National Institute on Drug Abuse's behavioral research agenda.

Basic behavioral research continues to play an integral role in the National Institute on Drug Abuse's (NIDA's) search for solutions to the complex social and public health problems posed by drug abuse and addiction. Along with NIDA's basic molecular and neuroscience research programs, behavioral research has played an important role in increasing clinician's understanding of the mechanisms and processes that underlie addiction. Much has been learned about the ways in which animals and humans respond to their environment and the role these basic behavioral processes play in drug abuse and other drug-abuse-related phenomena, such as withdrawal, craving, and relapse, but there is still much more to be known. The author discusses how NIDA will continue to build and promote its behavioral research agenda and ensure that behavioral research findings are applied in real-life settings when applicable. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Methamphetamine abuse and impairment of social functioning: A review of the underlying neurophysiological causes and behavioral implications.

The highly addictive drug methamphetamine has been associated with impairments in social cognitions as evidenced by changes in users' behaviors. Physiological changes in brain structure and functioning, particularly in the frontal lobe, have also been identified. The authors propose a biopsychosocial approach to understanding the effects of methamphetamine addiction by relating the physiological effects of the drug to the behaviors and social cognitions of its users, through the application of the theory of mind paradigm. Although onset of methamphetamine use has been linked to the desire for socialization, chronic use has been associated with an increase in depression, aggressiveness, and social isolation, behaviors that also implicate involvement of the frontal lobe. The reviewed literature provides strong circumstantial evidence that social-cognitive functioning is significantly impacted by methamphetamine use and that the social isolation, depression, and aggressiveness associated with chronic use is due to more than just the social withdrawal associated with addiction. Treatment considerations for methamphetamine must therefore consider the role of social cognition, and pharmacological responses must address the documented impact of the drug on frontal lobe functioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Drug use--chronic and relapsing or a treatable condition?

It is argued that the term "chronic relapsing disorder," which is used frequently to characterize drug use, does not capture the complexity of drug treatment evaluation findings and thereby limits an understanding and appreciation of the accomplishments of drug treatment. Specifically, it is noteworthy that a substantial minority (19%) of treated drug users have been found to maintain abstinence over a 6-year period posttreatment, and that the three major multisite treatment evaluations sponsored by NIDA have all found that overwhelming majorities of treated drug users do not revert to the levels of drug use (or criminal activity) shown pretreatment. Thus, the view of inevitable and continuing adoption of pretreatment behaviors, i.e., chronic relapse, gives undeserved comfort to those who deny the utility of drug treatment, and does so at a time when changes in the health care industry threaten the integrity of that treatment.     

Molecular and cellular basis of addiction

Drug addiction results from adaptations in specific brain neurons caused by repeated exposure to a drug of abuse. These adaptations combine to produce the complex behaviors that define an addicted state. Progress is being made in identifying such time-dependent, drug-induced adaptations and relating them to specific behavioral features of addiction. Current research needs to understand the types of adaptations that underlie the particularly long-lived aspects of addiction, such as drug craving and relapse, and to identify specific genes that contribute to individual differences in vulnerability to addiction. Understanding the molecular and cellular basis of addictive states will lead to major changes in how addiction is viewed and ultimately treated.     

Impulsivity as a mediating mechanism between early-life adversity and addiction: Theoretical comment on Lovic et al. (2011).

Early-life adversity, impulsivity, and dopaminergic function have all been implicated in adult drug addiction. The article by Lovic, Keen, Fletcher, and Fleming in this issue further elucidates this relationship by demonstrating that early-life adversity can increase impulsivity and decrease behavioral flexibility in adulthood. Recent literature suggests that these results are likely due to structural and functional changes in regions such as the orbitofrontal cortex (OFC) and nucleus accumbens (NAc), as well as altered dopamine activity. Impulsivity and behavioral inflexibility can increase susceptibility to addiction, and in turn, chronic substance abuse can impair the neurocircuitry underlying behavioral inhibition. Thus, early-life adversity may act as an entry point into a feed-forward spiral of impulsivity and addiction via the dysfunction of regions such as the OFC, NAc, and mesolimbic dopamine. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Recent developments in the pharmacotherapy of substance abuse

Modern concepts of addictive disorders emphasize the compulsive and relapsing drug-taking behaviors rather than tolerance and physical dependence. As with any chronic disorder, long-term treatment is necessary and medications may aid in the rehabilitative process. Specific medications have been demonstrated to be helpful for psychiatric disorders coexisting with addiction. Medications have also been demonstrated in controlled studies to aid in the rehabilitation of patients dependent on nicotine, alcohol, or opiates. Thus far, no medication has been clearly demonstrated to benefit patients suffering from abuse or dependence on cocaine, cannabinoids, nonalcohol sedatives, or hallucinogens.     

