Drug addiction: Functional neurotoxicity of the brain reward systems

Drug addiction is a chronic relapsing brain disorder characterized by a compulsion to take a drug with loss of control over drug intake. The hypothesis under discussion here is that chronic drug use produces long-lasting dysfunctions in neurons associated with the brain reward circuitry, and this “functional neurotoxicity” of drugs of abuse leads to vulnerability to relapse and continued drug dependence. Several sources of reinforcement are associated with various components of the drug addiction cycle and much progress has been made in identifying the midbrain-basal forebrain neural elements involved in the positive reinforcing effects of drugs of abuse and more recently in the neural elements involved in the negative reinforcement associated with drug addiction. Key elements for the acute reinforcing effects of drugs of abuse include a macrostructure in the basal f orebrain called the extended amygdala that contains parts of the nucleus accumbens and amgydala and involves key neurotransmitters such as dopamine, opioid peptides, serotonin, GABA, and glutamate. Withdrawal from drugs of abuse is associated with subjective symptoms of negative affect and dysregu-lation of brain reward systems involving some of the same neurochemical systems implicated in the acute reinforcing effects of drugs of abuse. In addition, the functional toxicity of acute withdrawal is accompanied by recruitment of the brain stress neurotransmitter system corticotropin-releasing factor. During more prolonged abstinence, post-acute withdrawal, evidence is accumulating of continued dysregulation of the neural systems associated with drug reinforcement and stress regulation that may represent more subtle but persistent functional neurotoxic effects of chronic drug use and could be responsible for long-lasting vulnerability to relapse. Such functional neurotoxicity could be hypothesized to lead to a change in set point for drug reward that may represent an allostatic state contributing to vulnerability to relapse and re-entry into the addiction cycle. Elucidation of the specific neuropharmacological changes contributing to this prolonged functional neurotoxicity will be the challenge of future research on the neurobiology of drug addiction.     

Glial mechanisms underlying substance use disorders

Addiction is a devastating disorder that produces persistent maladaptive changes to the central nervous system, including glial cells. Although there is an extensive body of literature examining the neuronal mechanisms of substance use disorders, effective therapies remain elusive. Glia, particularly microglia and astrocytes, have an emerging and meaningful role in a variety of processes beyond inflammation and immune surveillance, and may represent a promising therapeutic target. Indeed, glia actively modulate neurotransmission, synaptic connectivity and neural circuit function, and are critically poised to contribute to addictive‐like brain states and behaviors. In this review, we argue that glia influence the cellular, molecular, and synaptic changes that occur in neurons following drug exposure, and that this cellular relationship is critically modified following drug exposure. We discuss direct actions of abused drugs on glial function through immune receptors, such as Toll‐like receptor 4, as well as other mechanisms. We highlight how drugs of abuse affect glia‐neural communication, and the profound effects that glial‐derived factors have on neuronal excitability, structure, and function. Recent research demonstrates that glia have brain region‐specific functions, and glia in different brain regions have distinct contributions to drug‐associated behaviors. We will also evaluate the evidence demonstrating that glial activation is essential for drug reward and drug‐induced dopamine release, and highlight clinical evidence showing that glial mechanisms contribute to drug abuse liability. In this review, we synthesize the extensive evidence that glia have a unique, pivotal, and underappreciated role in the development and maintenance of addiction.     

