How contexts promote and prevent relapse to drug seeking

The contexts where drugs are self‐administered play an important role in regulating persistent drug taking and in relapse to such taking after periods of abstinence. Here, we review the behavioral and brain mechanisms enabling contexts to promote and prevent relapse to drug seeking. We review the key brain structures, their neuropharmacology and their connectivity. We discuss the similarities and differences between the mechanisms for context‐induced reinstatement of drug seeking vs. other forms of relapse to drug seeking in animal models and we highlight the numerous deficits in our understanding. We emphasize that current understanding, although significant, defies explanations in terms of models at the level of brain structures and their connectivity. Rather, we show that there is significant functional compartmentalization and segregation within these structures during reinstatement and extinction of drug seeking that parallels their anatomical segregation into circuits and channels. A key challenge is to recognize this complexity, understand how these circuits and channels are organized, as well as understand how different modes of activity of ensembles of neurons within them promote abstinence or relapse to drug seeking.     

A Procedure to Observe Context-induced Renewal of Pavlovian-conditioned Alcohol-seeking Behavior in Rats

Environmental contexts in which drugs of abuse are consumed can trigger craving, a subjective Pavlovian-conditioned response that can facilitate drug-seeking behavior and prompt relapse in abstinent drug users. We have developed a procedure to study the behavioral and neural processes that mediate the impact of context on alcohol-seeking behavior in rats. Following acclimation to the taste and pharmacological effects of 15% ethanol in the home cage, male Long-Evans rats receive Pavlovian discrimination training (PDT) in conditioning chambers. In each daily (Mon-Fri) PDT session, 16 trials each of two different 10 sec auditory conditioned stimuli occur. During one stimulus, the CS+, 0.2 ml of 15% ethanol is delivered into a fluid port for oral consumption. The second stimulus, the CS-, is not paired with ethanol. Across sessions, entries into the fluid port during the CS+ increase, whereas entries during the CS- stabilize at a lower level, indicating that a predictive association between the CS+ and ethanol is acquired. During PDT each chamber is equipped with a specific configuration of visual, olfactory and tactile contextual stimuli. Following PDT, extinction training is conducted in the same chamber that is now equipped with a different configuration of contextual stimuli. The CS+ and CS- are presented as before, but ethanol is withheld, which causes a gradual decline in port entries during the CS+. At test, rats are placed back into the PDT context and presented with the CS+ and CS- as before, but without ethanol. This manipulation triggers a robust and selective increase in the number of port entries made during the alcohol predictive CS+, with no change in responding during the CS-. This effect, referred to as context-induced renewal, illustrates the powerful capacity of contexts associated with alcohol consumption to stimulate alcohol-seeking behavior in response to Pavlovian alcohol cues.     

A multivariate regressor of patterned dopamine release predicts relapse to cocaine

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Review. Psychological and neural mechanisms of relapse

Relapse, the resumption of drug taking after periods of abstinence, remains the major problem for the treatment of addiction. Even when drugs are unavailable for long periods or when users are successful in curbing their drug use for extended periods, individuals remain vulnerable to events that precipitate relapse. Behavioural studies in humans and laboratory animals show that drug-related stimuli, drugs themselves and stressors are powerful events for the precipitation of relapse. Molecular, neurochemical and anatomical studies have identified lasting neural changes that arise from mere exposure to drugs and other enduring changes that arise from learning about the relationship between drug-related stimuli and drug effects. Chronic drug exposure increases sensitivity of some systems of the brain to the effects of drugs and stressful events. These changes, combined with those underlying conditioning and learning, perpetuate vulnerability to drug-related stimuli. Circuits of the brain involved are those of the mesocorticolimbic dopaminergic system and its glutamatergic connections, and the corticotropin-releasing factor and noradrenergic systems of the limbic brain. This paper reviews advances in our understanding of how these systems mediate the effects of events that precipitate relapse and of how lasting changes in these systems can perpetuate vulnerability to relapse.     

