There is a high degree of overlap between brain regions involved in processing natural rewards and drugs of abuse. “Non-drug” or “behavioral” addictions have become increasingly documented in the clinic, and pathologies include compulsive activities such as shopping, eating, exercising, sexual behavior, and gambling. Like drug addiction, non-drug addictions manifest in symptoms including craving, impaired control over the behavior, tolerance, withdrawal, and high rates of relapse. These alterations in behavior suggest that plasticity may be occurring in brain regions associated with drug addiction. In this review, I summarize data demonstrating that exposure to non-drug rewards can alter neural plasticity in regions of the brain that are affected by drugs of abuse. Research suggests that there are several similarities between neuroplasticity induced by natural and drug rewards and that, depending on the reward, repeated exposure to natural rewards might induce neuroplasticity that either promotes or counteracts addictive behavior.
novelty seeking; addiction; motivation; reinforcement; behavioral addiction; plasticity
Addiction and stress are linked at multiple levels. Drug abuse is often initiated as a maladaptive mechanism for coping with stress. It is maintained in part by negative reinforcement to prevent the aversive consequences of stress associated with abstinence. Finally, stress is a major factor leading to relapse in subjects in which drug seeking behavior has extinguished. These associations imply overlapping or converging neural circuits and substrates that underlie the processes of addiction and the expression of the stress response. Here we discuss the major brain serotonin (5-HT) system, the dorsal raphe nucleus (DRN)-5-HT system as a point of convergence that links these processes and how the stress-related neuropeptide, corticotropin-releasing factor (CRF) directs this by a bimodal regulation of DRN neuronal activity. The review begins by describing a structural basis for CRF regulation of the DRN-5-HT system. This is followed by a review of the effects of CRF and stress on DRN function based on electrophysiological and microdialysis studies. The concept that multiple CRF receptor subtypes in the DRN facilitate distinct coping behaviors is reviewed with recent evidence for a unique cellular mechanism by which stress history can determine the type of coping behavior. Finally, work on CRF regulation of the DRN-5-HT system is integrated with literature on the role of 5-HT-dopamine interactions in addiction.
serotonin; dorsal raphe nucleus; corticotropin-releasing factor; stress; receptor trafficking; drug abuse
Methamphetamine (MA) abuse is associated with neurotoxicity to frontostriatal brain regions with concomitant deleterious effects on cognitive processes. Deficits in behavioral control are thought to be one contributing factor to the sustainment of addictive behaviors in chronic MA abuse.
In order to examine patterns of behavioral control relevant to addiction, we employed a fast-event related fMRI design to examine trial to trial reaction time (RT) adjustments in 12 chronic MA abusers who met DSM-IV criteria for MA dependence and 16 non-substance abusing controls. A variant of the Stroop task was employed to contrast the groups on error rates, RT Stroop conflict effect and the level of trial-to-trial adjustments seen after incongruent trials.
The MA abusers exhibited reduced RT adjustments along with reduced activation in the right prefrontal cortex compared to controls on conditions that measured the ability to use exposure to conflict situations (i.e., conflict trials) to regulate behavior. MA abusers did not differ from controls on accuracy rates or within-trial Stroop conflict effects.
The observed deficits in trial to trial RT adjustments suggest that the ability to adapt a behavioral response based on prior experience may be compromised in MA abusers. Such adjustments are critical to everyday functioning and deficits in modifying behavior based on prior events may reflect a key deficit that contributes to maladaptive drug seeking behavior.
Methamphetamine; prefrontal; attention; fMRI; imaging
The anterior cingulate cortex (ACC) and lateral prefrontal (LPFC) cortex are brain regions important to executive cognitive functions (ECF). We determined ACC and LPFC function in 23-day abstinent cocaine abusers using positron emission tomography (PET H215O) during performance of a modified version of the Stroop Task. Cocaine abusers showed less activation than non-drug-using comparison subjects in the left ACC and the right LPFC and greater activation in the right ACC. Average amount of cocaine used per week was negatively correlated with activity in the rostral ACC and right LPFC. Disruption of ECF in substance abusers could interfere with attempts to stop drug use and undermine treatment. Since impairment in ECF may be a common feature of various neuropsychiatric disorders, these findings have applicability beyond the neurobiology of addiction.