Neural and psychological mechanisms underlying compulsive drug seeking habits and drug memories – indications for novel treatments of addiction

This review discusses the evidence for the hypothesis that the development of drug addiction can be understood in terms of interactions between Pavlovian and instrumental learning and memory mechanisms in the brain that underlie the seeking and taking of drugs. It is argued that these behaviours initially are goal‐directed, but increasingly become elicited as stimulus–response habits by drug‐associated conditioned stimuli that are established by Pavlovian conditioning. It is further argued that compulsive drug use emerges as the result of a loss of prefrontal cortical inhibitory control over drug seeking habits. Data are reviewed that indicate these transitions from use to abuse to addiction depend upon shifts from ventral to dorsal striatal control over behaviour, mediated in part by serial connectivity between the striatum and midbrain dopamine systems. Only some individuals lose control over their drug use, and the importance of behavioural impulsivity as a vulnerability trait predicting stimulant abuse and addiction in animals and humans, together with consideration of an emerging neuroendophenotype for addiction are discussed. Finally, the potential for developing treatments for addiction is considered in light of the neuropsychological advances that are reviewed, including the possibility of targeting drug memory reconsolidation and extinction to reduce Pavlovian influences on drug seeking as a means of promoting abstinence and preventing relapse.     

The role of impulsivity in psychostimulant- and stress-induced dopamine release: Review of human imaging studies

Drug addiction is a debilitating disorder and its pivotal problem is the high relapse rate. To solve this problem, the aim is to prevent people from becoming addicted in the first place. One of the key questions that is still unanswered is why some people become addicted to drugs and others, who take drugs regularly, do not. In recent years extensive research has been done to untangle the many factors involved in this disorder. Here, we review some of the factors that are related to dopamine, i.e., impulsivity and stress (hormones), and aim to integrate this into a neurobiological model. Based on this, we draw two conclusions: (1) in order to understand the transition from recreational drug use to addiction, we need to focus more on these recreational users; and (2) research should be aimed at finding therapies that can restore inhibitory control/frontal functioning and improve stress resiliency in addicts.     

The neurobiological mechanisms of physical exercise in methamphetamine addiction

Methamphetamine (METH) is the primary drug within amphetamine‐type stimulants which are the second most abused group of drugs worldwide. There is no pharmacological treatment addressed specifically to METH addiction, and behavioral therapy is shadowed by poor long‐term recovery and relapse. Therefore, novel approaches to manage METH addiction are an urgent need. This review aims to describe the current state of physical exercise use on methamphetamine addiction management. The following searching terms in PubMed were used: (“physical exercise” OR “exercise”) AND “methamphetamine.” Relevant references from key publications and gray literature were also reviewed to identify additional citations for inclusion. Original investigation regarding physical exercise and methamphetamine addiction (clinical data) or neurobiological mechanisms of physical exercise in animal models of methamphetamine administration (preclinical data) was included. Overall, METH users demonstrated improvements, including better fitness and emotional measures, lower relapse rates, and sustained abstinence when compared to nonexercised individuals. The neurobiological mechanisms of physical exercise in METH users seem to reflect an interplay of several agents, including neurochemicals, oxidative stress, neurogenesis, gliogenesis, and blood‐brain barrier as disclosed by preclinical data. Exercise‐based interventions alone or as a conjoint therapy may be a useful tool for managing METH addiction.     

Beyond drug‐induced alteration of glutamate homeostasis,astrocytes may contribute to dopamine‐dependent intrastriatal functional shifts that underlie the development of drug addiction: A working hypothesis

The transition from recreational drug use to compulsive drug‐seeking habits, the hallmark of addiction, has been shown to depend on a shift in the locus of control over behaviour from the ventral to the dorsolateral striatum. This process has hitherto been considered to depend on the aberrant engagement of dopamine‐dependent plasticity processes within neuronal networks. However, exposure to drugs of abuse also triggers cellular and molecular adaptations in astrocytes within the striatum which could potentially contribute to the intrastriatal transitions observed during the development of drug addiction. Pharmacological interventions aiming to restore the astrocytic mechanisms responsible for maintaining homeostatic glutamate concentrations in the nucleus accumbens, that are altered by chronic exposure to addictive drugs, abolish the propensity to relapse in both preclinical and, to a lesser extent, clinical studies. Exposure to drugs of abuse also alters the function of astrocytes in the dorsolateral striatum, wherein dopaminergic mechanisms control drug‐seeking habits, associated compulsivity and relapse. This suggests that drug‐induced alterations in the glutamatergic homeostasis maintained by astrocytes throughout the entire striatum may interact with dopaminergic mechanisms to promote aberrant plasticity processes that contribute to the maintenance of maladaptive drug‐seeking habits. Capitalising on growing evidence that astrocytes play a fundamental regulatory role in glutamate and dopamine transmission in the striatum, we present an innovative model of a quadripartite synaptic microenvironment within which astrocytes channel functional interactions between the dopaminergic and glutamatergic systems that may represent the primary striatal functional unit that undergoes drug‐induced adaptations eventually leading to addiction.     

