Animal Models Of Drug Addiction Research Articles

Toluene-Induced Behavioral Sensitization is Attenuated by Voluntary Physical Exercise and Social Interaction

Toluene-based inhalants found in some common products, such as paint thinner or glues, may be used to induce intoxication. Though addiction may be one of its most detrimental consequences, treatment options are insufficient or limited. Environmental enrichment (EE) refers to housing conditions that enhance sensory, cognitive, and motor stimulation. This paradigm induces beneficial effects in a variety of animal models of brain disorders, and also in animal models of drug addiction. Previous studies have shown that toluene induces behavioral sensitization and that EE treatment can reduce this response. Since EE comprises a variety of elements, the aim of the present study was to group mice into five different types of EE-shaping housing conditions (4 weeks) and to identify which of them are key elements in attenuating toluene-induced behavioral sensitization. The experimental groups were: Standard housing with conspecifics; EE with conspecifics; Toys stimulation with conspecifics; Exercise wheels with conspecifics; and Wheel and toy isolated. Mice in Standard housing and previously exposed to toluene exhibited high locomotor activity, suggesting behavioral sensitization. When animals were exposed to toluene and then housed in EE with conspecifics or Exercise wheels with conspecifics conditions an attenuation of behavioral sensitization was observed ( p < 0.001; 100% and 75% effectiveness, respectively). Toy with conspecifics housing also reduced behavioral sensitization, but in a less proportion than the two previous mentioned treatments ( p < 0.002; 33.5% effectiveness). Mice in the Wheel and toy isolated housing did not show significant changes in the assessed behavior ( p = 0.061; 12.4% effectiveness). We suggest that exercise and social interaction are the key enriched main elements to attenuate toluene-induced behavioral sensitization. Our results advise preclinical strategies for inhalant abuse interventions based on social interactions and physical exercise. Also, they provide guidelines to develop experimental models with diverse environments and groups that lead us to understand the complexity of environmental enrichment.

Effects of β -caryophyllene, A Dietary Cannabinoid, in Animal Models of Drug Addiction.

β-caryophyllene (BCP) is a natural bicyclic sesquiterpene found in Cannabis and other plants. BCP is currently used as a food additive, although pharmacological studies suggest its potential therapeutic application for the treatment of certain brain disorders. The mechanisms of action of BCP remain uncertain, possibly including full agonism at the cannabinoid CB2 receptor (CB2R). The study aims to investigate BCP's potential as a new drug for the treatment of substance use disorders by reviewing preclinical studies with animal models. BCP has been investigated in behavioral paradigms, including drug self-administration, conditioned place preference, and intracranial self-stimulation; the drugs tested were cocaine, nicotine, alcohol, and methamphetamine. Remarkably, BCP prevented or reversed behavioral changes resulting from drug exposure. As expected, the mechanism of action entails CB2R activation, although this is unlikely to constitute the only molecular target to explain such effects. Another potential target is the peroxisome proliferator-activated receptor. Preclinical studies have reported promising results with BCP in animal models of substance use disorders. Further research, including studies in humans, are warranted to establish its therapeutic potential and its mechanisms of action.

Investigating the potential of mirtazapine to induce drug-seeking behavior in free-choice drinking mouse model