Unique gene alterations are induced in FACS‐purified Fos‐positive neurons activated during cue‐induced relapse to heroin seeking

Cue‐induced heroin seeking after prolonged withdrawal is associated with neuronal activation and altered gene expression in prefrontal cortex (PFC). However, these previous studies assessed gene expression in all neurons regardless of their activity state during heroin seeking. Using Fos as a marker of neural activity, we describe distinct molecular alterations induced in activated versus non‐activated neurons during cue‐induced heroin seeking after prolonged withdrawal. We trained rats to self‐administer heroin for 10 days (6 h/day) and assessed cue‐induced heroin seeking in extinction tests after 14 or 30 days. We used fluorescent‐activated cell sorting (FACS) to purify Fos‐positive and Fos‐negative neurons from PFC 90 min after extinction testing. Flow cytometry showed that Fos‐immunoreactivity was increased in less than 10% of sparsely distributed PFC neurons. mRNA levels of the immediate early genes fosB, arc, egr1, and egr2, as well as npy and map2k6, were increased in Fos‐positive, but not Fos‐negative, neurons. In support of these findings, double‐label immunohistochemistry indicated substantial coexpression of neuropeptide Y (NPY)‐ and Arc‐immunoreactivity in Fos‐positive neurons. Our data indicate that cue‐induced relapse to heroin seeking after prolonged withdrawal induces unique molecular alterations within activated PFC neurons that are distinct from those observed in the surrounding majority of non‐activated neurons.     

Drug-primed reinstatement of cocaine seeking in mice: increased excitability of medium-sized spiny neurons in the nucleus accumbens

To examine the mechanisms of drug relapse, we first established a model for cocaine IVSA (intravenous self-administration) in mice, and subsequently examined electrophysiological alterations of MSNs (medium-sized spiny neurons) in the NAc (nucleus accumbens) before and after acute application of cocaine in slices. Three groups were included: master mice trained by AL (active lever) pressings followed by IV (intravenous) cocaine delivery, yoked mice that received passive IV cocaine administration initiated by paired master mice, and saline controls. MSNs recorded in the NAc shell in master mice exhibited higher membrane input resistances but lower frequencies and smaller amplitudes of sEPSCs (spontaneous excitatory postsynaptic currents) compared with neurons recorded from saline control mice, whereas cells in the NAc core had higher sEPSCs frequencies and larger amplitudes. Furthermore, sEPSCs in MSNs of the shell compartment displayed longer decay times, suggesting that both pre- and postsynaptic mechanisms were involved. After acute re-exposure to a low-dose of cocaine in vitro, an AP (action potential)-dependent, persistent increase in sEPSC frequency was observed in both NAc shell and core MSNs from master, but not yoked or saline control mice. Furthermore, re-exposure to cocaine induced membrane hyperpolarization, but concomitantly increased excitability of MSNs from master mice, as evidenced by increased membrane input resistance, decreased depolarizing current to generate APs, and a more negative Thr (threshold) for firing. These data demonstrate functional differences in NAc MSNs after chronic contingent versus non-contingent IV cocaine administration in mice, as well as synaptic adaptations of MSNs before and after acute re-exposure to cocaine. Reversing these functional alterations in NAc could represent a rational target for the treatment of some reward-related behaviors, including drug addiction.     

微针技术用于非经皮途径的药物递送研究进展

近年来,微针作为一种新兴的经皮给药技术,具有微创、无痛、使用方便和高效的特点,逐渐成为一种极具研究价值和应用潜力的给药策略。微针技术在过去20年中得到迅速发展并呈现出多样化的趋势,已可根据不同需求来定制微针的形状、组成、机械性能和其他特殊功能等。由于微针能以微创方式穿越各种生物屏障,因此许多研究人员探索了微针在除皮肤外各类组织和器官中的药物递送应用。本文综述了微针技术及其近年来在眼睛、血管、心脏等组织和器官的药物递送中的应用研究,以期推动微针技术的应用发展。     

