An unusual suspect in cocaine addiction

Most Mage family members code for antigens on melanoma tumor cells. Maged1 is the black sheep, promiscuously found in normal adult cells, including neurons of the basal ganglia and prefrontal cortex. In this issue of EMBO reports, De Backer et al 1 propose an unexpected role for Maged1. Acute effects of cocaine, such as enhanced locomotion and reinforcement, are gone in mice in which the gene is deleted. In a painstaking combinatorial approach comparing several conditional gene knockout (KO) mouse lines, the authors parse the relevant neural circuits.     

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.     

New perspectives on cocaine addiction: recent findings from animal research

Research with laboratory animals has provided several insights into the nature of cocaine abuse and addiction. First, the nature of drug addiction has been reevaluated and the emphasis has shifted from physical dependence to compulsive drug-taking behavior. Second, animal studies suggest that cocaine is at least as addictive as heroin and possibly even more addictive. Third, cocaine is potentially more dangerous than heroin as evidenced by the higher fatality rate seen in laboratory animals given unlimited access to these drugs. Fourth, the neural basis of cocaine reinforcement has been identified and involves an enhancement of dopaminergic neurotransmission in the ventral tegmental dopamine system. Other addictive drugs (e.g., opiates) may also derive at least part of their reinforcing impact by pharmacologically activating this reward system. Fifth, although the biological consequences of repeated cocaine self-administration on central nervous system functioning are poorly understood, preliminary findings suggest that intravenous cocaine self-administration may decrease neural functioning in this brain reward system. This has important clinical implications because diminished functioning of an important brain reward system may significantly contribute to relapse into cocaine addiction. These and other findings from experimentation with laboratory animals suggest new considerations for the etiology and treatment of drug addiction.     

Neural plasticity and addiction: integrin-linked kinase and cocaine behavioral sensitization

Behavioral sensitization of psychostimulants was accompanied by alterations in a variety of biochemical molecules in different brain regions. However, which change is actually related to drug-produced sensitization lacks of accurate clarification. In this study, we investigated the role of integrin-linked kinase (ILK) in both the induction and expression of cocaine sensitization. Conditional inhibition of ILK expression was established in the nucleus accumbens (NAc) core by microinjecting recombinant adeno-associated virus-carrying, tetracycline-on-regulated small interfering RNA which reversed the chronic cocaine-induced psychomotor sensitization, as well as the changes in protein kinase B Ser473 phosphorylation, dendritic density, and dendritic spine numbers locally. Importantly, the reversed psychomotor sensitization did not recover after cessation of the silencing for 8 days. We also demonstrated that inhibition of ILK expression pre- and during-chronic cocaine treatments blocked the induction of cocaine psychomotor sensitization and abolished the stimulant effect of cocaine on ILK expression. In contrast, inhibition of ILK expression in the NAc core has no significant effect on cocaine-induced stereotypical behaviors. This concludes that ILK is involved in cocaine sensitization with the earlier induction and later expression functioning as a kinase to regulate protein kinase B Ser473 phosphorylation and a scaffolding protein to regulate the reorganization of the NAc spine morphology.     

Genetic association analyses of PDYN polymorphisms with heroin and cocaine addiction

Genetic factors are believed to account for 30-50% of the risk for cocaine and heroin addiction. Dynorphin peptides, derived from the prodynorphin (PDYN) precursor, bind to opioid receptors, preferentially the kappa-opioid receptor, and may mediate the aversive effects of drugs of abuse. Dynorphin peptides produce place aversion in animals and produce dysphoria in humans. Cocaine and heroin have both been shown to increase expression of PDYN in brain regions relevant for drug reward and use. Polymorphisms in PDYN are therefore hypothesized to increase risk for addiction to drugs of abuse. In this study, 3 polymorphisms in PDYN (rs1022563, rs910080 and rs1997794) were genotyped in opioid-addicted [248 African Americans (AAs) and 1040 European Americans (EAs)], cocaine-addicted (1248 AAs and 336 EAs) and control individuals (674 AAs and 656 EAs). Sex-specific analyses were also performed as a previous study identified PDYN polymorphisms to be more significantly associated with female opioid addicts. We found rs1022563 to be significantly associated with opioid addiction in EAs [P = 0.03, odds ratio (OR) = 1.31; false discovery rate (FDR) corrected q-value]; however, when we performed female-specific association analyses, the OR increased from 1.31 to 1.51. Increased ORs were observed for rs910080 and rs199774 in female opioid addicts also in EAs. No statistically significant associations were observed with cocaine or opioid addiction in AAs. These data show that polymorphisms in PDYN are associated with opioid addiction in EAs and provide further evidence that these risk variants may be more relevant in females.     

An albumin-butyrylcholinesterase for cocaine toxicity and addiction: catalytic and pharmacokinetic properties

Butyrylcholinesterase (BChE, EC 3.1.1.8) is important in human cocaine metabolism despite its limited ability to hydrolyze this drug. Efforts to improve the catalytic efficiency of this enzyme have led to a quadruple mutant cocaine hydrolase, "CocH", that in animal models of addiction appears promising for treatment of overdose and relapse. We incorporated the CocH mutations into a BChE-albumin fusion protein, "Albu-CocH", and evaluated the pharmacokinetics of the enzyme after i.v. injection in rats. As assessed from the time course of cocaine hydrolyzing activity in plasma, Albu-CocH redistributed into extracellular fluid (16% of estimated total body water) with a t(1/2) of 0.66h and it underwent elimination with a t(1/2) of 8h. These results indicate that the enzyme has ample stability for short-term applications and may be suitable for longer-term treatment as well. Present data also confirm the markedly enhanced power of Albu-CocH for cocaine hydrolysis and they support the view that Albu-CocH might prove valuable in treating phenomena associated with cocaine abuse.     