Genes associated with addiction

Drug addiction is a complex disorder that has a large spectrum of causes. Vulnerability to addiction has been shown in twin studies to have a robust genetic component. This genetic basis for addiction has general and specific components for each drug abused. Although many genes have been implicated in drug addiction, only a handful have either been replicated to have an association or to have an identified functional mechanism related to specific effects of abused drugs. A few selected genetic variants that currently look promising for the study of alcohol, opiate, and cocaine addiction are discussed in this article.     

Dual diagnosis of substance abuse in schizophrenia: prevalence and impact on outcomes

Comorbid substance abuse disorders have emerged as one of the greatest obstacles to the effective treatment of persons with schizophrenia. Estimates of the prevalence of such comorbidity vary, but as many as half of persons with schizophrenia may suffer from a comorbid drug or alcohol disorder. Younger age, male gender, and lower educational attainment are associated with greater risk for addiction. Persons with schizophrenia and comorbid addiction tend to have an earlier onset of schizophrenia than do those without comorbid addiction. Research does not support a link between specific symptoms of schizophrenia and choice of abused drugs. Rather, drug choice is correlated with the pattern of ambient drug use in the community. Comorbid substance disorders are associated with a variety of poorer outcomes, including increased psychotic symptoms, poorer treatment compliance, violence, housing instability and homelessness, medical problems (including human immunodeficiency virus infection), poor money management, and greater use of crisis-oriented services that result in higher costs of care. Considerable progress has been made over the past decade in understanding the need to integrate substance abuse treatment and mental health treatment to provide more effective care for this population.     

Management of Phenibut Use Disorder and Withdrawal in a Geriatric Patient

Phenibut is a misused substance which has shown an increase in use over the past decade. Marketed as a “dietary supplement,” it is not approved in the United States for use and is not regulated by the Food and Drug Administration. The substance, however, is readily available for purchase through online markets. It has a similar drug profile as alcohol, gabapentin and benzodiazepines. Clinical effects of this drug include physiologic dependence, euphoria, anxiolysis, antispasticity, sedation, and possible nootropic properties.While there are emerging new cases of managing phenibut withdrawal, no cases currently feature phenibut addiction and withdrawal management in the geriatric population. Here we discuss such a case of phenibut addiction and withdrawal in a 68-year-old male who initially began misusing phenibut to alleviate anxiety and insomnia precipitated by worsening affective disorder, sedative, hypnotic, or anxiolytic use disorder, and alcohol use disorder.     

Corticostriatal circuitry in regulating diseases characterized by intrusive thinking

Intrusive thinking triggers clinical symptoms in many neuropsychiatric disorders. Using drug addiction as an exemplar disorder sustained in part by intrusive thinking, we explore studies demonstrating that impairments in corticostriatal circuitry strongly contribute to intrusive thinking. Neuroimaging studies have long implicated this projection in cue-induced craving to use drugs, and preclinical models show that marked changes are produced at corticostriatal synapses in the nucleus accumbens during a relapse episode. We delineate an accumbens microcircuit that mediates cue-induced drug seeking becoming an intrusive event. This microcircuit harbors many potential therapeutic targets. We focus on preclinical and clinical studies, showing that administering N-acetylcysteine restores uptake of synaptic glutamate by astroglial glutamate transporters and thereby inhibits intrusive thinking. We posit that because intrusive thinking is a shared endophenotype in many disorders, N-acetylcysteine has positive effects in clinical trials for a variety of neuropsychiatric disorders, including drug addiction, gambling, trichotillomania, and depression.     