Addiction to various drugs and chemicals is a significant public health concern worldwide. Addiction to prescription medications has increased due to the psychoactive effects of these medications, their availability, low price, and the lack of legal consequences for abusers. One of such prescription medication is mirtazapine (MIRT). MIRT is an antidepressant that has recently been reported to be abused and could induce withdrawal symptoms in different case studies. No previous study has investigated its abuse potential in animal models of drug addiction. Here, we conducted a free-choice drinking paradigm to investigate voluntary drinking of MIRT at two different concentrations. Male BALB/c mice were given unlimited access to two water bottles for five days before being divided into three groups: the first group had free access to two water bottles. The second group (MIRT10) and the third group (MIRT20) was allowed unlimited choice to one bottle of water and one bottle of MIRT at concentrations of 0.03 and 0.06 mg/mL, respectively. The average daily MIRT intake in the MIRT20 group was significantly higher on all tested days than that in the MIRT10 group. Moreover, mice in the MIRT20 group preferred to self-administer MIRT over water, indicating that MIRT can induce drug-seeking behavior. To further investigate the addictive potential of MIRT and its possible deterioration of memory and recognition, as reported with several known drugs of abuse, animals underwent a novel object recognition test. Mice in the MIRT20 group demonstrated significant deterioration in memory and recognition, indicating its effects on different brain regions involved in recognition, similar to other known drugs of abuse. The forced swimming test and tail suspension test were used to test MIRT-induced withdrawal symptoms after forced abstinence. After eight days of abstinence, mice in the MIRT20 group demonstrated significant depression-like symptoms in both the TST and FST, manifested by a significant increase in immobility time. MIRT was shown to induce drug-seeking behavior, deteriorate recognition, and cause withdrawal symptoms. This might confirm that MIRT has the potential to induce drug dependence and further studies are warranted to explore the neurobiological basis of MIRT-induced drug-seeking behavior.

Mirtazapine seeking and withdrawal in free‐choice drinking model

Drug addiction is one of the major public health concerns around the world. Addiction to prescription medications has been growing due to the psychoactive effects of these medications, availabilities, low price and no legal consequences were practiced against the abusers. One of these prescription medications is mirtazapine (MIRT). MIRT is an antidepressant that is recently reported in different case studies to be abused and could induce withdrawal symptoms. No previous study has investigated its abuse potential in animal model of drug addiction. Here we conducted a free‐choice drinking paradigm to investigate the voluntary drinking of MIRT in two different concentrations. Male bulb/c mice were allowed free access to two bottles of water for five days and their intake and body weight were recorded daily to calculate, based on consumed fluid, the concentrations of MIRT solutions. Mice were then divided into three groups; the first group had free access to two bottles of water. The second group (MIRT‐10) had free access to one bottle of water and one bottle of MIRT in a concentration that might yield daily intake of (10 mg/kg). The third group (MIRT‐20) had free access to one bottle of water and one bottle of MIRT in a concentration that might yield daily intake of (20 mg/kg). Interestingly, animals in MIRT‐20 showed a significant increase in MIRT intake as compared to MIRT‐10 group indicating that MIRT in higher doses can induce drug seeking effects. Following the drinking phase, and to confirm any effects on memory and recognition, animals underwent Novel Object Recognition test (NORT). Animals in MIRT‐20 showed a significant deterioration in the recognition of the novel objects as compared to the control and MIRT‐10 groups. This indicates the destructive nature of abusing MIRT on recognition and memory which is consistent with the effects of different drugs of abuse. All animals were then only exposed to two bottles of water to induce withdrawal symptoms. After five days of abstinence, animals in MIRT‐20 group showed a significant increase in the immobility time in forced swimming test and tail suspension test as compared to the control and MIRT‐10. This indicates that animals in MIRT‐20 might have depressive‐like symptoms as one of the indicators of withdrawal symptoms related to drug addiction. Together, MIRT was able to induce drug seeking behavior, deteriorate recognition, and cause withdrawal symptoms. This might confirm that MIRT has potential for inducing drug dependence and its use should be controlled by legal authorities. Further studies are needed to investigate the neurobiological basis of MIRT‐induced drug seeking behavior.

Quetiapine-Induced Place Preference in Mice: Possible Dopaminergic Pathway.

Quetiapine, an atypical antipsychotic, is effective in the management of schizophrenia, depression, and anxiety. Although quetiapine overdosage and misuse have been reported, its abuse potential has not been investigated in animals. In this study, the abuse potential of quetiapine was assessed based on the conditioned place preference (CPP) paradigm of drug addiction in a mouse model. First, mice received intraperitoneal injections of quetiapine (40, 80, or 120 mg/kg) every other day during the conditioning phase. In the second experiment, mice were pretreated with 0.03 mg/kg SKF-35866, a D1 receptor antagonist, before receiving saline or quetiapine (120 mg/kg) during the conditioning phase. No significant changes in time spent in the quetiapine-paired chamber were observed compared with time spent in the saline-paired chamber in mice treated with 40 or 80 mg/kg. In contrast, the preference to the quetiapine-paired chamber was significantly increased in mice treated with 120 mg/kg quetiapine, and this effect was blocked by SKF-35866 pretreatment. These results demonstrated, for the first time, the abuse potential of quetiapine in an animal model of drug addiction. Interestingly, this CPP-inducing effect was likely mediated by activating D1 receptors.

