Sex differences in the vulnerability to drug abuse: a review of preclinical studies

Clinical and preclinical findings indicate that males and females differ on several aspects of drug reinforcement. Females are more vulnerable than males during transition periods of drug use that are characteristic of drug addiction and relapse. Females are also more sensitive than males to the reinforcing effects of stimulants. It has been suggested that ovarian hormones contribute to the mechanisms of action underlying these sex differences. This review examines the preclinical literature on sex differences and ovarian hormonal influences on drug self-administration in animals. It summarizes the findings on the effects of these variables during different phases of drug addiction. Possible differences in the mechanisms of action of drugs of abuse due to interactions with sex differences or ovarian hormonal factors are considered. The animal literature on sex differences in drug abuse treatment effectiveness is also discussed.     

The neurobiology of addiction

Drug addiction includes complex neurobiological and behavioural processes. Acute reinforcing effects of drugs of abuse are responsible for the initiation of drug addiction, whereas the negative consequences of drug abstinence have a crucial motivational significance for relapse and maintenance of the addictive process. The mesocorticolimbic system represents a common neuronal substrate for the reinforcing properties of drugs of abuse. Both dopamine and opioid transmission play a crucial role in this reward pathway. Common neuronal changes have also been reported during the abstinence to different drugs of abuse that could underlie the negative motivational effects of withdrawal. These changes include decreased dopaminergic activity in the mesolimbic system and a recruitment of the brain stress pathways. All drugs of abuse interact with these brain circuits by acting on different molecular and neurochemical mechanisms. The existence of bidirectional interactions between different drugs of abuse, such as opioids and cannabinoids, provides further findings to support this common neurobiological substrate for drug addictive processes.     

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.     

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.     

Clinical Approach to Diagnosis of Comorbid Addictive and Psychiatric Disorders

Abstract

The outcome of severe mental illness is greatly diminished when persons also abuse alcohol and other drugs. This paper debunks any notion that substance abuse is acquired, rather portraying drug use and abuse to be an addiction and disease. The author then summarizes relevant factors related to diagnosing this disease including the need for a period of abstinence and the consideration of personality factors. Implications of an addiction diagnosis are discussed.     

PET imaging of dopamine D2 receptors in monkey models of cocaine abuse: genetic predisposition versus environmental modulation

OBJECTIVE: Animals self-administer many of the drugs that humans abuse, including cocaine. This article describes studies using preclinical animal models to differentiate the influences of neurobiological predisposition from environmental modulation of cocaine addiction, including studies from the authors' laboratory using nonhuman primates. METHOD: Addiction is described in terms of vulnerability, maintenance, and abstinence. This review focuses on dopamine receptor function, in particular that of the D2-like receptors, as measured by the noninvasive imaging procedure positron emission tomography. Findings from human studies of addiction and animal models are reviewed. RESULTS: There appears to be an inverse relationship between D2 receptor availability and vulnerability to the reinforcing effects of cocaine. Environmental variables can increase or decrease D2 receptor binding in an orderly fashion, and the resulting changes in D2 function influence the vulnerability to abuse cocaine. In maintenance, chronic cocaine exposure produces decreases in D2 receptor binding, which may be a mechanism that contributes to continued drug use. Finally, during abstinence there are individual differences in rates of recovery of D2 receptor availability. CONCLUSIONS: The goal of the preclinical research described in this review is to achieve a better understanding of individual differences in susceptibility and vulnerability to the reinforcing effects of cocaine. It is clear that the development of novel animal models will extend our understanding of the neurobiological basis of drug addiction to include a greater appreciation of the role of environmental factors in affecting predisposition, mediating continued drug use, and triggering relapse.     

Effect of environmental stressors on opiate and psychostimulant reinforcement, reinstatement and discrimination in rats: a review

Studies in humans suggest that exposure to life stressors is correlated with compulsive drug abuse and relapse to drugs during periods of abstinence. The behavioral and neurobiological mechanisms involved in the effect of stress on drug abuse, however, are not known. Here, we review data from studies using preclinical models in rats on the effect of environmental stressors on opiate and psychostimulant reinforcement, as measured by the intravenous drug self-administration and conditioned place preference procedures, on relapse to these drugs, as measured by the reinstatement procedure, and on the subjective effects of these drugs, as measured by the drug discrimination procedure. The results of the studies reviewed here suggest that while stressors are important modulators of the behavioral effects of opiate and psychostimulant drugs, the effect of stress on behavior in these animal models is stressor-specific, and to some degree, procedure- and drug-class-specific. The review of studies on the neurobiological mechanisms underlying stress-drug interactions in these animal models indicate that central noradrenaline and extrahypothalamic corticotropin-releasing factor mediate the effect of one form of stress (intermittent footshock) on reinstatement of opiate and psychostimulant seeking after prolonged drug-free periods. At present, however, little is known about the neuronal events that mediate the effect of environmental stressors on opiate and psychostimulant reinforcement or discrimination. The broader implications of the data reviewed here for future research and for the treatment of opiate and psychostimulant addiction are briefly discussed.     