The chronic effects of cocaine abuse on brain structure and function are blamed for the inability of most addicts to remain abstinent. Part of the difficulty in preventing relapse is the persisting memory of the intense euphoria or cocaine “rush”. Most abused drugs and alcohol induce neuroplastic changes in brain pathways subserving emotion and cognition. Such changes may account for the consolidation and structural reconfiguration of synaptic connections with exposure to cocaine. Adaptive hippocampal plasticity could be related to specific patterns of gene expression with chronic cocaine abuse. Here, we compare gene expression profiles in the human hippocampus from cocaine addicts and age-matched drug-free control subjects. Cocaine abusers had 151 gene transcripts upregulated, while 91 gene transcripts were downregulated. Topping the list of cocaine-regulated transcripts was RECK in the human hippocampus (FC = 2.0; p<0.05). RECK is a membrane-anchored MMP inhibitor that is implicated in the coordinated regulation of extracellular matrix integrity and angiogenesis. In keeping with elevated RECK expression, active MMP9 protein levels were decreased in the hippocampus from cocaine abusers. Pathway analysis identified other genes regulated by cocaine that code for proteins involved in the remodeling of the cytomatrix and synaptic connections and the inhibition of blood vessel proliferation (PCDH8, LAMB1, ITGB6, CTGF and EphB4). The observed microarray phenotype in the human hippocampus identified RECK and other region-specific genes that may promote long-lasting structural changes with repeated cocaine abuse. Extracellular matrix remodeling in the hippocampus may be a persisting effect of chronic abuse that contributes to the compulsive and relapsing nature of cocaine addiction.
Disinhibition and addictive behaviors are related and carry moral implications. Both typically involve diminished consideration of negative consequences, which may result in harm to oneself or others. Disinhibition may occur on state and trait levels, and addictive substances may elicit disinhibitory states, particularly when intoxication is reached. Data suggest that trait disinhibition and addictions may be conceptualized as involving misdirected motivation with underlying biological bases including genetic factors, alterations in neurotransmitter systems and differences in regional brain function. The influences of intoxication on the brain share similarities with cognitive impairments in individuals with chronic substance abuse and those with trait disinhibition related to frontal lobe injuries. These findings raise questions about volitional impairment and morality. Although impaired volition related to disinhibition and addictive behaviors has been studied from multiple perspectives, additional research is needed to further characterize mechanisms of impairment. Such findings may have important implications in multiple legal and psychiatric domains.
addiction; alcohol; disinhibition; impulsivity; intoxication; morality
To examine whether overlapping cognitive deficits exist in currently drug-abstinent chronic methamphetamine (MA) abusers and schizophrenia (SZ) patients.
Both SZ and chronic MA abuse are associated with frontostriatal disruption as well as deficits in cognitive control such as selective attention. To identify overlapping cognitive profiles, we compared performance of the two groups on the Stroop attention task.
Data were analyzed from 69 MA abusers who had been MA-abstinent for differing periods of time and from 23 SZ patients and 38 non-substance-abusing controls.
The MA abusers in early abstinence displayed more Stroop interference than the SZ patients (p= 0.004), long-term abstinent MA abusers (p= 0.009), and controls (p = 0.002). In the MA abusers, the magnitude of Stroop interference correlated positively with longer drug use [p = 0.01] and negatively with longer drug abstinence [p= 0.04]. No correlations were found between psychotic symptoms and task performance.