Influence of Prenatal Methamphetamine Abuse on the Brain.

Methamphetamine (MA), a psychostimulant, has become a serious problem in recent years. It is one of the most widely abused psychostimulants in the world. In the Czech Republic, ecstasy is the most commonly used non-cannabis drug, followed by hallucinogenic fungi, LSD, MA, cocaine, and finally heroin. The prevalence of the usage of all addictive substances is highest in the age category of 15–34. Approximately 17.2% of registered drug addicts, both male and female, in the Czech Republic use MA as their first-choice drug. This group consists mostly of women who are unemployed and addicted to MA (85%). Almost half of the addicted women switched to MA from other drugs in the course of pregnancy. Psychostimulants such as amphetamine and its synthetic derivate MA induce feelings of calm and happiness by suppressing anxiety and depression. When MA is abused for longer periods, it mimics symptoms of mania and can lead to the development of psychosis. MA is often abused for its anorectic effect, its simple preparation, and compared to heroin and cocaine, its low price. There are significant differences in the susceptibility of users to the stimulant, with reactions to MA fluctuating from person to person. Molecular mechanisms related to the variable response among users might represent an explanation for increased addiction-associated bipolar disorder and psychosis. Currently, there is limited information regarding genetic mechanisms linked to these disorders and the transmission of drug addiction. As such, animal models of drug addiction represent significant sources of information and assets in the research of these issues. The aim of this review is to summarize the mechanism of action of methamphetamine and its effect on pregnant addicted women and their children, including a detailed description of the anatomical structures involved.

Emergence of negative affect as motivation for drug taking in rats chronically self-administering cocaine.

The role of negative affect as a motivational factor in animal models of drug addiction has been underexplored in the context of cocaine self-administration. The present investigation studied the relationship between magnitude of affective response and quantity of cocaine consumed in order to clarify the affective components that drive drug use in a preclinical model. Rats self-administered (SA) cocaine 6h/day for 14 consecutive days while their ultrasonic vocalizations (USVs) were recorded. Animals displayed an increase in 50-kHz call rates (indicating positive affect) when their drug levels were rapidly rising and an increase in 22-kHz call rates (indicating negative affect) when forced to abstain. The rate of 50-kHz calls predicted drug consumption during the 1st week of SA, but not week two. Contrarily, there was a strongly predictive positive association between rate of 22-kHz calls and amount of drug consumed during the 2nd week of SA. Experimental results indicate that after chronic cocaine self-administration, negative affect emerges when animals are deprived of expected drug during withdrawal. Moreover, the increase in USVs indicating negative affect when deprived of drug was directly related to drug intake, concurrent with a decay in the direct relationship between USVs indicating positive affect and drug intake. The present preclinical support for the widely hypothesized shift from positive to negative affect as a salient motivational factor in human drug abuse adds to growing evidence of the unique value of rat USVs for understanding the role of emotion in drug addiction.

Psychostimulant-Induced Adaptations in Nucleus Accumbens Glutamatergic Transmission

Carrying different aspects of emotional and motivational signals, glutamatergic synaptic projections from multiple limbic and paralimbic brain regions converge to the nucleus accumbens (NAc), in which these arousing signals are processed and prioritized for behavioral output. In animal models of drug addiction, some key drug-induced alterations at NAc glutamatergic synapses underlie important cellular and circuit mechanisms that promote subsequent drug taking, seeking, and relapse. With the focus of cocaine, we review changes at NAc glutamatergic synapses that occur after different drug procedures and abstinence durations, and the behavioral impact of these changes.

Lasting reduction of nicotine-seeking behavior by chronic N-acetylcysteine during experimental cue-exposure therapy.