Neurobiological mechanisms of the reinstatement of drug-conditioned place preference

Drug addiction is a chronic disorder characterized by a high rate of relapse following detoxification. There are two main versions of the reinstatement model that are employed to study relapse to drug abuse; one based on the operant self-administration procedure, and the other on the classical conditioned place preference procedure. In the last seven years, the use of the latter version has become more widespread, and the results obtained complement those obtained in self-administration studies. It has been observed that the conditioned place preference induced by opioids, psychostimulants, nicotine, ethanol and other drugs of abuse can be extinguished and reinstated by drug priming or exposure to stressful events. Herein, the neuroanatomical and neurochemical basis of drug priming- and stress-induced reinstatement of morphine and cocaine, together with the molecular correlates of reinstatement behavior, are reviewed. Differences between the conditioned place preference and self-administration studies are also discussed. Evidence suggests that data of reinstatement with the CPP are to be viewed with caution until more extensive analysis of operant procedures has been performed, and that further research will undoubtedly improve our understanding of the neurobiological mechanisms of relapse to drug seeking.     

Differences among treatment clinic types in attitudes toward narcotic addiction

Factor analysis of data from a general survey of attitudes and opinions concerning narcotic addiction and its treatment revealed 10 major dimensions, five of which were likely to have significant implications for drug abuse intervention strategies. For these latter dimensions, differences were determined among clients and staff according to type of treatment clinic (three types involving the provision of methadone maintenance in various combinations with other treatments and one involving the use of abstinence only). The most pronounced differences were between the methadone clinics and those offering abstinence only. Both the clients and staff of abstinence clinics were more skeptical concerning treatment effectiveness, were more negative regarding the use of narcotic drugs, and were more disposed to the use of ex-addict counselors and group procedures in treatment.     

Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs

Substance abuse and addiction are the most costly of all the neuropsychiatric disorders. In the last decades, much progress has been achieved in understanding the effects of the drugs of abuse in the brain. However, efficient treatments that prevent relapse have not been developed. Drug addiction is now considered a brain disease, because the abuse of drugs affects several brain functions. Neurological impairments observed in drug addicts may reflect drug-induced neuronal dysfunction and neurotoxicity. The drugs of abuse directly or indirectly affect neurotransmitter systems, particularly dopaminergic and glutamatergic neurons. This review explores the literature reporting cellular and molecular alterations reflecting the cytotoxicity induced by amphetamines, cocaine and opiates in neuronal systems. The neurotoxic effects of drugs of abuse are often associated with oxidative stress, mitochondrial dysfunction, apoptosis and inhibition of neurogenesis, among other mechanisms. Understanding the mechanisms that underlie brain dysfunction observed in drug-addicted individuals may contribute to improve the treatment of drug addiction, which may have social and economic consequences.     

Pathways to relapse: the neurobiology of drug- and stress-induced relapse to drug-taking

Relapse is a major characteristic of drug addiction, and remains the primary problem in treating drug abuse. Without an understanding of the factors that determine renewed drug-seeking, the urge to use drugs, and the persistent craving for them, it is unlikely that health care professionals can provide effective treatment. Using an animal model of relapse, the author and her team are studying factors that induce reinstatement of drug-taking behaviour after short and long periods of abstinence, and they are exploring the neurobiological basis of these effects. In their experiments, rats are trained to self-administer drugs intravenously by pressing 1 of 2 levers. During a subsequent period, the drug is no longer available, but the rats are free to try to obtain the drug (a period of "extinction training"). After extinction of responding, the investigators test for the ability of various events to reinitiate drug-seeking. On this background of renewed drug-seeking or relapse, the investigators search for pharmacological and neurochemical manipulations that might block or attenuate such behaviour. They have found that the 2 most effective events for reinstating responding after both short and long drug-free periods are re-exposure to the drug itself and exposure to a brief period of stress. The critical neurochemical pathways mediating drug-induced relapse are not identical to those mediating stress-induced relapse. Relapse induced by "priming" injections of heroin or cocaine involves activation of the mesolimbic dopaminergic pathways, whereas relapse induced by stress involves actions of corticotropin-releasing factor (CRF) in the brain, and of brain noradrenergic (NE) systems. In addition, evidence shows that CRF and NE may interact at the level of the bed nucleus of the stria terminalis in stress-induced relapse. By contrast, relapse induced by "priming" injections of drugs is relatively unaffected by manipulation of CRF and NE systems of the brain.     

