The neuroadaptation theory of addiction suggests that, similar to the development of most memories, exposure to drugs of abuse induces adaptive molecular and cellular changes in the brain which likely mediate addiction-related memories or the addictive state. Compared to other types of memories, addiction-related memories develop fast and last extremely long, suggesting that the cellular and molecular processes that mediate addiction-related memories are exceptionally adept and efficient. We recently demonstrated that repeated exposure to cocaine generated a large portion of “silent” glutamatergic synapses within the nucleus accumbens (NAc). Silent glutamatergic synapses are synaptic connections in which only N-methyl-D-aspartic acid receptor (NMDAR)-mediated responses are readily detected whereas alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are absent or highly labile. Extensive experimental evidence suggests that silent synapses are conspicuously efficient plasticity sites at which long-lasting plastic changes can be more easily induced and maintained. Thus, generation of silent synapses can be regarded as a process of metaplasticity, which primes the NAc for subsequent durable and robust plasticity for addiction-related memories. Focusing on silent synapse-based metaplasticity, this review discusses how key brain regions, such as the NAc, utilize the metaplasticity mechanism to optimize the plasticity machineries to achieve fast and durable plastic changes following exposure to cocaine. A summary of recent related results suggests that upon cocaine exposure, newly generated silent synapses may prime excitatory synapses within the NAc for long-term potentiation (LTP), thus setting the direction of future plasticity. Furthermore, because cocaine-generated silent synapses are enriched in NMDARs containing the NR2B subunit, the enhanced NR2B-signaling may set up a selective recruitment of certain types of AMPARs. Thus, silent synapse-based metaplasticity may lead to not only quantitative but also qualitative alterations in excitatory synapses within the NAc. This review is one of the first systematic analyses regarding the hypothesis that drugs of abuse induce metaplasticity, which regulates the susceptibility, the direction, and the molecular details of subsequent plastic changes. Taken together, metaplasticity ultimately serves as a key step in mediating cascades of addiction-related plastic alterations.
metaplasticity; silent synapses; cocaine; NMDA; AMPA; membrane excitability
We begin with a theoretical overview of the concepts of recollection and familiarity, focusing, in the spirit of this special issue, on the important contributions made by Andrew Mayes. In particular, we discuss the issue of when the generation of semantically-related information in response to a retrieval cue might be experienced as recollection rather than familiarity. We then report a series of experiments in which two different types of masked prime, presented immediately prior to the test cue in a recognition memory paradigm, produced opposite effects on Remember vs. Know judgments. More specifically, primes that were conceptually related to the test item increased the incidence of Remember judgments, though only when intermixed with repetition primes (which increased the incidence of Know judgments instead, as in prior studies). One possible explanation—that the fluency of retrieval of item–context associations can be experienced as recollection, even when the source of that fluency is unknown—is counter to conventional views of recollection and familiarity, though it was anticipated by Andrew in his writings nearly two decades ago.
► We review the estimation of recollection and familiarity, inspired by Andrew Mayes. ► In a recognition memory experiment, masked primes were shown before test cue words. ► Repetition primes increased ‘familiar’ responses, both hits and false alarms. ► Conceptual primes increased remember' responses (recollection), for hits only.
Remember/know; Source memory; Context; Episodic; Priming
Over the past several years, drug addiction has increasingly been accepted to be a disease of the brain as opposed to simply being due to a lack of willpower or personality flaw. Exposure to addictive substances has been shown to create enduring changes in brain structure and function that are thought to underlie the transition to addiction. Specific genetic and environmental vulnerability factors also influence the impact of drugs of abuse on the brain and can enhance the likelihood of becoming an addict. Long-lasting alterations in brain function have been found in neural circuits that are known to be responsible for normal appetitive learning and memory processes and it has been hypothesized that drugs of abuse enhance positive learning and memory about the drug while inhibiting learning about the negative consequences of drug use. Therefore, the addict's behavior becomes increasingly directed towards obtaining and using drugs of abuse, while at the same time developing a poorer ability to stop using, even when the drug is less rewarding or interferes with functioning in other facets of life. In this review we will discuss the clinical evidence that addicted individuals have altered learning and memory and describe the possible neural substrates of this dysfunction. In addition, we will explore the preclinical evidence that drugs of abuse cause a progressive disorder of learning and memory, review the molecular and neurobiological changes that may underlie this disorder, determine the genetic and environmental factors that may increase vulnerability to addiction, and suggest potential strategies for treating addiction through manipulations of learning and memory.