Accessories to addiction: G protein regulators play a key role in cocaine seeking and neuroplasticity

The prefrontal cortex mediates many aspects of addiction. In this issue of Neuron, Bowers et al. demonstrate that an activator of G protein signaling (AGS3) is persistently upregulated in the prefrontal cortex after cessation of chronic cocaine treatment. Furthermore, they find that AGS3 is responsible for altered behavior, such as enhanced drug seeking, and altered neurotransmission in cocaine-treated rats, representing a novel therapeutic target.     

An albumin–butyrylcholinesterase for cocaine toxicity and addiction: Catalytic and pharmacokinetic properties

Butyrylcholinesterase (BChE, EC 3.1.1.8) is important in human cocaine metabolism despite its limited ability to hydrolyze this drug. Efforts to improve the catalytic efficiency of this enzyme have led to a quadruple mutant cocaine hydrolase, “CocH”, that in animal models of addiction appears promising for treatment of overdose and relapse. We incorporated the CocH mutations into a BChE–albumin fusion protein, “Albu-CocH”, and evaluated the pharmacokinetics of the enzyme after i.v. injection in rats. As assessed from the time course of cocaine hydrolyzing activity in plasma, Albu-CocH redistributed into extracellular fluid (16% of estimated total body water) with a t_1/2 of 0.66 h and it underwent elimination with a t_1/2 of 8 h. These results indicate that the enzyme has ample stability for short-term applications and may be suitable for longer-term treatment as well. Present data also confirm the markedly enhanced power of Albu-CocH for cocaine hydrolysis and they support the view that Albu-CocH might prove valuable in treating phenomena associated with cocaine 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。     

Cdc42 signaling regulated by dopamine D2 receptor correlatively links specific brain regions of hippocampus to cocaine addiction

BackgroundHippocampus plays critical roles in drug addiction. Cocaine-induced modifications in dopamine receptor function and the downstream signaling are important regulation mechanisms in cocaine addiction. Rac regulates actin filament accumulation while Cdc42 stimulates the formation of filopodia and neurite outgrowth. Based on the region specific roles of small GTPases in brain, we focused on the hippocampal subregions to detect the regulation of Cdc42 signaling in long-term morphological and behavioral adaptations to cocaine.MethodsGenetically modified mouse models of Cdc42, dopamine receptor D1 (D1R) and D2 (D2R) and expressed Cdc42 point mutants that are defective in binding to and activation of its downstream effector molecules PAK and N-WASP were generated, respectively, in CA1 or dentate gyrus (DG) subregion.ResultsCocaine induced upregulation of Cdc42 signaling activity. Cdc42 knockout or mutants blocked cocaine-induced increase in spine plasticity in hippocampal CA1 pyramidal neurons, leading to a decreased conditional place preference (CPP)-associated memories and spatial learning and memory in water maze. Cdc42 knockout or mutants promoted cocaine-induced loss of neurogenesis in DG, leading to a decreased CPP-associated memories and spatial learning and memory in water maze. Furthermore, by using D1R knockout, D2R knockout, and D2R/Cdc42 double knockout mice, we found that D2R, but not D1R, regulated Cdc42 signaling in cocaine-induced neural plasticity and behavioral changes.ConclusionsCdc42 acts downstream of D2R in the hippocampus and plays an important role in cocaine-induced neural plasticity through N-WASP and PAK-LIMK-Cofilin, and Cdc42 signaling pathway correlatively links specific brain regions (CA1, dentate gyrus) to cocaine-induced CPP behavior.     

Decoding olfaction in Drosophila

Recent experiments in Drosophila demonstrate striking stereotypy in the neural architecture of the olfactory system. Functional imaging experiments in mammals and honeybees suggest a mechanism of odor coding that translates discrete patterns of activity in olfactory glomeruli into an odor image. Future experiments in Drosophila may permit a direct test of this odor-coding hypothesis.     

Psychophysiology of sports addiction (exercises addiction)

Addiction is a prevalent and growing concern in all aspects of our modern society. There are considerable concerns for the growing frequency of addictions to drugs, alcohol, gambling, eating, and even sex. Though exercise is generally accepted as a positive behaviour that has many benefits associated with enhanced physical and psychological wellbeing, there is an increasing awareness that exercise addiction is becoming a common phenomenon. Theories regarding how exercise can become addictive, and studies of withdrawal from exercise are reviewed. Several physiological mechanisms, including endogenous opioids, catecholamines, functional asymmetry of brain activity and thermoregulation have been implicated in exercise dependence.     

Decoding development in Xenopus tropicalis

Xenopus tropicalis is rapidly being adopted as a model organism for developmental biology research and has enormous potential for increasing our understanding of how embryonic development is controlled. In recent years there has been a well-organized initiative within the Xenopus community, funded largely through the support of the National Institutes of Health in the US, to develop X. tropicalis as a new genetic model system with the potential to impact diverse fields of research. Concerted efforts have been made both to adapt established methodologies for use in X. tropicalis and to develop new techniques. A key resource to come out of these efforts is the genome sequence, produced by the US Department of Energy's Joint Genome Institute and made freely available to the community in draft form for the past three years. In this review, we focus on how advances in X. tropicalis genetics coupled with the sequencing of its genome are likely to form a foundation from which we can build a better understanding of the genetic control of vertebrate development and why, when we already have other vertebrate genetic models, we should want to develop genetic analysis in the frog.