Cyclodextrins in drug delivery: An updated review

The purpose of this review is to discuss and summarize some of the interesting findings and applications of cyclodextrins (CDs) and their derivatives in different areas of drug delivery, particularly in protein and peptide drug delivery and gene delivery. The article highlights important CD applications in the design of various novel delivery systems like liposomes, microspheres, microcapsules, and nanoparticles. In addition to their well-known effects on drug solubility and dissolution, bioavailability, safety, and stability, their use as excipients in drug formulation are also discussed in this article. The article also focuses on various factors influencing inclusion complex formation because an understanding of the same is necessary for proper handling of these versatile materials. Some important considerations in selecting CDs in drug formulation such as their commercial availability, regulatory status, and patent status are also summarized. CDs, because of their continuing ability to find several novel applications in drug delivery, are expected to solve many problems associated with the delivery of different novel drugs through different delivery routes. Published: October 14, 2005     

Zwitterionic polymers in drug delivery: A review

Developments of novel drug delivery vehicles are sought-after to augment the therapeutic effectiveness of standard drugs. An urgency to design novel drug delivery vehicles that are sustainable, biocompatible, have minimized cytotoxicity, no immunogenicity, high stability, long circulation time, and are capable of averting recognition by the immune system is perceived. In this pursuit for an ideal candidate for drug delivery vehicles, zwitterionic materials have come up as fulfilling almost all these expectations. This comprehensive review is presenting the progress made by zwitterionic polymeric architectures as prospective sustainable drug delivery vehicles. Zwitterionic polymers with varied architecture such as appending protein conjugates, nanoparticles, surface coatings, liposomes, hydrogels, etc, used to fabricate drug delivery vehicles are reviewed here. A brief introduction of zwitterionic polymers and their application as reliable drug delivery vehicles, such as zwitterionic polymer–protein conjugates, zwitterionic polymer-based drug nanocarriers, and stimulus-responsive zwitterionic polymers are discussed in this discourse. The prospects shown by zwitterionic architecture suggest the tremendous potential for them in this domain. This critical review will encourage the researchers working in this area and boost the development and commercialization of such devices to benefit the healthcare fraternity.     

Modelling diseases with relapse and nonlinear incidence of infection: a multi-group epidemic model

In this paper, we introduce a basic reproduction number for a multi-group SIR model with general relapse distribution and nonlinear incidence rate. We find that basic reproduction number plays the role of a key threshold in establishing the global dynamics of the model. By means of appropriate Lyapunov functionals, a subtle grouping technique in estimating the derivatives of Lyapunov functionals guided by graph-theoretical approach and LaSalle invariance principle, it is proven that if it is less than or equal to one, the disease-free equilibrium is globally stable and the disease dies out; whereas if it is larger than one, some sufficient condition is obtained in ensuring that there is a unique endemic equilibrium which is globally stable and thus the disease persists in the population. Furthermore, our results suggest that general relapse distribution are not the reason of sustained oscillations. Biologically, our model might be realistic for sexually transmitted diseases, such as Herpes, Condyloma acuminatum, etc.     

Addiction,cognitive decline and therapy: seeking ways to escape a vicious cycle

Any type of behavioral change is an effortful process. Thus, the process of behavioral therapy, where clients seek to change maladaptive behavioral patterns, requires high‐level cognitive engagement. It is unfortunate, then, that cognitive impairment is a feature of substance use disorders (SUDs), and especially because the domains that tend to be impaired are the very ones involved in the process of therapeutic behavioral change. In this review, we compare the cognitive profile that is frequently observed with chronic SUD with the skills that are required to initiate and sustain behavioral change during rehabilitation. Furthermore, we look to new therapeutic developments that seek to improve cognitive function. We propose that the use of these cognitive enhancing agents as adjuncts to behavioral therapy should help to overcome some of the cognitive barriers imposed by the disorder itself, and hence reduce the chance of relapse.     