Nicotine-associated cues can trigger reinstatement in humans as well as in animal models of drug addiction. To date, no behavioral intervention or pharmacological treatment has been effective in preventing relapse in the long term. A large body of evidence indicates that N-acetylcysteine (N-AC) blunts the activation of glutamatergic (GLUergic) neurons in the nucleus accumbens (Nacc) associated with reinstatement. We evaluated the effect of an experimental cue exposure therapy (eCET) alone or in combination with N-AC to verify whether restoring GLU homeostasis enhances extinction of nicotine-associated cues. Rats were trained to associate discriminative stimuli with intravenous nicotine or saline self-administration. Reinforced response was followed by cue signals. After rats met the self-administration criteria, the lasting anti-relapse activity of i.p. N-AC or vehicle was assessed in three different experimental conditions after 14days of treatment: treatment+eCET; treatment+lever-presses extinction (LP-EXT); and treatment+abstinence. N-AC 100mg/kg, but not 60mg/kg, induced anti-relapse activity that persisted 50days after treatment only when paired with either LP-EXT or eCET with the greater activity found in the latter condition. To identify potential mechanisms for behavioral results, separate groups of rats that received either N-AC or vehicle+eCET were killed at different time points for Nacc Western-blot analysis. Seven days after treatment, chronic N-AC restored the expression of proteins crucial for GLU homeostasis, while at 50days, it increased the expression of type II metabotropic GLU receptors. These results suggest that N-AC treatment in combination with eCET may offer a novel strategy to prevent relapse in nicotine addiction.

A potential role for the gut microbiome in substance use disorders.

Pathological substance use disorders represent a major public health crisis with limited effective treatment options. While much work has been done to understand the neuronal signaling networks and intracellular signaling cascades associated with prolonged drug use, these studies have yielded few successful treatment options for substance use disorders. In recent years, there has been a growing interest to explore interactions between the peripheral immune system, the gut microbiome, and the CNS. In this review, we will present a summary of existing evidence, suggesting a potential role for gut dysbiosis in the pathogenesis of substance use disorders. Clinical evidence of gut dysbiosis in human subjects with substance use disorder and preclinical evidence of gut dysbiosis in animal models of drug addiction are discussed in detail. Additionally, we examine how changes in the gut microbiome and its metabolites may not only be a consequence of substance use disorders but may in fact play a role in mediating behavioral response to drugs of abuse. While much work still needs to be done, understanding the interplay of gut microbiome in substance use disorders may offer a promising avenue for future therapeutic development.

The Involvement of GLT‐1 in The Drug Seeking Like Effects of Pregabalin

Pregabalin is a GABA analogue that can bind with high affinity to voltage‐gated calcium channel to minimize excitatory neurotransmitters release. However, several case reports in Middle East and other parts of the world raised the concern of its abuse potential. We have shown in our previous studies that higher doses of pregabalin can cause drug seeking like effect in conditioned place preference (CPP) mouse model. In this study, we tested the involvement of glutamate transporter 1 (GLT‐1), which has a significant role in glutamate homeostasis and in mediating the rewarding and drug seeking effects of several drugs of abuse. Male BALB/c mice were randomly separated into four groups; the control group (C‐C) received saline in home cages and during the conditioning training. The second group (CEF‐C) received ceftriaxone (CEF) in a dose that was consistently shown to upregulate GLT‐1, (200 mg/kg, i.p.), in home cages and received saline during conditioning training. The third group (C‐Preg) received saline in home cages and were administered pregabalin in a dose that previously shown to induce CPP (60 mg/kg) during conditioning training. The last group (CEF‐Preg) received CEF in home cages and injections of pregabalin during the conditioning training. Consistent with our previous studies, the time spent in drug‐paired chamber as compared to the vehicle‐paired chamber was significantly increased in C‐Preg group. Importantly, CEF treatment for eight days blocked pregabalin induced CPP. These results showed for the first time the possible involvement of GLT‐1 in mediating the rewarding effects of pregablin in animal model of drug addiction.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Response dynamics of midbrain dopamine neurons and serotonin neurons to heroin, nicotine, cocaine, and MDMA

