的作用研究进展,将为深入阐明药物成瘾的机制以及药物成瘾临床有效干预和诊治提供新思路。     

A cannabinoid mechanism in relapse to cocaine seeking

Treatment of cocaine addiction is hampered by high rates of relapse even after prolonged drug abstinence. This relapse to compulsive cocaine use can be triggered by re-exposure to cocaine, by re-exposure to stimuli previously associated with cocaine or by exposure to stress. In laboratory rats, similar events reinstate cocaine seeking after prolonged withdrawal periods, thus providing a model to study neuronal mechanisms underlying the relapse to cocaine. The endocannabinoid system has been implicated in a number of neuropsychiatric conditions, including drug addiction. The active ingredient of marijuana, Delta9-tetrahydrocannabinol, activates the mesolimbic dopamine (DA) reward system and has rewarding effects in preclinical models of drug abuse. We report here that the synthetic cannabinoid agonist, HU210 (ref. 13), provokes relapse to cocaine seeking after prolonged withdrawal periods. Furthermore, the selective CB1 receptor antagonist, SR141716A (ref. 14), attenuates relapse induced by re-exposure to cocaine-associated cues or cocaine itself, but not relapse induced by exposure to stress. These data reveal an important role of the cannabinoid system in the neuronal processes underlying relapse to cocaine seeking, and provide a rationale for the use of cannabinoid receptor antagonists for the prevention of relapse to cocaine use.     

Assessment of heat production, heat loss, and core temperature during nitrous oxide exposure: a new paradigm for studying drug effects and opponent responses

Studies using core temperature (T(c)) have contributed greatly to theoretical explanations of drug tolerance and its relationship to key features of addiction, including dependence, withdrawal, and relapse. Many theoretical accounts of tolerance propose that a given drug-induced psychobiological disturbance elicits opponent responses that contribute to tolerance development. This proposal and its theoretical extensions (e.g., conditioning as a mechanism of chronic tolerance) have been inferred from dependent variables, such as T(c), which represent the summation of multiple underlying determinants. Direct measurements of determinants could increase the understanding of opponent processes in tolerance, dependence, and withdrawal. The proximal determinants of T(c) are metabolic heat production (HP) and heat loss (HL). We developed a novel system for simultaneously quantifying HP (indirect calorimetry), HL (direct gradient layer calorimetry), and T(c) (telemetry) during steady-state administrations of nitrous oxide (N(2)O), an inhalant with abuse potential that has been previously used to study acute and chronic tolerance development to its hypothermia-inducing property. Rats were administered 60% N(2)O (n = 18) or placebo gas (n = 16) for 5 h after a 2-h placebo baseline exposure. On average, N(2)O rapidly but transiently lowered HP and increased HL, each by approximately 16% (P < 0.001). On average, rats reestablished and maintained thermal equilibrium (HP = HL) at a hypothermic T(c) (-1.6 degrees C). However, some rats entered positive heat balance (HP > HL) after becoming hypothermic such that acute tolerance developed, i.e., T(c) rose despite continued drug administration. This work is the first to directly quantify the thermal determinants of T(c) during administration of a drug of abuse and establishes a new paradigm for studying opponent processes involved in acute and chronic hypothermic tolerance development.     

Persistent histone modifications at the BDNF and Cdk‐5 promoters following extinction of nicotine‐seeking in rats

Drugs of addiction lead to a wide range of epigenetic changes at the promoter regions of genes directly implicated in learning and memory processes. We have previously shown that the histone deactylase inhibitor, sodium butyrate (NaB), accelerates the extinction of nicotine‐seeking and provides resistance to relapse. Here, we explore the potential molecular mechanisms underlying this effect. Rats received intravenous nicotine or saline self‐administration, followed by 6 days of extinction training, with each extinction session followed immediately by treatment with NaB or vehicle. On the last day of extinction, rats were killed and the medial ventral prefrontal cortex retained for chromatin immunoprecipitation and quantitative polymerase chain reaction (qPCR). A history of nicotine exposure significantly decreased H3K14 acetylation at the brain‐derived neurotrophic factor (BDNF) exon IV promoter, and this effect was abolished with NaB treatment. In contrast, nicotine self‐administration alone, resulted in a significant decrease in histone methylation at the H3K27me3 and H3K9me2 marks in the promoter regions of BDNF exon IV and cyclin‐dependent kinase 5 (Cdk‐5). Quantitative PCR‐identified changes in several genes associated with NaB treatment that were independent of nicotine exposure; however, an interaction of nicotine history and NaB treatment was detected only in the expression of BDNF IV and BDNF IX. Together these results suggest that nicotine self‐administration leads to a number of epigenetic changes at both the BDNF and Cdk‐5 promoters, and that these changes may contribute to the enhanced extinction of nicotine‐seeking by NaB.     

Adolescent rats are resistant to adaptations in excitatory and inhibitory mechanisms that modulate mesolimbic dopamine during nicotine withdrawal

Adolescent smokers report enhanced positive responses to tobacco and fewer negative effects of withdrawal from this drug than adults, and this is believed to propel higher tobacco use during adolescence. Differential dopaminergic responses to nicotine are thought to underlie these age‐related effects, as adolescent rats experience lower withdrawal‐related deficits in nucleus accumbens (NAcc) dopamine versus adults. This study examined whether age differences in NAcc dopamine during withdrawal are mediated by excitatory or inhibitory transmission in the ventral tegmental area (VTA) dopamine cell body region. In vivo microdialysis was used to monitor extracellular levels of glutamate and gamma‐aminobutyric acid (GABA) in the VTA of adolescent and adult rats experiencing nicotine withdrawal. In adults, nicotine withdrawal produced decreases in VTA glutamate levels (44% decrease) and increases in VTA GABA levels (38% increase). In contrast, adolescents did not exhibit changes in either of these measures. Naïve controls of both ages did not display changes in NAcc dopamine, VTA glutamate, or VTA GABA following mecamylamine. These results indicate that adolescents display resistance to withdrawal‐related neurochemical processes that inhibit mesolimbic dopamine function in adults experiencing nicotine withdrawal. Our findings provide a potential mechanism involving VTA amino acid neurotransmission that modulates age differences during withdrawal.