The past two decades have witnessed a dramatic accumulation of evidence indicating that the excitatory amino acid glutamate plays an important role in drug addiction and alcoholism. The purpose of ...this review is to summarize findings on glutamatergic substrates of addiction, surveying data from both human and animal studies. The effects of various drugs of abuse on glutamatergic neurotransmission are discussed, as are the effects of pharmacological or genetic manipulation of various components of glutamate transmission on drug reinforcement, conditioned reward, extinction, and relapse-like behavior. In addition, glutamatergic agents that are currently in use or are undergoing testing in clinical trials for the treatment of addiction are discussed, including acamprosate,
N-acetylcysteine, modafinil, topiramate, lamotrigine, gabapentin and memantine. All drugs of abuse appear to modulate glutamatergic transmission, albeit by different mechanisms, and this modulation of glutamate transmission is believed to result in long-lasting neuroplastic changes in the brain that may contribute to the perseveration of drug-seeking behavior and drug-associated memories. In general, attenuation of glutamatergic transmission reduces drug reward, reinforcement, and relapse-like behavior. On the other hand, potentiation of glutamatergic transmission appears to facilitate the extinction of drug-seeking behavior. However, attempts at identifying genetic polymorphisms in components of glutamate transmission in humans have yielded only a limited number of candidate genes that may serve as risk factors for the development of addiction. Nonetheless, manipulation of glutamatergic neurotransmission appears to be a promising avenue of research in developing improved therapeutic agents for the treatment of drug addiction and alcoholism.
Rationale
The number of synthetic derivatives of cathinone, the primary psychoactive alkaloid found in
Catha edulis
(khat), has risen exponentially in the past decade. Synthetic cathinones ...(frequently referred to as “bath salts”) produce adverse cognitive and behavioral sequelae, share similar pharmacological mechanisms of action with traditional psychostimulants, and may therefore trigger similar cellular events that give rise to neuroinflammation and neurotoxicity.
Objectives
In this review, we provide a brief overview of synthetic cathinones, followed by a summary of cognitive deficits in animals and humans that have been documented following acute or repeated exposure. We also summarize growing evidence from in vitro and in vivo studies for synthetic cathinone-induced neurotoxicity, and provide a working hypothetic model of potential cellular mechanisms.
Results
Synthetic cathinones produce varying effects on markers of monoaminergic terminal function and can increase the formation of reactive oxygen and nitrogen species, induce apoptotic signaling, and cause neurodegeneration and cytotoxicity. We hypothesize that these effects result from biochemical events similar to those induced by traditional psychostimulants. However, empirical evidence for the ability of synthetic cathinones to induce neuroinflammatory processes is currently lacking.
Conclusions
Like their traditional psychostimulant counterparts, synthetic cathinones appear to induce neurocognitive dysfunction and cytotoxicity, which are dependent on drug type, dose, frequency, and time following exposure. However, additional studies on synthetic cathinone-induced neuroinflammation are clearly needed, as are investigations into the neurochemical and neuroimmune mechanisms underlying their neurotoxic effects. Such endeavors may lead to novel therapeutic avenues to promote recovery in habitual synthetic cathinone users.
Historically, most pharmacological approaches to the treatment of addictive disorders have utilized either substitution-based methods (i.e., nicotine replacement or opioid maintenance) or have ...targeted monoaminergic or endogenous opioidergic neurotransmitter systems. However, substantial evidence has accumulated indicating that ligands acting on glutamatergic transmission are also of potential utility in the treatment of drug addiction, as well as various behavioral addictions such as pathological gambling. The purpose of this review is to summarize the pharmacological mechanisms of action and general clinical efficacy of glutamatergic medications that are currently approved or are being investigated for approval for the treatment of addictive disorders. Medications with effects on glutamatergic transmission that will be discussed include acamprosate, N-acetylcysteine,
d-cycloserine, gabapentin, lamotrigine, memantine, modafinil, and topiramate. We conclude that manipulation of glutamatergic neurotransmission is a relatively young but promising avenue for the development of improved therapeutic agents for the treatment of drug and behavioral addictions.
► Glutamate plays a critical role in both drug and behavioral addictions. ► Medications with glutamatergic actions show promise for addiction treatment. ► Mechanisms of action and clinical efficacy of glutamatergic medications are reviewed.