addiction; extinction; reconsolidation; cue; reinstatement; memory; neuroadaptation
Opioid addiction is a chronic disease with high genetic contribution and a large inter-individual variability in therapeutic response. The goal of this study was to identify pharmacodynamic factors that modulate methadone dose requirement. The neurotrophin family is involved in neural plasticity, learning memory and behavior and deregulated neural plasticity may underlie the pathophysiology of drug addiction. BDNF was shown to affect the response to methadone maintenance treatment. This study explores the effects of polymorphisms in the nerve growth factor (beta polypeptide) gene, NGFB, on the methadone doses required for successful maintenance treatment for heroin addiction. Genotypes of 14 NGFB polymorphisms were analyzed for association with the stabilizing methadone dose in 72 former severe heroin addicts with no major co-medications. There was significant difference in methadone doses required by subjects with different genotypes of the NGFB intronic SNP rs2239622 (P = 0.0002). These results may have clinical importance.
methadone; opioid addiction; nerve growth factor; NGFB; heroin addiction
Sensory system information is thought to play an important role in drug addiction related responses. However, how somatic sensory information participates in the drug related behaviors is still unclear. Many studies demonstrated that drug addiction represents a pathological usurpation of neural mechanisms of learning and memory that normally relate to the pursuit of rewards. Thus, elucidate the role of somatic sensory in drug related learning and memory is of particular importance to understand the neurobiological mechanisms of drug addiction.
In the present study, we investigated the role of somatosensory system in reward-related associative learning using the conditioned place preference model. Lesions were made in somatosensory cortices either before or after conditioning training. We found that lesion of somatosensory cortices before, rather than after morphine conditioning impaired the acquisition of place preference.
These results demonstrate that somatosensory cortices are necessary for the acquisition but not retention of morphine induced place preference.
Drug-associated memories are a hallmark of addiction and a contributing factor in the continued use and relapse to drugs of abuse. Repeated association of drugs of abuse with conditioned stimuli leads to long-lasting behavioral responses that reflect reward-controlled learning and participate in the establishment of addiction. A greater understanding of the mechanisms underlying the formation and retrieval of drug-associated memories may shed light on potential therapeutic approaches to effectively intervene with drug use-associated memory. There is evidence to support the involvement of serotonin (5-HT) neurotransmission in learning and memory formation through the families of the 5-HT1 receptor (5-HT1R) and 5-HT2R which have also been shown to play a modulatory role in the behavioral effects induced by many psychostimulants. While there is a paucity of studies examining the effects of selective 5-HT1AR ligands, the available dataset suggests that 5-HT1BR agonists may inhibit retrieval of cocaine-associated memories. The 5-HT2AR and 5-HT2CR appear to be integral in the strong conditioned associations made between cocaine and environmental cues with 5-HT2AR antagonists and 5-HT2CR agonists possessing potency in blocking retrieval of cocaine-associated memories following cocaine self-administration procedures. The complex anatomical connectivity between 5-HT neurons and other neuronal phenotypes in limbic-corticostriatal brain structures, the heterogeneity of 5-HT receptors (5-HTXR) and the conflicting results of behavioral experiments which employ non-specific 5-HTXR ligands contribute to the complexity of interpreting the involvement of 5-HT systems in addictive-related memory processes. This review briefly traces the history of 5-HT involvement in retrieval of drug-cue associations and future targets of serotonergic manipulation that may reduce the impact that drug cues have on addictive behavior and relapse.
Serotonin receptors; cocaine; self-administration; memory retrieval; extinction; conditioned stimuli
Cancer coping styles have been associated with several cancer-related outcomes. We examined whether baseline lifestyle behaviors differed between cancer survivors with fatalistic vs fighting-spirit coping styles, and whether there was differential response to two diet-exercise mailed-print interventions, one standardized and another individually tailored.