Heroin, nicotine, cocaine, and MDMA are abused by billions of people. They are believed to target midbrain dopamine neurons and/or serotonin neurons, but their effects on the dynamic neuronal activity remain unclear in behaving states. By combining cell-type-specific fiber photometry of Ca2+ signals and intravenous drug infusion, here we show that these four drugs of abuse profoundly modulate the activity of mouse midbrain dopamine neurons and serotonin neurons with distinct potency and kinetics. Heroin strongly activates dopamine neurons, and only excites serotonin neurons at higher doses. Nicotine activates dopamine neurons in merely a few seconds, but produces minimal effects on serotonin neurons. Cocaine and MDMA cause long-lasting suppression of both dopamine neurons and serotonin neurons, although MDMA inhibits serotonin neurons more profoundly. Moreover, these inhibitory effects are mediated through the activity of dopamine and serotonin autoreceptors. These results suggest that the activity of dopamine neurons and that of serotonin neurons are more closely associated with the drug's reinforcing property and the drug's euphorigenic property, respectively. This study also shows that our methodology may facilitate further in-vivo interrogation of neural dynamics using animal models of drug addiction.

Characterization of a Novel Series of D4 Dopamine Receptor Ligands Reveals Structure‐Activity Relationships for Selective Partial Agonists

D4 dopamine receptors (D4R) are G protein‐coupled receptors that play important roles in cognition, attention, and decision making. D4R ligands have been shown to alter cognition and behavior in animal models of drug addiction and variations in the DRD4 gene have been associated with novelty‐seeking and risk behavior, as well as ADHD. A better understanding of D4R‐mediated signaling is essential to understanding and treating D4R‐associated disorders, including substance abuse disorders. Despite its clinical implications, there are currently few compounds that selectively modulate the D4R receptor. Such compounds are important to study D4R function and identify favorable pharmacology for disease treatment. We created a small next‐generation compound library using computational modelling to design D4R ligands based on the parental scaffold of the prototypical D4R partial agonist A‐412997. This library was analyzed for D2R, D3R, and D4R activity using both agonist and antagonist radioligand competition binding assays and functional signaling readouts (β‐arrestin recruitment and cAMP inhibition). We found that substitutions on the piperidine and pyridine moieties, as well as modifications in linker length, led to several novel lead compounds with improved selectivity and potency, and varying degrees of agonist efficacy. Compounds were identified that displayed high binding affinity (<100 nM) for the D4R coupled with a >1000‐fold selectivity vs. the D3R and D2R. Importantly, these ligands displayed a range of agonist efficacies from highly efficacious partial agonists to full antagonists of the D4R. Interestingly, some compounds with similar binding affinities showed divergent functional efficacies, allowing for the generation of a preliminary structure‐activity relationship underlying functional efficacy. Further optimization may allow for directed tuning of functional efficacy that, when coupled to in vivo behavioral studies, may provide insight into the importance of relative efficacy levels as a means to treat D4R‐related disorders.Support or Funding InformationNINDS IRPThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

2. A role for DA Mechanisms in the ovBNST in Compulsive Responding in Rats

Out of the primary characteristics of drug addiction, compulsive drug seeking and intake is perhaps the most insidious, as it results in voluntary substance use despite negative physical and social consequences. For substances that are not considered classically addictive, such as sucrose, animal models of drug addiction may be utilized to explore reward-related synaptic changes underlying compulsive behavior similarly observed in binge eating disorders. Binge eaters, like those who compulsively seek out and consume drugs, continue to consume food despite the negative consequences. Based on previous work done by Maracle (2012), we examined the effects of modulating signalling in the oval bed nucleus of the stria terminalis (ovBNST) with a competitive D1 antagonist and its effects on compulsive intake. Prior to the intermitted access phase, subjects (N=66) underwent intracranial surgeries targeting the ovBNST. We utilized the same intermitted access cycle developed by (Avena, 2010). The subjects were randomly assigned to one of the four groups, 12-hr sucrose (primary experimental group),12-hr saccharine (sweet taste control group), 12-hr food only group, and a 24-hr sucrose/food group. After the 28-day cycle, subjects were then randomly assigned to received infusions of either saline or a selective D1 antagonist (SCH 23390) 10mins prior to testing. Compulsive responding for sucrose was then assessed using a conditioned suppression paradigm. It was hypothesized that infusing a DA antagonist into the ovBNST will decrease compulsive responding in subjects who demonstrate bingeing behaviour during the intermitted access phase, but will not affect animals that do not demonstrate bingeing behavior.