Multigenerational and transgenerational effects of paternal exposure to drugs of abuse on behavioral and neural function

Addictions are highly heritable disorders, with heritability estimates ranging from 39% to 72%. Multiple studies suggest a link between paternal drug abuse and addiction in their children. However, patterns of inheritance cannot be explained purely by Mendelian genetic mechanisms. Exposure to drugs of abuse results in epigenetic changes that may be passed on through the germline. This mechanism of epigenetic transgenerational inheritance may provide a link between paternal drug exposure and addiction susceptibility in the offspring. Recent studies have begun to investigate the effect of paternal drug exposure on behavioral and neurobiological phenotypes in offspring of drug‐exposed fathers in rodent models. This review aims to discuss behavioral and neural effects of paternal exposure to alcohol, cocaine, opioids, and nicotine. Although a special focus will be on addiction‐relevant behaviors, additional behavioral effects including cognition, anxiety, and depressive‐like behaviors will be discussed.     

Genetic vulnerability to drug abuse.

Addiction to various substances, including drugs and alcohol, probably arises from a combination of environmental and genetic factors. The genetic vulnerability to drug addiction is supported by several familial, adoption and twin studies. However, as in other mental disorders, the genetic vulnerability to drug addiction appears complex: these disorders do not follow the rules of Mendelian inheritance. Instead, they are probably influenced by multiple susceptibility genes, each of which contributes to the disorder. The more genes necessary for a disorder, the harder it is to detect any of them. This difficulty is magnified by the role of environmental factors. Association studies using the candidate gene approach can identify susceptibility genes for drug abuse supported by the pathophysiological hypothesis of the illness. This review will focus on the clinical and molecular genetic studies in drug abuse.     

Stress, dysregulation of drug reward pathways, and the transition to drug dependence

This review provides a neuroadaptive perspective regarding the role of the hormonal and brain stress systems in drug addiction with a focus on the changes that occur during the transition from limited access to drugs to long-term compulsive use of drugs. A dramatic escalation in drug intake with extended access to drug self-administration is characterized by a dysregulation of brain reward pathways. Hormonal studies using an experimenter-administered cocaine binge model and an escalation self-administration model have revealed large increases in ACTH and corticosterone in rats during an acute binge with attenuation during the chronic binge stage and a reactivation of the hypothalamic-pituitary-adrenal axis during acute withdrawal. The activation of the hypothalamic-pituitary-adrenal axis with cocaine appears to depend on feed-forward activation of the mesolimbic dopamine system. At the same time, escalation in drug intake with either extended access or dependence-induction produces an activation of the brain stress system's corticotropin-releasing factor outside of the hypothalamus in the extended amygdala, which is particularly evident during acute withdrawal. A model of the role of different levels of hormonal/brain stress activation in addiction is presented that has heuristic value for understanding individual vulnerability to drug dependence and novel treatments for the disorder.     

Initial rewarding effects of cocaine and amphetamine assessed in a day using the single‐exposure place preference protocol