Baseline differences by coping style are presented for 628 breast and prostate cancer survivors who participated in the FRESH START trial, along with multivariable analyses on rates of uptake by coping style and arm assignment for those completing the 2-year trial.
At baseline, several differences were observed between fighting-spirits and fatalists, with the former significantly more likely to be white, younger, leaner, more-educated and at risk for depression, and less likely to consume 5+ fruits and vegetables (F&V)/day (p-values<0.05). Improvements in physical activity were observed, with fighting-spirits exhibiting the greatest gains from baseline to Year-1, regardless of intervention type; but by Year-2, these differences diminished as fatalists gained ground. Moreover, fatalists who received standardized intervention material also charted steady improvements in F&V intake over the study period; by Year-2, 58.1% of fatalists achieved the 5-a-day goal vs 44.6% of fighting-spirits (p-value<0.05).
Lifestyle behaviors and health message uptake differs by cancer coping style. Although tailored interventions appear most effective and minimize differential uptake, standardized interventions also can improve behaviors, though fighting-spirits may require additional boosters to maintain change.
coping; personality traits; diet; exercise; interventions; cancer survivors
Following the report of the presence of nitrosamine-like substances in samples of homemade spirit from Zambia, which had been obtained from an area where cancer of the oesophagus is common, samples of distilled alcoholic drinks were collected throughout western Kenya and southern Uganda from areas where the frequency of cancer of the oesophagus varies from very common to very rare. The 44 samples of spirit were screened by polarography and substances giving a similar response to nitrosamines were indicated at levels as high as 21 ppm. Subsequent analysis by gas chromatography for selected individual nitrosamines showed no evidence for the occurrence of methylethylnitrosamine (MEN), diethylnitrosamine (DEN), dipropylnitrosamine (DPN), ethylbutylnitrosamine (EBN), dibutylnitrosamine (DBN), nor of N nitrosopiperidine (N Pipn), but traces of compounds having a similar retention time as dimethylnitrosamine (DMN) were observed. However, subsequent examination by mass spectrometry showed no evidence of dimethylnitrosamine. There was no apparent association between the levels of unknown constituents indicated by polarography and gas chromatography, nor between either of these levels and the frequency of cancer of the oesophagus. The results by gas chromatography and mass spectrometry confirm that polarography is too unspecific to be a useful indicator of nitrosamines.
Drug use and relapse involve learned associations between drug-associated environmental cues and drug effects. Extinction procedures in the clinic can suppress conditioned responses to drug cues, but the extinguished responses typically reemerge after exposure to the drug itself (reinstatement), the drug-associated environment (renewal), or the passage of time (spontaneous recovery). We describe a memory retrieval-extinction procedure that decreases conditioned drug effects and drug seeking in rat models of relapse, and drug craving in abstinent heroin addicts. In rats, daily retrieval of drug-associated memories 10 minutes or 1 hour but not 6 hours before extinction sessions attenuated drug-induced reinstatement, spontaneous recovery, and renewal of conditioned drug effects and drug seeking. In heroin addicts, retrieval of drug-associated memories 10 minutes before extinction sessions attenuated cue-induced heroin craving 1, 30, and 180 days later. The memory retrieval-extinction procedure is a promising nonpharmacological method for decreasing drug craving and relapse during abstinence.