Cognitive function as an emerging treatment target for marijuana addiction.

Cannabis is the most widely used illicit substance in the world, and demand for effective treatment is increasing. However, abstinence rates following behavioral therapies have been modest, and there are no effective pharmacotherapies for the treatment of cannabis addiction. We propose a novel research agenda and a potential treatment strategy, based on observations that both acute and chronic exposure to cannabis are associated with dose-related cognitive impairments, most consistently in attention, working memory, verbal learning, and memory functions. These impairments are not completely reversible upon cessation of marijuana use, and moreover may interfere with the treatment of marijuana addiction. Therefore, targeting cognitive impairment associated with chronic marijuana use may be a promising novel strategy for the treatment of marijuana addiction. Preclinical studies suggest that medications enhancing the cholinergic transmission may attenuate cannabis-induced cognitive impairments, but these cognitive enhancing medications have not been examined in controlled human studies. Preliminary evidence from individuals addicted to other drugs suggests that computerized cognitive rehabilitation may also have utility to improve cognitive function in marijuana users. Future clinical studies optimally designed to measure cognitive function as well as drug use behavior would be needed to test the efficacy of these treatments for marijuana addiction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A behavioral economic analysis of the relative persistence of behavior: Comment on Meisch (2000).

This commentary examines and reinterprets the concept of relative persistence in drug self-administration studies, described by R. A. Meisch (see record 2000-00465-009), in behavioral economic terms. Over the past several years, investigators in the behavioral sciences have successfully applied consumer demand theory to the study of drug abuse and addiction. The economic concept of demand elasticity (i.e., the changes in the amount of a commodity demanded as a function of changes in price) and the concept of unit price are described in detail, and this commentary shows these concepts provide an alternative interpretation to the relative persistence of behavior. The application of the behavioral economic approach to understanding abuse potential of putative drugs of abuse, in development of medications for drug addiction and in characterizing the transition from drug use to drug addiction, is discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Polysubstance abuse--a case study

This article presents the case history of a 23-year-old white male's recovery from 12 years of alcohol and other substance abuse. The peer pressures that led to the experimental use of marijuana at age 11 and the evolving social relations that contributed to chronic substance use are described. Included are details about the subject's family life, peer relationships, criminal involvement, and transition from alcohol and marijuana use to chronic amphetamine addiction. Experiences with drug burn-out and the eventual rehabilitation and recovery process that led to a lifestyle that is currently free of drugs. The case is discussed in the context of current theoretical and empirical research in adolescent drug abuse.     

Biological consequences of drug administration: Implications for acute and chronic tolerance.

The authors presented a model that extrapolates the biological consequences of drug administration to account for acute and chronic tolerance. Drug-induced changes of regulated parameters provide detectable perturbations to which the brain responds. With experience, these centrally mediated responses are learned and can be activated in the absence of the drug-induced perturbation. Although neural responses following drug administration are often obscured, the model shows how these responses may be identified and provides a reinterpretation of drug conditioning paradigms. The authors made comparisons between the present empirical model of drug administration and existing theories of drug tolerance. The authors also presented a unified framework for understanding the consequences of repeated drug use and made specific predictions as to the relationships among acute and chronic tolerance, drug sensitization, and individual differences in vulnerability to drug addiction. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Regulation of Drug Taking by Sensitization and Habituation.