In rodents, only a single dose of cocaine or amphetamine is required to cause a marked increase in extracellular dopamine, induce hyperlocomotion and cause persistent plasticity changes within dopaminergic neurons of the ventral tegmental area (VTA). The initial drug experience is suggested to predict vulnerability of developing addiction, but only few studies have assessed the perception of reward accompanying this initial exposure. We recently presented an approach to assess the initial rewarding effects of cocaine in mice with a single‐exposure place preference (sePP) protocol, avoiding repeated drug injections. Here, we demonstrate a condensed version of the sePP, allowing assessment of initial subjective reward‐perception within a day. By using this protocol, we demonstrate that a single exposure to both cocaine and amphetamine is sufficient to induce place preference. Furthermore, we use chemogenetics ( Designer Receptors Exclusively Activated by Designer Drugs [DREADD]) to show that both inhibitory and stimulatory modulation of VTA DA signalling disrupts cocaine‐induced place preference in the condensed sePP. Our findings support the presence of initial reward‐perception of both cocaine and amphetamine, and the formation of drug‐context association. In addition, our data support that VTA DA signalling prior to drug exposure affects either reward‐perception or the time during which associations are formed, thereby preventing induction of cocaine‐induced place preference in the sePP. The easy and timesaving sePP protocol should form a critical basis for further deciphering the complex mechanisms underlying the progression from the initial drug experience to escalating drug intake and addiction.     

Development of short‐form and screening cutoff point of the Smartphone Addiction Inventory (SPAI‐SF)

Smartphone addiction is considered a form of technological addiction that has attracted increasing attention. The present study developed and validated the short‐form Smartphone Addiction Inventory (SPAI‐SF) and established cutoff point for screening smartphone addiction based on diagnostic criteria established by psychiatric interview. A total of 268 participants completed an online survey that collected demographic data, smartphone use behaviours, and responses to the 26‐item SPAI. Each participant also completed a psychiatric interview. Confirmatory factor analysis (CFA) revealed that the 10‐item SPAI‐SF replicated the structure of original 26‐item SPAI accurately, yielding a four‐factor model consisting of compulsive behaviour, functional impairment, withdrawal, and tolerance. For maximal diagnostic accuracy, a cutoff point of 24/25 best discriminated cases of smartphone addiction from diagnostic negatives. The present findings suggest that both the 26‐item SPAI and SPAI‐SF manifest the four constructs of behavioural addiction and the characteristics of smartphone addiction. The cutoff point determined by psychiatrists' diagnostic interview will be useful for clinical screening and epidemiologic research.     

Characteristics of nursing home patients who receive medications with the potential for addiction on a regular and long-term basis: A retrospective pilot study

Benzodiazepines are among the most commonly prescribed drugs in nursing homes. Other potentially addictive drugs, including other sedative/hypnotics and oral narcotics, are also prescribed quite frequently. These drugs are not always prescribed for appropriate clinical indications, may be prescribed for extended periods of time and may cause significant side-effects. Among the concerns about the regular use of these medications is their potential for abuse and dependence. In this study, we examined the records of 253 consecutive psychiatric consultations in nursing homes. All consultations were performed by the senior author. At the time of consultation, one-third of the subjects were receiving a potentially addictive drug on a regular, and usually daily basis. We compared the group receiving these drugs and the group not receiving these drugs on several variables, including psychiatric and family histories, psychopharmacologic treatments, personal and family addiction histories, psychiatric diagnoses and clinical symptoms. This article presents the results of this study. There were 84 patients in the addictive drug use group and 167 patients in the addictive drug non-use group. We found that regular use of these drugs was associated with several variables. These included the possibility of a biologic vulnerability to addiction, the presence and severity of the psychiatric disorder(s) of the patients, and the third was the presence of major depression or depressive symptoms. The implications of these data are reviewed. In addition, methodologic and diagnostic issues are discussed. The implications for clinical practice and future research in this area are also discussed.     