On this task of attentional selection, only the MA abusers in early stages of abstinence showed performance deficits compared to controls. More research is needed to further elucidate overlapping patterns between MA abuse and SZ.
schizophrenia; methamphetamine; selective attention; Stroop; cognition
Addiction is a complex disorder because many factors contribute to the development and maintenance of addiction. One factor is learning. For example, drug–context associations that develop during drug use could facilitate drug craving upon re-exposure to contexts previously associated with drugs. Additionally, deficits in cognitive processes associated with withdrawal could precipitate relapse in attempts to ameliorate those deficits. Because addiction and learning involve common neural areas and cell signaling cascades, addiction-related changes in processes underlying plasticity may contribute to addiction. This article examines similarities between addiction and learning at the behavioral, neural, and cellular levels, with emphasis on the neural substrates underlying the effects of acute nicotine, chronic nicotine, and withdrawal from chronic nicotine on hippocampus-dependent contextual learning.
Learning; addiction; acetylcholine; nicotine; hippocampus; contextual fear conditioning; CREB; MAPK; withdrawal; plasticity
Studies of the neurobiological processes underlying drug addiction primarily have focused on limbic subcortical structures. Here the authors evaluated the role of frontal cortical structures in drug addiction.
An integrated model of drug addiction that encompasses intoxication, bingeing, withdrawal, and craving is proposed. This model and findings from neuroimaging studies on the behavioral, cognitive, and emotional processes that are at the core of drug addiction were used to analyze the involvement of frontal structures in drug addiction.
The orbitofrontal cortex and the anterior cingulate gyrus, which are regions neuroanatomically connected with limbic structures, are the frontal cortical areas most frequently implicated in drug addiction. They are activated in addicted subjects during intoxication, craving, and bingeing, and they are deactivated during withdrawal. These regions are also involved in higher-order cognitive and motivational functions, such as the ability to track, update, and modulate the salience of a reinforcer as a function of context and expectation and the ability to control and inhibit prepotent responses.
These results imply that addiction connotes cortically regulated cognitive and emotional processes, which result in the overvaluing of drug reinforcers, the undervaluing of alternative reinforcers, and deficits in inhibitory control for drug responses. These changes in addiction, which the authors call I-RISA (impaired response inhibition and salience attribution), expand the traditional concepts of drug dependence that emphasize limbic-regulated responses to pleasure and reward.
Glutamate plays a pivotal role in regulating drug self-administration and drug-seeking behavior, and the past decade has witnessed a substantial surge of interest in the role of Group I metabotropic glutamate receptors (mGlu1 and mGlu5 receptors) in mediating these behaviors. As will be reviewed here, Group I mGlu receptors are involved in normal and drug-induced synaptic plasticity, drug reward, reinforcement and relapse-like behaviors, and addiction-related cognitive processes such as maladaptive learning and memory, behavioral inflexibility, and extinction learning. Animal models of addiction have revealed that antagonists of Group I mGlu receptors, particularly the mGlu5 receptor, reduce self-administration of virtually all drugs of abuse. Since inhibitors of mGlu5 receptor function have now entered clinical trials for other medical conditions and appear to be well-tolerated, a key question that remains unanswered is - what changes in cognition are produced by these compounds that result in reduced drug intake and drug-seeking behavior? Finally, in contrast to mGlu5 receptor antagonists, recent studies have indicated that positive allosteric modulation of mGlu5 receptors actually enhances synaptic plasticity and improves various aspects of cognition, including spatial learning, behavioral flexibility, and extinction of drug-seeking behavior. Thus, while inhibition of Group I mGlu receptor function may reduce drug reward, reinforcement, and relapse-related behaviors, positive allosteric modulation of the mGlu5 receptor subtype may actually enhance cognition and potentially reverse some of the cognitive deficits associated with chronic drug use.
drug addiction; rodent models; glutamate; metabotropic glutamate receptor; allosteric modulators; learning; memory; cognition; extinction
Early maladaptive schemas, defined as cognitive and behavioural patterns of viewing oneself and the world that cause considerable distress, are increasingly being recognized as an important underlying correlate of mental health problems. Recent research has begun to examine early maladaptive schemas among individuals seeking treatment for substance abuse. Unfortunately, there is limited research on whether substance abusers score higher on early maladaptive schemas than non-clinical controls. Thus, the current study examined whether a sample of young adult female substance abuse treatment seekers (n = 180) scored higher than a non-clinical group of female college students (n = 284) on early maladaptive schemas. Results demonstrated that the substance abuse group scored higher than the non-clinical group on 16 of the 18 early maladaptive schemas. In addition, a number of differences in early maladaptive schemas were large in effect size. Implications of these findings for future research and substance abuse treatment programmes are discussed.