Floating drug delivery systems: A review

The purpose of writing this review on floating drug delivery systems (FDDS) was to compile the recent literature with special focus on the principal mechanism of floatation to achieve gastric retention. The recent developments of FDDS including the physiological and formulation variables affecting gastric retention, approaches to design single-unit and multiple-unit floating systems, and their classification and formulation aspects are covered in detail. This review also summarizes the in vitro techniques, in vivo studies to evaluate the performance and application of floating systems, and applications of these systems. These systems are useful to several problems encountered during the development of a pharmaceutical dosage form. Published: October 19, 2005     

PREDICT: a method for inferring novel drug indications with application to personalized medicine

Inferring potential drug indications, for either novel or approved drugs, is a key step in drug development. Previous computational methods in this domain have focused on either drug repositioning or matching drug and disease gene expression profiles. Here, we present a novel method for the large‐scale prediction of drug indications (PREDICT) that can handle both approved drugs and novel molecules. Our method is based on the observation that similar drugs are indicated for similar diseases, and utilizes multiple drug–drug and disease–disease similarity measures for the prediction task. On cross‐validation, it obtains high specificity and sensitivity (AUC=0.9) in predicting drug indications, surpassing existing methods. We validate our predictions by their overlap with drug indications that are currently under clinical trials, and by their agreement with tissue‐specific expression information on the drug targets. We further show that disease‐specific genetic signatures can be used to accurately predict drug indications for new diseases (AUC=0.92). This lays the computational foundation for future personalized drug treatments, where gene expression signatures from individual patients would replace the disease‐specific signatures.     

Down-regulated miR-331-5p and miR-27a are associated with chemotherapy resistance and relapse in leukaemia

Multidrug resistance (MDR) and disease relapse are challenging clinical problems in the treatment of leukaemia. Relapsed disease is frequently refractory to chemotherapy and exhibits multiple drug resistance. Therefore, it is important to identify the mechanism by which cancer cells develop resistance. In this study, we used microRNA (miRNA) microarray and qRT-PCR approaches to investigate the expression of miRNAs in three leukaemia cell lines with different degrees of resistance to doxorubicin (DOX) compared with their parent cell line, K562. The expression of miR-331-5p and miR-27a was inversely correlated with the expression of a drug-resistant factor, P-glycoprotein (P-gp), in leukaemia cell lines with gradually increasing resistance. The development of drug resistance is regulated by the expression of the P-gp. Transfection of the K562 and, a human promyelocytic cell line (HL) HL60 DOX-resistant cells with miR-331-5p and miR-27a, separately or in combination, resulted in the increased sensitivity of cells to DOX, suggesting that correction of altered expression of miRNAs may be used for therapeutic strategies to overcome leukaemia cell resistance. Importantly, miR-331-5p and miR-27a were also expressed at lower levels in a panel of relapse patients compared with primary patients at diagnosis, further illustrating that leukaemia relapse might be a consequence of deregulation of miR-331-5p and miR-27a.     

What the honeybee sees: a review of the recognition system of Apis mellifera

Abstract. For many years, two opposing theories have dominated our ideas of what honeybees see. The earliest proposal based on training experiments was that bees detected only simple attributes or features, irrespective of the actual pattern. The features demonstrated experimentally before 1940 were the disruption of the pattern (related to spatial frequency), the area of black or colour, the length of edge, and the angle of orientation of a bar or grating. Cues discovered recently are the range, and radial and tangential edges, and symmetry, relative to the fixation point, which is usually the reward hole. This theory could not explain why recognition failed when the pattern was moved. In the second theory, proposed in 1969, the bee detected the retinotopic directions of black or coloured areas, and estimated the areas of overlap and nonoverlap on each test pattern with the corresponding positions in the training pattern. This proposal explained the progressive loss of recognition as a test pattern was moved or reduced in size, but required that the bees saw and remembered the layout of every learned pattern and calculated the mismatch with each test image. Even so, the same measure of the mismatch was given by many test patterns and could not detect a pattern uniquely. Moreover, this theory could not explain the abundant evidence of simple feature detectors. Recent work has shown that bees learn one or more of a limited number of simple cues. A newly discovered cue is the position, mainly in the vertical direction, of the common centre (centroid) of black areas combined together. Significantly, however, the trained bees look for the cues mentioned above only in the range of places where they had occurred during the training. These two observations made possible a synthesis of both theories. There is no experimental evidence that the bees detect or re-assemble the layout of patterns in space; instead, they look for a cue in the expected place. With an array of detectors of the known cues, together with their directions, this mechanism would enable bees to recognize each familiar place from the coincidences of cues in different directions around the head.