Sensitive periods of substance abuse: Early risk for the transition to dependence

Early adolescent substance use dramatically increases the risk of lifelong substance use disorder (SUD). An adolescent sensitive period evolved to allow the development of risk-taking traits that aid in survival; today these may manifest as a vulnerability to drugs of abuse. Early substance use interferes with ongoing neurodevelopment to induce neurobiological changes that further augment SUD risk. Although many individuals use drugs recreationally, only a small percentage transition to SUD. Current theories on the etiology of addiction can lend insights into the risk factors that increase vulnerability from early recreational use to addiction. Building on the work of others, we suggest individual risk for SUD emerges from an immature PFC combined with hyper-reactivity of reward salience, habit, and stress systems. Early identification of risk factors is critical to reducing the occurrence of SUD. We suggest preventative interventions for SUD that can be either tailored to individual risk profiles and/or implemented broadly, prior to the sensitive adolescent period, to maximize resilience to developing substance dependence. Recommendations for future research include a focus on the juvenile and adolescent periods as well as on sex differences to better understand early risk and identify the most efficacious preventions for SUD.     

Sexual and physical abuse during early childhood or adolescence and later drug addiction

Sexual or physical abuse of children are discussed as possible causes or risk-factors for psychiatric disorders like posttraumatic stress disorder, alcohol and drug addiction. The aim of this study was to identify possible differences between sexually or physically abused and non-abused patients with polytoxic drug abuse. METHOD: 100 patients with polytoxic drug abuse were interviewed during their therapy about a history of sexual abuse prior to the age of sixteen. Using different questionnaires we tried to find possible differences between drug users being sexually abused or not and risk factors for later drug addiction. RESULTS: 70% of the female and 56% of the male drug users had been sexually abused as children, 40% of the male and 50% of the female participants had a history of severe sexual abuse with sexual intercourse. In over 50% friends or relatives were the perpetrators committed the crime, in no case the parents had. More than 40% showed also a history of physical abuse. Significantly more drug users than alcohol abusers had a sexual trauma. Especially severe sexual abuse was associated with abuse of hard illegal drugs. Furthermore, we could find significantly more symptoms such as autoaggressive and suicidal behaviour, social isolation, reduced emotional binding to others, tendency to be persistently victimized, prostitution and violence against others in the group of sexually abused. Many of these symptoms are not only characteristic of addiction, but can be found also in other psychiatric diseases such as borderline and eating disorder. In conclusion, we could not find a significant correlation between sexual abuse and later drug addiction. 80% of the drug users themselves did not relate the fact of being sexually abused as child to later drug abuse. However, there seems to be a positive correlation between sexual abuse and a more severe addiction to illegal drugs as well as higher rates of symptoms with a negative course of the disease. For this group of patients with an unfavourable prognosis special therapeutic concepts are needed.     

Long term effects of stress on hippocampal function: Emphasis on early life stress paradigms and potential involvement of neuropeptide Y

The brain is both central in orchestrating the response to stress, and, a very sensitive target when such response is not controlled. In fact, stress has long been associated with the onset and/or exacerbation of several neuropsychiatric disorders such as anxiety, depression, and drug addiction. The hippocampus is a key brain region involved in the response to stress, not only due to its anatomical connections with the hypothalamic‐pituitary‐adrenal axis but also as a major target of stress mediators. The hippocampal dentate gyrus (DG)‐CA3 circuit, composed of DG granule cells axons (mossy fibers) synapsing onto CA3 pyramidal cells, plays an essential role in memory encoding and retrieval, functions that are vulnerable to stress. Although naturally excitatory, this circuit is under the inhibitory control of GABAergic interneurons that maintain the excitation/inhibition balance. One subgroup of such interneurons produces neuropeptide Y (NPY), which has emerged as a promising endogenous stress “resilience molecule” due to its anxiolytic and anti‐epileptic properties. Here we examine existing evidence that reveals a potential role for hilar NPY+ interneurons in mediating stress‐induced changes in hippocampal function. We will focus specifically on rodent models of early life stress (ELS), defined as adverse conditions during the early postnatal period that can have profound consequences for neurodevelopment. Collectively, these findings suggest that the long‐lasting effects of ELS might stem from the loss of GABAergic NPY+ cells, which then can lead to reduced inhibition in the DG‐CA3 pathway. Such change might then lead to hyperexcitability and concomitant hippocampal‐dependent behavioral deficits.