The authors argue that drug taking is an operant behavior that is reinforced by the drug itself. The effectiveness of a drug as a reinforcer is modulated by sensitization and habituation to the drug as it is consumed. According to this model, drug taking stops when habituation reduces the ability of the drug to reinforce its own consumption. Drug taking resumes when spontaneous recovery restores the effectiveness of the drug as a reinforcer. This parsimonious model provides a framework for understanding many findings in the drug literature, including acute and chronic tolerance, the effect of deprivation on consumption, the contextual specificity of tolerance, polydrug abuse, cross-sensitization between stress and drugs, behavioral sensitization, priming, and reinstatement. Although this model cannot explain all aspects of drug taking (e.g., the effect of cognitive manipulations), it has many implications for understanding and controlling human drug consumption and addiction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

CB1 cannabinoid receptor antagonist-induced opiate withdrawal in morphine-dependent rats

Recent reports have provided evidence of a link between the endogenous brain cannabinoid system and the endogenous central opioid systems. Here we report that the selective CB1 receptor antagonist SR 141716A induced behavioral and endocrine alterations associated with opiate withdrawal in morphine-dependent animals in a dose-dependent manner and that naloxone induced an opiate withdrawal syndrome in animals made cannabinoid-dependent by repeated administration of the potent cannabinoid agonist HU-210. Additionally CB1 and mu-opioid receptor mRNAs were co-localized in brain areas relevant for opiate withdrawal such as the nucleus accumbens, septum, dorsal striatum, the central amygdaloid nucleus and the habenular complex. These results suggest that CB1 cannabinoid receptors may play a role in the neuroadaptive processes associated with opiate dependence, and they lend further support for the hypothesis of a potential role of cannabinoid receptors in the neurobiological changes that culminate in drug addiction.     

Behavioral reversal of lithium effects by four inositol isomers correlates perfectly with biochemical effects on the PI cycle: depletion by chronic lithium of brain inositol is specific to hypothalamus, and inositol levels may be abnormal in postmortem brain from bipolar patients

The inositol depletion hypothesis of lithium (Li) action has been criticized, because depletion of inositol after chronic Li treatment has not been reproducible, effects of inositol to reverse Li-induced behaviors occurred also with epi-inositol, a unnatural isomer, and because inositol is ubiquitous in brain and hard to relate to the pathogenesis of affective disorder. Therefore, we review our studies showing that lithium depletion of brain inositol occurs chronically in the hypothalamus, a region not previously examined; that behavioral effects of four different inositol isomers including epi-inositol correlate perfectly with their biochemical effects; and that inositol in postmortem human brain is reduced by 25% in frontal cortex of bipolars and suicides as compared with controls. Because inositol in postmortem brain is reduced and not increased in bipolar patients, the relationship between inositol, lithium, and affective disorder is complex.     

Specific cue reactivity on computer game-related cues in excessive gamers.

It has been posited that excessive computer game playing behavior, referred to as computer game addiction, meets criteria that have been internationally established to define drug addiction. Nevertheless, there have been no psychophysiological investigations of the underlying mechanisms available to support the characterization of excessive computer gaming as behavioral addiction. To investigate whether excessive computer gaming parallels learning processes in development and maintenance (which are assumed to underlie drug addiction), the authors obtained a psychophysiological assessment of the (learned) emotional processing of computer game-relevant and -irrelevant cues. For this purpose, electroencephalographic recordings in excessive and casual computer game players were conducted. Significant between-group differences in event-related potentials evoked by computer game related-cues were found at parietal regions and point to an increased emotional processing of these cues in excessive pathological players compared with casual players. These results are in concordance with the suggestion that addiction is characterized and maintained through sensitization of the mesolimbic dopaminergic system along with incentive salience of specific addiction-associated cues. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

In vitro intercellular adhesion molecule-1 expression on brain endothelial cells in multiple sclerosis

To investigate the origin of intercellular adhesion molecule-1 (ICAM-1) and its expression on brain endothelial cells, we studied the expression in vitro of ICAM-1 on human brain endothelial cells after incubation of T cells from patients with multiple sclerosis (MS) using a histochemical technique and flow cytometry. We determined soluble forms of ICAM-1 (ICAM-1) in the supernatants after mixtures of brain endothelial cells and T cells from patients with MS using an enzyme-liked immunosorbent assay. Flow cytometric analysis showed that a number of ICAM-1-positive cells were significantly increased after incubation of brain endothelial cells with T cells from patients with acute relapsing MS during an exacerbation as compared with those of controls (P < 0.01). Patients with acute relapsing MS during an exacerbation and chronic progressive MS exhibited higher levels of ICAM-1 in the supernatants of mixtures with brain endothelial cells and lymphocytes than those of controls (P < 0.001 and P < 0.01, respectively). These results suggest that lymphocytes from patients with acute relapsing MS during an exacerbation lead to an increased expression of ICAM-1 on the brain endothelial cells and add to evidence involving this adhesion molecule in the pathogenesis of MS.     