Understanding the neurobiological underpinnings of putative memory stabilization processes that maintain context-response-cocaine associations in long-term memory and underlie contextual control over addictive behavior is of great interest from an addiction treatment perspective. Using an instrumental animal model of contextual drug relapse, we show that the protein synthesis inhibitor, anisomycin, administered into the basolateral amygdala (BLA) immediately after limited (15- or 60-min) re-exposure to a previously cocaine-paired context subsequently disrupted the ability of the previously cocaine-paired context to reinstate extinguished cocaine-seeking behavior relative to vehicle. Consistent with a BLA-mediated memory reconsolidation deficit, similar impairment in cocaine-seeking behavior was not observed in “no-reactivation” control groups that received anisomycin into the BLA after (re)exposure to either a novel unpaired or an extinction-paired context nor in a neuroanatomical control group that received anisomycin into the posterior caudate-putamen, dorsally adjacent to the BLA, after re-exposure to the cocaine-paired context. Furthermore, anisomycin administered into the BLA after brief (5-min) or extensive (120-min) re-exposure to the cocaine-paired context (which was sufficient to extinguish cocaine-seeking behavior in a vehicle control group) also failed to alter responding. Together, these findings suggest that re-exposure to a cocaine-paired context in the absence of cocaine reinforcement is sufficient to trigger memory reconsolidation processes that support future drug-seeking behavior. The presence and duration of drug-related memory reactivation critically influences and anisomycin-sensitive mechanisms in the BLA selectively control this phenomenon. These findings support the feasibility of novel pharmacotherapeutic approaches that selectively inhibit the reconsolidation of cocaine-related memories in order to prevent drug relapse.
cocaine; context; reinstatement; anisomycin; rat
Preliminary studies on the effects of antabus (tetraethylthiuram disulfide) in the therapy of alcoholic patients indicate that it is very valuable in providing a “chemical foundation” for sobriety, even in those with a severe, long term drinking problem. In the first 30 patients treated, a favorable degree of control of the alcoholism has been effected in approximately 80 per cent. When taken regularly the drug maintains in the patient a very high degree of sensitivity to alcohol, quickly producing a number of very distressing bodily reactions whenever even very small amounts of spirits are ingested. Because of its potential dangers, antabus should be used only after thorough clinical and laboratory studies in properly staffed institutions. It is contraindicated in individuals with existing major psychosis or drug addiction and must be used only with caution in patients with diabetes mellitus, cardiovascular disease, goiter, pregnancy, epilepsy, asthma, and hepatic disease. Antabus therapy should be considered only one aspect of the total treatment program for the alcoholic patient.
Book review of "The Globalisation Of Addiction: A Study In Poverty Of The Spirit" by Bruce K. Alexander
Drug abuse and addiction are major problems in the United States. In particular methamphetamine (METH) use has increased dramatically. A greater understanding of how METH acts on the brain to induce addiction may lead to better therapeutic targets for this problem. The hippocampus is recognized as an important structure in learning and memory, but is not typically associated with drug reinforcement or reward processes. Here, the focus is on the hippocampus which has been largely ignored in the addiction literature as compared to the nucleus accumbens (NAc), ventral tegmental area (VTA), and prefrontal cortex (PFC). The results show that METH administered unilaterally via a microdialysis probe to rats’ right dorsal hippocampus will induce drug-seeking (place preference) and drug-taking (lever-pressing) behavior. Furthermore, both of these responses are dependent on local dopamine (DA) receptor activation, as they are impaired by a selective D1/D5 receptor antagonist. The results suggest that the hippocampus is part of the brain's reward circuit that underlies addiction.
reward; hippocampus; methamphetamine
No medications have been proven to be effective for cocaine and methamphetamine addiction. Attenuation of drug reward has been the main strategy for medications development, but this approach has not led to effective treatments. Thus, there is a need to identify novel treatment targets in addition to the brain reward system.
To propose a novel treatment strategy for stimulant addiction that will focus on medications enhancing cognitive function and attenuating drug reward.
Preclinical and clinical literature on potential use of cognitive enhancers for stimulant addiction pharmacotherapy was reviewed.
Results and conclusions
Cocaine and methamphetamine users show significant cognitive impairments, especially in attention, working memory and response inhibition functions. The cognitive impairments seem to be predictive of poor treatment retention and outcome. Medications targeting acetylcholine (Ach) and norepinephrine (NE) are particularly well-suited for enhancing cognitive function in stimulant users. Many cholinergic and noradrenergic medications are on the market, have a good safety profile, and low abuse potential. These include galantamine, donepezil, and rivastigmine (cholinesterase inhibitors), varenicline (partial nicotine agonist), guanfacine (alpha2-adrenergic agonist), and atomoxetine (norepinephrine transporter inhibitor). Future clinical studies optimally designed to measure cognitive function as well as drug use behavior would be needed to test the efficacy of these cognitive enhancers for stimulant addiction.