Early Maladaptive Schemas; Substance Use; Female; Clinical
Investigations of the neural consequences of the effects of cocaine on cognition have centered on specific brain circuits including prefrontal cortex, medial temporal lobe and striatum and their roles in controlling drug dependent behavior and addiction. These regions are critical to many aspects of drug abuse; however recent investigations in addicted individuals have reported possible cognitive deficits that impact recovery and other therapeutic interventions.
Therefore a direct assessment of the effects of cocaine as a reward for cognitive function provides a means of determining how brain systems involved such as prefrontal cortex are affected under normal vs. conditions of acute drug exposure as a precursor to the final impaired function in the addicted state.
Nonhuman primates (NHPs) were tested in a delayed-match-to-sample decision making task to determine effects of high vs. low cognitive load trials on single neuron activity and fluorodeoxyglucose-positron emission tomography (FDG-PET) determined metabolic activation of prefrontal cortex when juice vs. intravenous cocaine were employed as rewards for successful performance.
Cognitive processing in prefrontal cortex was altered primarily on high load trials in which cocaine was randomly presented as the signaled and delivered reward on particular trials. The detrimental actions of cocaine rewards were also shown to persist and impair task performance on subsequent juice rewarded trials.
The findings indicate that one of the ways in which cocaine use may disrupt performance of a cognitive task is to alter neural processing in prefrontal cortex when involved in discriminating circumstances on the basis of low vs. high cognitive demand.
Prefrontal Cortex; Neural recording; PET Imaging; Cocaine rewards; Decision processes
Compulsive drug-seeking and drug-taking are important substance-abuse behaviors that have been linked to alterations in dopaminergic neurotransmission and to impaired inhibitory control. Evidence supports the notions that abnormal D2 receptor-mediated dopamine transmission and inhibitory control may be heritable risk factors for addictions, and that they also reflect drug-induced neuroadaptations. To provide a mechanistic explanation for the drug-induced emergence of inhibitory-control deficits, this study examined how a chronic, escalating-dose regimen of methamphetamine administration affected dopaminergic neurochemistry and cognition in monkeys. Dopamine D2-like receptor and dopamine transporter (DAT) availability and reversal-learning performance were measured before and after exposure to methamphetamine (or saline), and brain dopamine levels were assayed at the conclusion of the study. Exposure to methamphetamine reduced dopamine D2-like receptor and DAT availability, and produced transient, selective impairments in the reversal of a stimulus-outcome association. Furthermore, individual differences in the change in D2-like receptor availability in the striatum were related to the change in response to positive feedback. These data provide evidence that chronic, escalating-dose methamphetamine administration alters the dopamine system in a manner similar to that observed in methamphetamine-dependent humans. They also implicate alterations in positive-feedback sensitivity associated with D2-like receptor dysfunction as the mechanism by which inhibitory control deficits emerge in stimulant-dependent individuals. Finally, a significant degree of neurochemical and behavioral variation in response to methamphetamine was detected, indicating that individual differences affect the degree to which drugs of abuse alter these processes. Identification of these factors ultimately may assist in the development of individualized treatments for substance dependence.
Addiction; methamphetamine; dopamine; D2-like receptor; inhibitory control; feedback sensitivity
Individual differences may impact susceptibility to addiction. The impact of personality features on drug craving, however, has not been studied, particularly in women.
Ninety-five treatment-seeking women with substance dependence, abstinent for at least 5 and no more than 21 days, were investigated regarding the correlation between personality factors and craving. Personality was assessed using the Temperament and Character Inventory (TCI), the NEO Personality Inventory Revised (NEO-PI-R), and the Barratt Impulsiveness Scale version 11 (BIS-11). Cravings were assessed through the Pennsylvania Craving Scale (PCS), and the Craving Questionnaire (CQ). Anxiety and depressive symptomatology were also recorded.