Animal models of drug addiction.

The development of animal models of drug reward and addiction is an essential factor for progress in understanding the biological basis of this disorder and for the identification of new therapeutic targets. Depending on the component of reward to be studied, one type of animal model or another may be used. There are models of reinforcement based on the primary hedonic effect produced by the consumption of the addictive substance, such as the self-administration (SA) and intracranial self-stimulation (ICSS) paradigms, and there are models based on the component of reward related to associative learning and cognitive ability to make predictions about obtaining reward in the future, such as the conditioned place preference (CPP) paradigm. In recent years these models have incorporated methodological modifications to study extinction, reinstatement and reconsolidation processes, or to model specific aspects of addictive behavior such as motivation to consume drugs, compulsive consumption or drug seeking under punishment situations. There are also models that link different reinforcement components or model voluntary motivation to consume (two-bottle choice, or drinking in the dark tests). In short, innovations in these models allow progress in scientific knowledge regarding the different aspects that lead individuals to consume a drug and develop compulsive consumption, providing a target for future treatments of addiction.

EIF2α-mediated translational control regulates the persistence of cocaine-induced LTP in midbrain dopamine neurons.

Recreational drug use leads to compulsive substance abuse in some individuals. Studies on animal models of drug addiction indicate that persistent long-term potentiation (LTP) of excitatory synaptic transmission onto ventral tegmental area (VTA) dopamine (DA) neurons is a critical component of sustained drug seeking. However, little is known about the mechanism regulating such long-lasting changes in synaptic strength. Previously, we identified that translational control by eIF2α phosphorylation (p-eIF2α) regulates cocaine-induced LTP in the VTA (Huang et al., 2016). Here we report that in mice with reduced p-eIF2α-mediated translation, cocaine induces persistent LTP in VTA DA neurons. Moreover, selectively inhibiting eIF2α-mediated translational control with a small molecule ISRIB, or knocking down oligophrenin-1-an mRNA whose translation is controlled by p-eIF2α-in the VTA also prolongs cocaine-induced LTP. This persistent LTP is mediated by the insertion of GluR2-lacking AMPARs. Collectively, our findings suggest that eIF2α-mediated translational control regulates the progression from transient to persistent cocaine-induced LTP.

Evidence of memory generalization in contextual locomotor sensitization induced by amphetamine

Addiction is a multifactorial disease that comprises physiological mechanisms of learning and memory. Addict subjects have intense plasticity in cortical and limbic circuits during intoxication, abstinence or even in drug seeking behavior. Locomotor sensitization is a classic animal model of drug addiction that mimics the changes that occur in the transition from drug use to drug addiction. Several studies have demonstrated the importance of contextual associative processes in this task. However, whether the mechanisms of sensitization are maintained and precise over the time remain an open question. Thus, the aim of this study was to investigate the importance of context in the maintenance and precision of locomotor sensitization across time. For this, male c57bl/6 mice were submitted to different contexts during the acquisition phase of amphetamine-induced locomotor sensitization. We found that after 3days of withdrawal, the expression of locomotor sensitization was context dependent, as characterized by an increased locomotion in the acquisition context (A), but not in the novel context (B). Surprisingly, when the expression of locomotor sensitization was tested after 28days of withdrawal, mice that acquired sensitization in the context A exhibited increased locomotion in both contexts (A and B), suggesting that memories associated with amphetamine drugs generalize following long periods of abstinence. The same generalization did not occur in mice sensitized in a well-known context (home cage). These results demonstrate, for the first time, the influence of memory generalization in amphetamine-induced locomotor sensitization. The evidence that memory generalization also occurs in sensitization provides new advances in the comprehension of the mechanisms underlying memory role in addiction process. Elucidating the mechanisms of amphetamine sensitization may shed some light on understanding the transition from drug use to addiction.