Cognition; stimulants; cognitive enhancers; pharmacotherapy
Addiction is a person-level phenomenon that involves twin normative failures. A failure of normal rational effective agency or self-control with respect to the substance; and shame at both this failure, and the failure to live up to the standards for a good life that the addict himself acknowledges and aspires to. Feeling shame for addiction is not a mistake. It is part of the shape of addiction, part of the normal phenomenology of addiction, and often a source of motivation for the addict to heal. Like other recent attempts in the addiction literature to return normative concepts such as “choice” and “responsibility” to their rightful place in understanding and treating addiction, the twin normative failure model is fully compatible with investigation of genetic and neuroscientific causes of addiction. Furthermore, the model does not re-moralize addiction. There can be shame without blame.
addiction; alcoholism; substance-related disorders; shame; blame; guilt; willing addicts; resigned addicts
Addictive drugs induce a dopamine signal that contributes to the initiation of addiction, and the dopamine signal influences drug-associated memories that perpetuate drug use. The addiction process shares many commonalities with the synaptic plasticity mechanisms normally attributed to learning and memory. Environmental stimuli repeatedly linked to addictive drugs become learned associations, and those stimuli come to elicit memories or sensations that motivate continued drug use. Applying in vivo recording techniques to freely moving mice, we show that physiologically relevant concentrations of the addictive drug, nicotine, directly cause in vivo hippocampal synaptic potentiation of the kind that underlies learning and memory. The drug-induced long-term synaptic plasticity required a local hippocampal dopamine signal. Disrupting general dopamine signaling prevented the nicotine-induced synaptic plasticity and conditioned place preference. These results suggest that dopaminergic signaling serves as a functional label of salient events by enabling and scaling synaptic plasticity that underlies drug-induced associative memory.
mesolimbic; addiction; dopaminergic; hippocampus; dentate gyrus; LTP
Persistent, unwanted memories are believed to be key contributors to drug addiction and the chronic relapse problem over the lifetime of the addict. Contrary to the long-held idea that memories are static and fixed, new studies in the last decade have shown that memories are dynamic and changeable. However, they are changeable only under specific conditions. When a memory is retrieved (reactivated), it becomes labile for a period of minutes to hours and then is reconsolidated to maintain long-term memory. Recent findings indicate that even well-established long-term memories may be susceptible to disruption by interfering with reconsolidation through delivery of certain amnestic agents during memory retrieval. Here I review the growing literature on memory reconsolidation in animal models of addiction, including sensitization, conditioned place preference and self-administration. I also discuss (a) several issues that need to be considered in interpreting the findings from reconsolidation studies and (b) future challenges and directions for memory reconsolidation studies in the field of addiction. The findings indicate promise for using this approach as a therapy for disrupting the long-lasting memories that can trigger relapse.
Addiction; Alcohol; Amnesia; Cocaine; Conditioned place preference; Drug abuse; Memory; Morphine; Reconsolidation; Self-administration
The majority of adult people in western societies regularly consume psychoactive drugs. While this consumption is integrated in everyday life activities and controlled in most consumers, it may escalate and result in drug addiction. Non-addicted drug use requires the systematic establishment of highly organized behaviors, such as drug-seeking and -taking. While a significant role for classical and instrumental learning processes is well established in drug use and abuse, declarative drug memories have largely been neglected in research. Episodic memories are an important part of the declarative memories. Here a role of episodic drug memories in the establishment of non-addicted drug use and its transition to addiction is suggested. In relation to psychoactive drug consumption, episodic drug memories are formed when a person prepares for consumption, when the drug is consumed and, most important, when acute effects, withdrawal, craving, and relapse are experienced. Episodic drug memories are one-trial memories with emotional components that can be much stronger than “normal” episodic memories. Their establishment coincides with drug-induced neuronal activation and plasticity. These memories may be highly extinction resistant and influence psychoactive drug consumption, in particular during initial establishment and at the transition to “drug instrumentalization.” In that, understanding how addictive drugs interact with episodic memory circuits in the brain may provide crucial information for how drug use and addiction are established.
episodic drug memory; experimental consumption; drug instrumentalization; addiction
High quality protocols facilitate proper conduct, reporting, and external review of clinical trials. However, the completeness of trial protocols is often inadequate. To help improve the content and quality of protocols, an international group of stakeholders developed the SPIRIT 2013 Statement (Standard Protocol Items: Recommendations for Interventional Trials). The SPIRIT Statement provides guidance in the form of a checklist of recommended items to include in a clinical trial protocol.