Craving scores were positively correlated with depression and negatively correlated with number of days abstinent from substance use. Also, craving scores were positively associated with the novelty-seeking factor from the TCI and the total score on the BIS-11, and negatively associated with the conscientiousness and agreeableness facets of the NEO-PI-R.
Findings suggest that personality features, particularly impulsiveness, can be important predictors of craving in women, which has important implications for treatment planning.
Substance dependence is complex and multifactorial, with many distinct pathways involved in both the development and subsequent maintenance of addictive behaviors. Various cognitive mechanisms have been implicated, including impulsivity, compulsivity, and impaired decision-making. These mechanisms are modulated by emotional processes, resulting in increased likelihood of initial drug use, sustained substance dependence, and increased relapse during periods of abstinence. Emotional traits, such as sensation-seeking, are risk factors for substance use, and chronic drug use can result in further emotional dysregulation via effects on reward, motivation, and stress systems. We will explore theories of hyper and hypo sensitivity of the brain reward systems that may underpin motivational abnormalities and anhedonia. Disturbances in these systems contribute to the biasing of emotional processing toward cues related to drug use at the expense of natural rewards, which serves to maintain addictive behavior, via enhanced drug craving. We will additionally focus on the sensitization of the brain stress systems that result in negative affect states that continue into protracted abstinence that is may lead to compulsive drug-taking. We will explore how these emotional dysregulations impact upon decision-making controlled by goal-directed and habitual action selections systems, and, in combination with a failure of prefrontal inhibitory control, mediate maladaptive decision-making observed in substance dependent individuals such that they continue drug use in spite of negative consequences. An understanding of the emotional impacts on cognition in substance dependent individuals may guide the development of more effective therapeutic interventions.
addiction; emotion; cognition; reward; stress; decision-making
It was suggested in 1986 that cue-induced drug craving in cocaine addicts progressively increases over the first several weeks of abstinence and remains high for extended periods. During the last decade, investigators have identified an analogous incubation phenomenon in rodents, in which time-dependent increases in cue-induced drug seeking are observed after withdrawal from intravenous cocaine self-administration. Such an incubation of drug craving is not specific to cocaine, as similar findings have been observed after self-administration of heroin, nicotine, methamphetamine, and alcohol in rats. In this review, we discuss recent results that have identified important brain regions involved in the incubation of drug craving, as well as evidence for the underlying cellular mechanisms. Understanding the neurobiology of the incubation of drug craving in rodents is likely to have significant implications for furthering our understanding of brain mechanisms and circuits that underlie drug craving in human addicts.
Craving is a hallmark of addiction and characterized by obsessive thoughts about, and compulsive urges to use, a substance. While craving is frequently thought of as primarily being a feature of acute withdrawal, there is evidence to suggest that it increases in strength over extended periods of abstinence. While several measures are available to assess acute craving states, there remains a lack of clinical measures appropriate for capturing the enduring cognitive aspects of urges to use drugs. The present study was designed to develop and validate a measure of obsessive-compulsive thoughts in cocaine-dependent individuals.
The proposed 14-item Obsessive Compulsive Cocaine Use Scale (OCCUS) was administered to 107 individuals; 55 participants meeting diagnostic criteria for cocaine dependence and 52 recreational users of cocaine. In addition to the OCCUS, participants also completed the Drug Abuse Screening Test, Cocaine Craving Questionnaire-Now, and Social Desirability Scale of the California Personality Inventory.
Results of confirmatory factor analysis indicated that the OCCUS fit the two-factor structure of the Obsessive Compulsive Drinking Scale on which it was based, independently assessing the “obsessive” and “compulsive” aspects of cocaine dependence. The OCCUS demonstrated good internal consistency reliability and convergent, discriminant, and criterion validity.