Neighborhood Social Disorder as a Determinant of Drug Injection Behaviors: A Structural Equation Modeling Approach.

Neighborhood environments are increasingly recognized as a contextual determinant of health, behaviors, and disease; however, the pathways through which neighborhood characteristics impact health behaviors are poorly understood. This article examines pathways to elucidate how neighborhood social disorder may lead to HIV transmission. Data are from a baseline survey of 701 injection drug users from the Self-Help in Eliminating Lethal Diseases Study, an HIV prevention intervention in Baltimore. Structural equation modeling was used to examine the pathways among social disorder, psychological distress, and drug injection behaviors. The relationship between disorder and injection behaviors in the models tested suggests that psychological distress is higher in more socially disordered neighborhoods, that distress leads to greater injection frequency and equipment sharing, and that injection frequency predicts equipment sharing. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Posttraumatic stress disorder: Silent problem among older combat veterans.

Examines posttraumatic stress disorder (PTSD) among older Vietnam combat veterans. It is suggested that PTSD among these veterans is generally chronic, silent, and exacerbated by the problems of aging. These Ss with PTSD can be divided into those with full PTSD and those with partial PTSD. Studies are cited showing prevalence rates for PTSD. The difficulties in measuring PTSD are described. Several moderating variables influence the expression of trauma problems at later life, including the presence of other stressors, health status, social support, and comorbidity. Several forms of therapy are considered, including cognitive behavioral therapy, reminiscence, and relaxational desensitization. Also, several treatment suggestions are given, advocating interventions of a stuck narrative in an aging population. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mesolimbic dopaminergic decline after cannabinoid withdrawal

The mesolimbic dopamine system has recently been implicated in the long-term aversive consequences of withdrawal from major drugs of abuse. In the present study we sought to determine whether mesolimbic dopamine neurons are involved in the neurobiologic mechanisms underlying withdrawal from chronic cannabinoid exposure. Rats were treated chronically with the major psychoactive ingredient of hashish and marijuana, Delta9-tetrahydrocannabinol (Delta9-THC). Administration of the cannabinoid antagonist SR 141716A precipitated an intense behavioral withdrawal syndrome, whereas abrupt Delta9-THC suspension failed to produce overt signs of abstinence. In contrast, both groups showed a reduction in dopamine cells activity as indicated by extracellular single unit recordings from antidromically identified meso-accumbens dopamine neurons. The administration of Delta9-THC to spontaneously withdrawn rats restored neuronal activity. Conversely, SR 141716A produced a further decrease of spontaneous activity in cannabinoid-treated although it was ineffective in control rats. These data indicate that withdrawal from chronic cannabinoid administration is associated with reduced dopaminergic transmission in the limbic system, similar to that observed with other addictive drugs; these changes in neuronal plasticity may play a role in drug craving and relapse into drug addiction.     

The in vivo antibody response in rat gut-associated lymphoid tissue (GALT) after immunization with bacterial polysaccharide antigen

There are major clinical observations in alcohol and other drug addicts and neurochemical studies in animals and humans that support the hypothesis for a common neurochemical basis for alcohol and other drug addiction. The common occurrence of concurrent alcohol and multiple drug dependence in clinical and general populations, family history and genetic studies, and basic and clinical research in the neurochemistry of addictive behavior provide evidence for a common genealogical vulnerability to combined alcohol and other drug addiction. Clinical neurochemical models for addictive behaviors can be derived from neurochemical pathways for the initiation and sustenance of addictive disorders. The role of tolerance and dependence is not specific to addiction but indicates a homeostatic response of the brain to the presence of a foreign substance. Animal and human studies are analyzed for clinical synthesis of a neurochemical basis for addictive disorders.