Glutamate plays a pivotal role in regulating drug self-administration and drug-seeking behavior, and the past decade has witnessed a substantial surge of interest in the role of Group I metabotropic ...glutamate receptors (mGlu
1 and mGlu
5 receptors) in mediating these behaviors. As will be reviewed here, Group I mGlu receptors are involved in normal and drug-induced synaptic plasticity, drug reward, reinforcement and relapse-like behaviors, and addiction-related cognitive processes such as maladaptive learning and memory, behavioral inflexibility, and extinction learning. Animal models of addiction have revealed that antagonists of Group I mGlu receptors, particularly the mGlu
5 receptor, reduce self-administration of virtually all drugs of abuse. Since inhibitors of mGlu5 receptor function have now entered clinical trials for other medical conditions and appear to be well-tolerated, a key question that remains unanswered is — what changes in cognition are produced by these compounds that result in reduced drug intake and drug-seeking behavior? Finally, in contrast to mGlu
5 receptor antagonists, recent studies have indicated that positive allosteric modulation of mGlu
5 receptors actually enhances synaptic plasticity and improves various aspects of cognition, including spatial learning, behavioral flexibility, and extinction of drug-seeking behavior. Thus, while inhibition of Group I mGlu receptor function may reduce drug reward, reinforcement, and relapse-related behaviors, positive allosteric modulation of the mGlu5 receptor subtype may actually enhance cognition and potentially reverse some of the cognitive deficits associated with chronic drug use.
Opioid use disorders are characterized in part by impairments in social functioning. Previous research indicates that laboratory rats, which are frequently used as animal models of addiction‐related ...behaviors, are capable of prosocial behavior. For example, under normal conditions, when a ‘free’ rat is placed in the vicinity of rat trapped in a plastic restrainer, the rat will release or ‘rescue’ the other rat from confinement. The present study was conducted to determine the effects of heroin on prosocial behavior in rats. For 2 weeks, rats were given the opportunity to rescue their cagemate from confinement, and the occurrence of and latency to free the confined rat was recorded. After baseline rescuing behavior was established, rats were randomly selected to self‐administer heroin (0.06 mg/kg/infusion i.v.) or sucrose pellets (orally) for 14 days. Next, rats were retested for rescuing behavior once daily for 3 days, during which they were provided with a choice between freeing the trapped cagemate and continuing to self‐administer their respective reinforcer. Our results indicate that rats self‐administering sucrose continued to rescue their cagemate, whereas heroin rats chose to self‐administer heroin and not rescue their cagemate. These findings suggest that rats with a history of heroin self‐administration show deficits in prosocial behavior, consistent with specific diagnostic criteria for opioid use disorder. Behavioral paradigms providing a choice between engaging in prosocial behavior and continuing drug use may be useful in modeling and investigating the neural basis of social functioning deficits in opioid addiction.
Rats can exhibit prosocial behavior as evidenced by releasing their cagemate trapped in a plastic restrainer. Rats with a history of heroin, but not sucrose, self‐administration fail to exhibit this behavior when provided with the opportunity to continue self‐administration and/or release its cagemate. These findings indicate deficits in prosocial behavior in rodent models of heroin use.
Cue-induced drug craving progressively intensifies after withdrawal from self-administration of cocaine, methamphetamine, and other drugs of abuse, a phenomenon termed incubation of craving. For ...cocaine and methamphetamine, expression of incubated craving ultimately depends on strengthening of nucleus accumbens (NAc) synapses through an accumulation of high conductance Ca
-permeable AMPA receptors (CP-AMPARs) that is detectable with electrophysiological approaches. This study sought to further characterize glutamate receptor adaptations in NAc core during methamphetamine incubation. Previous biochemical studies revealed that the CP-AMPARs accumulating after cocaine incubation are mainly homomeric GluA1 receptors and that their accumulation is reflected by increased cell surface GluA1. Here, for methamphetamine, we observed no significant change in surface or total GluA1 (GluA2 and GluA3 were also unchanged). Nonetheless, GluA1 translation was elevated after incubation of methamphetamine craving, as recently found for cocaine. Additionally, for cocaine, we previously observed a withdrawal-dependent decrease in mGlu1 surface expression that precedes and enables CP-AMPAR accumulation and incubation of craving, reflecting weakening of mGlu1-dependent mechanisms that normally limit synaptic CP-AMPAR levels in the NAc core. Here, we observed no change in surface or total mGlu1 protein or its coupling to Homer scaffolding proteins after methamphetamine withdrawal, nor did elevation of mGlu1 tone through repeated injections of an mGlu1-positive allosteric modulator delay incubation of craving. These findings suggest a common role for increased GluA1 translation, but not decreased mGlu1 function, in the incubation of methamphetamine and cocaine craving. We speculate that increased GluA1 translation near synapses may drive formation and synaptic insertion of homomeric GluA1 receptors in the absence of detectable changes in GluA1 protein levels.