The proposed measure is a promising step towards the successful capture of the long-term cognitive features of craving for cocaine via self-report, and should represent a useful tool for clinical and research use.
cocaine dependence; obsessive; compulsive; craving; substance abuse; psychometric properties
Like a number of neuropeptides, galanin can alter neural activity in brain areas that are important for both stress-related behaviors and responses to drugs of abuse. Accordingly, drugs that target galanin receptors can alter behavioral responses to drugs of abuse and can modulate stress-related behaviors. Stress and drug-related behaviors are interrelated: stress can promote drug-seeking, and the behavioral signs of drug withdrawal result from increased activity in brain circuits involved in the stress response. We review here what is known about the ability of galanin and galanin receptors to alter neuronal activity, and we discuss potential mechanisms that may underlie the effects of galanin on behaviors involved in responses to stress and addictive drugs. Understanding the mechanisms underlying galanin's effects on neuronal function in brain regions related to stress and addiction may be useful in developing novel therapeutics for the treatment of stress- and addiction-related disorders.
galanin; drug abuse; opiates; psychostimulants; addiction; stress; locus coeruleus; mesolimbic dopamine system; HPA axis; dorsal raphe; opiate withdrawal
Methamphetamine (meth) is a highly addictive and widely abused psychostimulant. Repeated use of meth can quickly lead to dependence, and may be accompanied by a variety of persistent psychiatric symptoms and cognitive impairments. The neuroadaptations underlying motivational and cognitive deficits produced by chronic meth intake remain poorly understood. Altered glutamate neurotransmission within the prefrontal cortex (PFC) and striatum has been linked to both persistent drug-seeking and cognitive dysfunction. Therefore, the current study investigated changes in presynaptic mGluR receptors within corticostriatal circuitry after extended meth self-administration. Rats self-administered meth (or received yoked-saline) in 1 hr/day sessions for 7 days (short-access) followed by 14 days of 6 hrs/day (long-access). Rats displayed a progressive escalation of daily meth intake up to 6 mg/kg per day. After cessation of meth self-administration, rats underwent daily extinction or abstinence without extinction training for 14 days before being euthanized. Synaptosomes from the medial PFC, nucleus accumbens (NAc), and the dorsal striatum (dSTR) were isolated and labeled with membrane-impermeable biotin in order to measure surface mGluR2/3 and mGluR7 receptors. Extended access to meth self-administration followed by abstinence decreased surface and total levels of mGluR2/3 receptors in the NAc and dSTR, while in the PFC, only a loss of surface mGluR2/3 and mGluR7 receptors was detected. Daily extinction trials reversed the downregulation of mGluR2/3 receptors in the NAc and dSTR and mGluR7 in the PFC, but downregulation of surface mGluR2/3 receptors in the PFC was present regardless of post-meth experience. Thus, extinction learning can selectively restore some populations of downregulated mGluRs after prolonged exposure to meth. The present findings could have implications for our understanding of the persistence (or recovery) of meth-induced motivational and cognitive deficits.
Cocaine produces its psychoactive and addictive effects primarily by acting on the brain’s limbic system, a set of interconnected regions that regulate pleasure and motivation. An initial, short-term effect—a buildup of the neurochemical dopamine—gives rise to euphoria and a desire to take the drug again. Researchers are seeking to understand how cocaine’s many longer term effects produce addiction’s persistent cravings and risk of relapse. In the author’s laboratory, work has focused on buildup of the genetic transcription factor ΔFosB. Levels of ΔFosB in the limbic system correlate with addiction-like behaviors in mice and may precipitate very long-lasting changes to nerve cell structure. Further pursuit of this and similar leads are first steps toward a complete understanding of the transition from cocaine abuse to addiction—and, ultimately, more effective treatments for those who are addicted.