This SPIRIT 2013 Explanation and Elaboration paper provides important information to promote full understanding of the checklist recommendations. For each checklist item, we provide a rationale and detailed description; a model example from an actual protocol; and relevant references supporting its importance. We strongly recommend that this explanatory paper be used in conjunction with the SPIRIT Statement. A website of resources is also available (www.spirit-statement.org).
The SPIRIT 2013 Explanation and Elaboration paper, together with the Statement, should help with the drafting of trial protocols. Complete documentation of key trial elements can facilitate transparency and protocol review for the benefit of all stakeholders.
It has become increasingly clear that molecular and neural mechanisms underlying learning and memory and drug addiction are largely shared. To confirm and extend these findings, we analyzed ethanol-responsive behaviors of a collection of Drosophila long-term memory mutants.
For each mutant, sensitivity to the acute uncoordinating effects of ethanol was quantified using the inebriometer. Additionally, 2 distinct forms of ethanol tolerance were measured: rapid tolerance, which develops in response to a single brief exposure to a high concentration of ethanol vapor; and chronic tolerance, which develops following a sustained low-level exposure.
Several mutants were identified with altered sensitivity, rapid or chronic tolerance, while a number of mutants exhibited multiple defects.
The corresponding genes in these mutants represent areas of potential overlap between learning and memory and behavioral responses to alcohol. These genes also define components shared between different ethanol behavioral responses.
Alcohol; Sensitivity; Tolerance; Drosophila; Learning/Memory
Despite intense scrutiny over the past 20 years, the reasons for the high addictive liability of nicotine and extreme rates of relapse in smokers have remained elusive. One factor that contributes to the development and maintenance of nicotine addiction is the ability of nicotine to produce long-lasting modifications of behavior, yet little is known about the mechanisms by which nicotine alters the underlying synaptic plasticity responsible for changes in behavior. The present study is the first to explore how nicotine interacts with learning to alter gene transcription, a process necessary for long-term memory consolidation. Transcriptional upregulation of hippocampal jun-N terminal kinase 1 (JNK1) mRNA was found in mice that learned contextual fear conditioning in the presence of nicotine whereas neither learning alone nor nicotine administration alone had an effect. Furthermore, the upregulation of JNK1 was absent in β2 nicotinic receptor subunit knockout mice, which are mice that do not show enhanced learning by nicotine. Finally, hippocampal JNK activation was increased in mice that were administered nicotine prior to conditioning and inhibition of JNK during consolidation prevented the nicotine-induced enhancement of contextual fear conditioning. These data suggest that nicotine and learning interact to alter hippocampal JNK1 gene expression and related signaling processes, thus resulting in strengthened contextual memories.
Hippocampus; acetylcholine; MAPK; addiction; learning; gene transcription
Acetylcholine (ACh), the first neurotransmitter discovered, participates in many CNS functions including sensory and motor processing, sleep, nociception, mood, stress response, attention, arousal, memory, motivation and reward. These diverse cholinergic effects are mediated by nicotinic (nAChR) and muscarinic (mAChR) type cholinergic receptors. The goal of this review is to synthesize a growing literature that supports the potential role of ACh as a treatment target for stimulant addiction. ACh interacts with the dopaminergic reward system in the ventral tegmental area (VTA), nucleus accumbens (NAc) and prefrontal cortex (PFC). In the VTA, both nAChR and mAChR stimulate the dopaminergic system. In the NAc, cholinergic interneurons integrate cortical and subcortical information related to reward. In the PFC, the cholinergic system contributes to the cognitive aspects of addiction. Preclinical studies support a facilitative role of nicotinic agonists in the development of stimulant addiction. Muscarinic agonists seem to have an inhibitory role depending on the subtype of mAChR. In human studies acetylcholine esterase (AChE) inhibitors, which increase synaptic ACh levels, have shown promise for the treatment of stimulant addiction. Further studies testing the efficacy of cholinergic medications for stimulant addiction are warranted.