GDNF and addiction

Biochemical adaptations to drugs of abuse and alcohol are especially profound in midbrain dopaminergic neurons. Long-lasting molecular and structural changes in mesolimbic dopaminergic neurons that result from chronic exposure to drugs of abuse and alcohol are thought to underlie adverse behaviors such as compulsive drug seeking and relapse. Recent studies suggest that a subset of these changes is prevented/reversed by activation of the glial cell line-derived neurotrophic factor (GDNF) signaling pathway. Behavioral effects of drugs of abuse such as cocaine and alcohol are also negatively regulated by GDNF: inhibition of the endogenous GDNF pathway enhances the activity of drugs of abuse, while administration of GDNF reduces the severity of the effects. In this review, we summarize the data implicating GDNF as a negative regulator of drug and alcohol addiction. We also provide evidence to suggest that therapies that activate GDNF signaling may be useful for the treatment of drug and alcohol addiction.     

New Findings on Biological Factors Predicting Addiction Relapse Vulnerability

Relapse is a highly prevalent phenomenon in addiction. This paper examines the new research on identifying biological factors that contribute to addiction relapse risk. Prospective studies examining relapse risk are reviewed, and clinical, biological, and neural factors that predict relapse risk are identified. Clinical factors, patient-related factors, and subjective and behavioral measures such as depressive symptoms, stress, and drug craving all predict future relapse risk. Among biological measures, endocrine measures such as cortisol and cortisol/corticotropin (ACTH) ratio as a measure of adrenal sensitivity and serum brain-derived neurotrophic factor were also predictive of future relapse risk. Among neural measures, brain atrophy in the medial frontal regions and hyperreactivity of the anterior cingulate during withdrawal were identified as important in drug withdrawal and relapse risk. Caveats pertaining to specific drug abuse type and phase of addiction are discussed. Finally, significant implications of these findings for clinical practice are presented, with a specific focus on determining biological markers of relapse risk that may be used to identify those individuals who are most at risk of relapse in the clinic. Such markers may then be used to assess treatment response and develop specific treatments that will normalize these neural and biological sequelae so as to significantly improve relapse outcomes.     

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.     

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.     

Modeling the role of environment in addiction

The aim of this review is to provide an overview of the main types of animal models used to investigate the modulatory role of environment on drug addiction. The environment can alter the responsiveness to addictive drugs in at least three major ways. First, adverse life experiences can make an individual more vulnerable to develop drug addiction or to relapse into drug seeking. Second, neutral environmental cues can acquire, through Pavlovian conditioning, the ability to trigger drug seeking even after long periods of abstinence. Third, the environment immediately surrounding drug taking can alter the behavioral, subjective, and rewarding effects of a given drug, thus influencing the propensity to use the same drug again. We have focused in particular on the results obtained using an animal model we have developed to study the latter type of drug–environment interaction.     

Regulation of AMPA Receptor Trafficking in the Nucleus Accumbens by Dopamine and Cocaine

Nucleus accumbens (NAc) neurons are excited primarily by AMPA-type glutamate receptors (AMPAR). This is required for cocaine seeking in animal models of cocaine addiction, suggesting AMPAR transmission in the NAc as a key control point for cocaine-related behaviors. This review will briefly describe AMPAR properties and trafficking, with a focus on studies in NAc neurons, and then consider mechanisms by which cocaine may alter AMPAR transmission. Two examples will be discussed that may be important in two different stages of addiction: learning about drugs and drug-related cues during the period of drug exposure, and persistent vulnerability to craving and relapse after abstinence is achieved. The first example is drawn from studies of cultured NAc neurons. Elevation of dopamine levels (as would occur following cocaine exposure) facilitates activity-dependent strengthening of excitatory synapses onto medium spiny neurons, the main cell type and projection neuron of the NAc. This occurs because activation of D1-class dopamine receptors primes AMPAR for synaptic insertion. This may create a temporal window in which stimuli related to cocaine-taking are more efficacious at eliciting synaptic plasticity and thus being encoded into memory. The second example involves rat models of cocaine addiction. Cell surface and synaptic expression of AMPAR on NAc neurons is persistently increased after withdrawal from repeated cocaine exposure. We hypothesize that this increases the reactivity of NAc neurons to glutamate inputs from cortex and limbic structures, facilitating the ability of these inputs to trigger cocaine seeking and thus contributing to the persistent vulnerability to relapse that characterizes addiction.     

Animal Models of Addiction and Neuropsychiatric Disorders and Their Role in Drug Discovery: Honoring the Legacy of Athina Markou

Each of the co-authors worked with Athina Markou, at different stages of our careers and in different capacities, to develop, optimize, and use animal models of drug addiction and, more generally, mental health disorders such as anxiety, depression, and schizophrenia. Here, we briefly summarize some of our work with Athina, primarily involving the use of the intracranial self-stimulation and intravenous drug self-administration procedures. This work established that excessive consumption of addictive drugs can induce profound dysfunction in brain reward circuits. Such drug-induced reward deficits are likely to play a key role in precipitating the emergence of compulsive drug-seeking behaviors. We also summarize findings suggesting that perturbations in glutamatergic transmission contribute to brain reward deficits in drug-dependent animals and that metabotropic glutamate receptors are potential targets for the development of novel medications to facilitate long-term drug abstinence and prevention of relapse.