Drug addiction is a chronic relapsing disease in which drug administration becomes the primary stimulus that drives behavior regardless of the adverse consequence that may ensue. As drug use becomes more compulsive, motivation for natural rewards that normally drive behavior decreases. The discontinuation of drug use is associated with somatic signs of withdrawal, dysphoria, anxiety and anhedonia. These consequences of drug use are thought to contribute to the maintenance of drug use and to the reinstatement of compulsive drug use that occurs during the early phase of abstinence. Even, however, after prolonged periods of abstinence, 80-90% of human addicts relapse to addiction suggesting that repeated drug use produces enduring changes in brain circuits that subserve incentive motivation and stimulus-response (habit) learning. A major goal of addiction research is the identification of the neural mechanisms by which drugs of abuse produce these effects. This article will review data showing that the dynorphin/κ-opioid receptor system serves an essential function in opposing alterations in behavior and brain neurochemistry that occur as a consequence of repeated drug use and that aberrant activity of this system may not only contribute to the dysregulation of behavior that characterizes addiction but to individual differences in vulnerability to the pharmacological actions of cocaine and alcohol. We will provide evidence that the repeated administration of cocaine and alcohol up-regulates the dynorphin/κ-opioid receptor system and that pharmacological treatments that target this system may prove effective in the treatment of drug addiction.
dynorphin; kappa opioid receptor; glutamate; dopamine; drug and alcohol addiction
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
It is now known that brain development continues into adolescence and early adulthood and is highly influenced by experience-dependent adaptive plasticity during this time. Behaviorally, this period is also characterized by increased novelty-seeking and risk-taking. This heightened plasticity appears to be important in shaping behaviors and cognitive processes that contribute to proper development of an adult phenotype. However, increasing evidence has linked these same experience-dependent learning mechanisms with processes that underlie drug addiction. As such, the adolescent brain appears be particularly susceptible to experience-dependent learning processes associated with consumption of alcohol and addictive drugs. At the level of the synapse, homeostatic changes during ethanol consumption are invoked to counter the destabilizing effects of ethanol on neural networks. This homeostatic response may be especially pronounced in the adolescent and young adult brain due to its heightened capacity to undergo experience-dependent changes, and appears to involve increased synaptic targeting of NMDA receptors. Interestingly, recent work from our lab also indicates that the enhanced synaptic localization of NMDA receptors promotes increases in the size of dendritic spines. This increase may represent a structural-based mechanism that supports the formation and stabilization of maladapted synaptic connections that, in a sense, “fix” the addictive behavior in the adolescent and young adult brain.
NMDA receptors; dendritic spines; experience-dependent plasticity; adolescence; ethanol
Addiction is a chronic relapsing disorder associated with compulsive drug taking and drug seeking and a loss of control in limiting intake, reflected in three stages of a recurrent cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation (“craving”). This review discusses the role of adult-born neural and glial progenitors in drug-seeking associated with the different stages of the addiction cycle. A review of the current literature suggests that the loss of newly born progenitors, particularly in hippocampal and cortical regions, may play a role in determining vulnerability to relapse in rodent models of drug addiction. The normalization of drug-impaired neurogenesis or gliogenesis may help reverse neuroplasticity during abstinence, and thus may help reduce the vulnerability to relapse and aid recovery.
Prefrontal cortex; Gliogenesis; Hippocampus; neurogenesis; addiction
Substance abuse and psychiatric disorders commonly occur together. This form of dual diagnosis is notable because it complicates assessment and makes treatment more difficult for both psychiatric and drug abuse problems. Drugs can cause psychiatric disorders and can also be used as an attempt to "cure" them by self-medication. The spread of the human immunodeficiency virus (HIV) among drug users has added a third potential clinical problem, that of the acquired immunodeficiency syndrome, to the difficulties already presented by drug abuse and psychiatric disorders. Patients with this triple diagnosis pose challenges to primary care physicians as well as addiction medicine specialists or psychiatrists. Assessment should include a drug abuse history, preferably corroborated by others, evaluation of the mental state, and examination focusing on signs of drug abuse and HIV infection. Treatment should include the management of HIV disease, abstinence from drug abuse, and access to psychiatric care. New systems of health care service, including interdisciplinary case management, may be needed to manage patients with a triple diagnosis.