acetylcholine; dopamine; nicotinic; muscarinic; stimulant addiction; brain reward system
Despite intense scrutiny over the past 20 years, the reasons for the high addictive liability of nicotine and extreme rates of relapse in smokers have remained elusive. One factor that contributes to the development and maintenance of nicotine addiction is the ability of nicotine to produce long-lasting modifications of behavior, yet little is known about the mechanisms by which nicotine alters the underlying synaptic plasticity responsible for behavioral changes. This study is the first to explore how nicotine interacts with learning to alter gene transcription, which is a process necessary for long-term memory consolidation. Transcriptional upregulation of hippocampal jun-N terminal kinase 1 (JNK1) mRNA was found in mice that learned contextual fear conditioning (FC) in the presence of nicotine, whereas neither learning alone nor nicotine administration alone exerted an effect. Furthermore, the upregulation of JNK1 was absent in β2 nicotinic receptor subunit knockout mice, which are mice that do not show enhanced learning by nicotine. Finally, hippocampal JNK activation was increased in mice that were administered nicotine before conditioning, and the inhibition of JNK during consolidation prevented the nicotine-induced enhancement of contextual FC. These data suggest that nicotine and learning interact to alter hippocampal JNK1 gene expression and related signaling processes, thus resulting in strengthened contextual memories.
hippocampus; acetylcholine; MAPK; addiction; learning; gene transcription
The persistence of the motivational salience of drug-related environmental cues and contexts is one of the most problematic obstacles to successful treatment of drug addiction. Behavioral approaches to extinguishing the salience of drug-associated cues, such as cue exposure therapy, have generally produced disappointing results which have been attributed to, among other things, the context specificity of extinction and inadequate consolidation of extinction learning. Extinction of any behavior or conditioned response is a process of new and active learning, and increasing evidence suggests that glutamatergic neurotransmission, a key component of the neural plasticity that underlies normal learning and memory, is also involved in extinction learning. This review will summarize findings from both animal and human studies that suggest that pharmacological enhancement of glutamatergic neurotransmission facilitates extinction learning in the context of drug addiction. Pharmacological agents that have shown potential efficacy include NMDA partial agonists, mGluR5 receptor positive allosteric modulators, inhibitors of the GlyT1 glycine transporter, AMPA receptor potentiators, and activators of the cystine-glutamate exchanger. These classes of cognition-enhancing compounds could potentially serve as novel pharmacological adjuncts to cue exposure therapy to increase success rates in attenuating cue-induced drug craving and relapse.
Extinction; learning; glutamate; NMDA; AMPA; mGluR5; GlyT1 glycine transporter; receptor potentiator; allosteric modulator; cystine-glutamate exchanger.
The Mediterranean tradition offers a cousine rich in colors, aromas and memories, which support the taste and the spirit of those who live in harmony with nature. Everyone is talking about the Mediterranean diet, but few are those who do it properly, thus generating a lot of confusion in the reader. And so for some it coincides with the pizza, others identified it with the noodles with meat sauce, in a mixture of pseudo historical traditions and folklore that do not help to solve the question that is at the basis of any diet: combine and balance the food so as to satisfy the qualitative and quantitative needs of an individual and in a sense, preserves his health through the use of substances that help the body to perform normal vital functions. The purpose of our work is to demonstrate that the combination of taste and health is a goal that can be absolutely carried out by everybody, despite those who believe that only a generous caloric intake can guarantee the goodness of a dish and the satisfaction of the consumers. That should not be an absolute novelty, since the sound traditions of the Mediterranean cuisine we have used for some time in a wide variety of tasty gastronomic choices, from inviting colors and strong scents and absolutely in line with health.
Mediterranean diet; Food pyramid; Obesity; Cardiovascular disease