Epigenetic Mechanisms of Psychostimulant-Induced Addiction.

Psychostimulant-induced addiction involves potentially life-long behavioral abnormalities that are caused by repeated exposure to a drug of abuse in vulnerable individuals. The persistence of these behavioral changes suggests that long-lasting alterations in gene expression, particularly within the brain's reward regions, may contribute significantly to the addiction phenotype. An increasing number of works over the past decade have demonstrated the important role of epigenetic regulatory events in mediating the lasting effects of drugs of abuse (including psychostimulants, such as cocaine and amphetamine) in animal models of drug addiction. In this review, we have introduced the importance of epigenetic processes in regulating gene expression and have described the role that dynamic epigenetic changes may play in psychostimulant-induced addiction via long-lasting transcriptional changes following repeated drug exposure. We overviewed the evidence showing that repeated exposure to psychostimulants induces three major modes of epigenetic regulation within the brain's reward regions-histone modification, DNA methylation, and noncoding RNAs. In several instances, it has been possible to demonstrate directly the contribution of these epigenetic changes to psychostimulant-related behavioral abnormalities. Studies of epigenetics may also help to determine the role environmental factors play in an individual's vulnerability to addiction. Further studies are required to validate these epigenetic changes in human addiction and to evaluate the possibility of developing new diagnostic tests and more effective treatments for addiction syndromes.

∆FosB: A transcriptional regulator of stress and antidepressant responses

ΔFosB is a member of the Fos family of transcription factors. While other family members are induced rapidly but transiently in response to a host of acute stimuli, ΔFosB is unique in that it accumulates in response to repeated stimulation due to its unusual protein stability. Such prolonged induction of ΔFosB, within nucleus accumbens (NAc), a key brain reward region, has been most studied in animal models of drug addiction, with considerable evidence indicating that ΔFosB promotes reward and motivation and serves as a mechanism of drug sensitization and increased drug self-administration. In more recent years, prolonged induction of ∆FosB has also been observed within NAc in response to chronic administration of certain forms of stress. Increasing evidence indicates that this induction represents a positive, homeostatic adaptation to chronic stress, since overexpression of ∆FosB in this brain region promotes resilience to stress, whereas blockade of its activity promotes stress susceptibility. Chronic administration of several antidepressant medications also induces ∆FosB in the NAc, and this induction is required for the therapeutic-like actions of these drugs in mouse models. Validation of these rodent findings is the demonstration that depressed humans, examined at autopsy, display reduced levels of ∆FosB within the NAc. As a transcription factor, ΔFosB produces this behavioral phenotype by regulating the expression of specific target genes, which are under current investigation. These studies of ΔFosB are providing new insight into the molecular basis of depression and antidepressant action, which is defining a host of new targets for possible therapeutic development.

The "addicted" spine.

Units of dendritic branches called dendritic spines represent more than simply decorative appendages of the neuron and actively participate in integrative functions of “spinous” nerve cells thereby contributing to the general phenomenon of synaptic plasticity. In animal models of drug addiction, spines are profoundly affected by treatments with drugs of abuse and represent important sub cellular markers which interfere deeply into the physiology of the neuron thereby providing an example of the burgeoning and rapidly increasing interest in “structural plasticity”. Medium Spiny Neurons (MSNs) of the Nucleus Accumbens (Nacc) show a reduced number of dendritic spines and a decrease in TH-positive terminals upon withdrawal from opiates, cannabinoids and alcohol. The reduction is localized “strictly” to second order dendritic branches where dopamine (DA)-containing terminals, impinging upon spines, make synaptic contacts. In addition, long-thin spines seems preferentially affected raising the possibility that cellular learning of these neurons may be selectively hampered. These findings suggest that dendritic spines are affected by drugs widely abused by humans and provide yet another example of drug-induced aberrant neural plasticity with marked reflections on the physiology of synapses, system structural organization, and neuronal circuitry remodeling.