•Viral-mediated inhibition of nucleus accumbens core (NAc core) NF-κB signaling suppresses cue-motivated cocaine seeking in male, but not female, rats.•Inhibition of NAc core NF-κB signaling does not ...significantly alter cue-motivated sucrose seeking.•Suppression of NAc core NF-κB signaling decreases NAc core, but not NAcSh, MMP-9 expression in males but not females.•Male rats exhibit greater NAc core and NAcSh MMP-9 expression compared to females.
Chronic drug self-administration and withdrawal are associated with distinct neuroimmune adaptations that may increase drug craving and relapse vulnerability in humans. The nuclear factor kappa-B (NF-κB) pathway is a critical regulator of many immune- and addiction-related genes such as the extracellular matrix enzyme matrix metalloproteinase-9 (MMP-9), which is a known modulator of learning, memory, and synaptic plasticity. While some studies suggest striatal NF-κB signaling may regulate drug-conditioned behavior, no studies to date have examined whether NF-κB signaling within the nucleus accumbens core (NAc core) alters downstream neuroimmune function and cue-motivated cocaine seeking following a period of forced abstinence, whether any effects are specific to cocaine over other reinforcers, or whether sex differences exist. Here, we examined whether viral-mediated knockdown of the p65 subunit of NF-κB within the NAc core would alter MMP-9 expression and cue-induced cocaine- and sucrose-seeking behavior following a period of forced abstinence in male and female rats. We demonstrate that NAc core p65 knockdown results in a significant decrease in cue-induced cocaine seeking in males but not females. This effect was specific to cocaine, as p65 knockdown did not significantly affect cue-induced sucrose seeking in either males or females. Moreover, we demonstrate that males express higher levels of MMP-9 within the NAc core and nucleus accumbens shell (NAcSh) compared to females, and that p65 knockdown significantly decreases MMP-9 in the NAc core of males but not females among cocaine cue-exposed animals. Altogether, these results suggest that NAc core NF-κB signaling exerts modulatory control over cue-motivated drug-seeking behavior and downstream neuroimmune function in a sex-specific manner. These findings highlight the need to consider sex as an important biological variable when examining immunomodulatory mechanisms of cocaine seeking.
A leading crisis in the United States is the opioid use disorder (OUD) epidemic. Opioid overdose deaths have been increasing, with over 100,000 deaths due to overdose from April 2020 to April 2021. ...This paper presents a mathematical model to address illicit OUD (IOUD), initiation, casual use, treatment, relapse, recovery, and opioid overdose deaths within an epidemiological framework. Within this model, individuals remain in the recovery class unless they relapse back to use and due to the limited availability of specialty treatment facilities for individuals with OUD, a saturation treatment function was incorporated. Additionally, a casual user class and its corresponding specialty treatment class were incorporated. We use both heroin and all-illicit opioids datasets to find parameter estimates for our models. Bistability of equilibrium solutions was found for realistic parameter values for the heroin-only dataset. This result implies that it would be beneficial to increase the availability of treatment. An alarming effect was discovered about the high overdose death rate: by 2046, the disorder-free equilibrium would be the only stable equilibrium. This consequence is concerning because it means the epidemic would end due to high overdose death rates. The IOUD model with a casual user class, its sensitivity results, and the comparison of parameters for both datasets, showed the importance of not overlooking the influence that casual users have in driving the all-illicit opioid epidemic. Casual users stay in the casual user class longer and are not going to treatment as quickly as the users of the heroin epidemic. Another result was that the users of the all-illicit opioids were going to the recovered class by means other than specialty treatment. However, the change in the relapse rate has more of an influence for those individuals than in the heroin-only epidemic. The results above from analyzing this model may inform health and policy officials, leading to more effective treatment options and prevention efforts.
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