Search

Rationale: Stress during childhood or adolescence increases vulnerability to psychiatric disorders in adults. In adult rodents, the delayed effects of stress can increase anxiety-like behavior. These effects, however, can be prevented with post-stress administration of corticosterone (CORT). The effectiveness of CORT in preventing adolescent stress-induced emotional behavior alterations in adulthood has yet to be investigated. Objectives: Here, we investigated the interactions between early adolescent stress and exogenous corticosterone on adult social, aversive, and drug-seeking behavior in mice, which are translationally related to symptoms associated with psychiatric and substance abuse disorders. Methods and results: A single administration of CORT in drinking water (400ug/mL) for 24 h after social defeat or context fear conditioning prevents defeat-induced social avoidance, alters fear processing, prevents adolescent stress-induced anhedonia, and prevents stress-potentiated morphine place preference in adulthood. Exogenous CORT did not immediately prevent stress-induced potentiation of morphine conditioned-place preference in adolescents but did so in adult mice. However, when administered to adolescent mice, CORT also prevented the incubation of morphine-conditioned place preference into adulthood. Lastly, exogenous CORT administration blunted endogenous corticosterone but was unrelated to freezing behavior during a fear test. Conclusions: This is the first demonstration of adolescent post-stress CORT promoting socio-emotional resilience and preventing drug-seeking behavior. Our data suggest elevated corticosterone after a stress experience promotes resilience for at least 40 days across the developmental transition from adolescence to adulthood and is effective for socio-emotional and drug-seeking behavior. These results are critical for understanding how adolescent stress impacts emotional and drug-seeking behavior into adulthood. [ABSTRACT FROM AUTHOR]

[Display omitted] • Methamphetamine induces gene expression changes in microglia that vary by phase of self-administration (maintenance; forced abstinence). • Methamphetamine induces morphological changes in microglia consistent with activation. • These transcriptional and morphological changes persist for up to 21 days after final exposure to methamphetamine. • Transcriptional analysis suggests possible involvement of microglia in regulation of neurotransmitter signaling. • PLX5622 treatment ablates microglia and increases methamphetamine-taking. • PLX5622 treatment during 21-day forced abstinence does not affect context-induced methamphetamine-seeking. Methamphetamine use disorder (MUD) is a chronic, relapsing disease that is characterized by repeated drug use despite negative consequences and for which there are currently no FDA-approved cessation therapeutics. Repeated methamphetamine (METH) use induces long-term gene expression changes in brain regions associated with reward processing and drug-seeking behavior, and recent evidence suggests that methamphetamine-induced neuroinflammation may also shape behavioral and molecular responses to the drug. Microglia, the resident immune cells in the brain, are principal drivers of neuroinflammatory responses and contribute to the pathophysiology of substance use disorders. Here, we investigated transcriptional and morphological changes in dorsal striatal microglia in response to methamphetamine-taking and during methamphetamine abstinence, as well as their functional contribution to drug-taking behavior. We show that methamphetamine self-administration induces transcriptional changes associated with protein folding, mRNA processing, immune signaling, and neurotransmission in dorsal striatal microglia. Importantly, many of these transcriptional changes persist through abstinence, a finding supported by morphological analyses. Functionally, we report that microglial ablation increases methamphetamine-taking, possibly involving neuroimmune and neurotransmitter regulation. In contrast, microglial depletion during abstinence does not alter methamphetamine-seeking. Taken together, these results suggest that methamphetamine induces both short and long-term changes in dorsal striatal microglia that contribute to altered drug-taking behavior and may provide valuable insights into the pathophysiology of MUD. [ABSTRACT FROM AUTHOR]

IntroductionGiven the rapid increase in teen vaping over recent years it is critical to understand mechanisms underlying addiction and relapse to tobacco use at this age. To evaluate the role of non-nicotine constituents in cigarette smoke, our lab has previously established a model of intravenous self-administration of aqueous cigarette smoke extract (CSE). We now compare the sensitivity of male adolescent and adult rats who have self-administered CSE or nicotine to reinstatement with the pharmacological stressor, yohimbine, with and without cues.MethodsAdolescents and adults, aged postnatal day (P) 34 and 84, were tested for the effect of yohimbine (0-2.5 mg/kg) on plasma corticosterone levels to establish a dose that was an effective stressor at both ages. Separate groups of animals were trained to lever press for food before beginning 1-hour drug self-administration sessions for nicotine or CSE (15 μg/kg/infusion nicotine content). Once stable responding was reached, drug was removed, and behavior extinguished. Drug-seeking behavior was reinstated with yohimbine, cues, or a combination of yohimbine and cues.ResultsAlthough adolescents and adults showed different dose-responses for yohimbine-induced corticosterone release, a dose of 2.5 mg/kg increased stress hormone levels at both ages. Whereas both ages displayed similar responding for CSE and nicotine, adolescents self-administered more CSE and nicotine as compared to adults. Cues and cues + stress reinstated responding to a greater extent in animals that had self-administered CSE, regardless of age.DiscussionThese findings suggest that non-nicotine tobacco smoke constituents influence later but not earlier stages of addiction in both adolescent and adult male rats.

IntroductionOver 50 years of approaching drug use from the “War on Drugs” has led to ignoring the systemic structural and social determinants of health, enforced drug use stigma, and damaging stereotypes of people who use drugs or are labeled as “drug-seeking,” and sorely failed to support those needing assistance.On philosophy of harm reduction and powerPeople who use drugs are often disenfranchised and pathologized by being labeled as “a drug addict,” which then serves as a rationalization for mistreatment by healthcare providers. This is in opposition to a harm-reduction approach. Harm reduction philosophy is an epistemic valuation necessary for drug use stigma and our moral obligation to reduce harm from interlocking systems of power that perpetuate harm.On drug-seeking, mistrust, and human rightsWe have encountered many clients who use drugs that report harmful interactions with healthcare providers. Harm reduction is an issue of health equity, social justice, and fundamental human rights. This paper presents three vignettes, the author’s experiences of being labeled as—and advocating for family members labeled as “drug-seeking.”DiscussionTo better serve as healthcare providers, workers must be equipped to work with people who use drugs and reinforce the social justice commitment against medical stigma, neglect, racism, and inadequate pain coverage and withdrawal treatment. Nurses and our epistemic lens can meet the challenge of complex intersectional issues affecting our use of power to develop more just and equitable health systems and advance our rebuilding of a trusting relationship with the people we serve.

IntroductionGiven the rapid increase in teen vaping over recent years it is critical to understand mechanisms underlying addiction and relapse to tobacco use at this age. To evaluate the role of non-nicotine constituents in cigarette smoke, our lab has previously established a model of intravenous self-administration of aqueous cigarette smoke extract (CSE). We now compare the sensitivity of male adolescent and adult rats who have self-administered CSE or nicotine to reinstatement with the pharmacological stressor, yohimbine, with and without cues.MethodsAdolescents and adults, aged postnatal day (P) 34 and 84, were tested for the effect of yohimbine (0–2.5 mg/kg) on plasma corticosterone levels to establish a dose that was an effective stressor at both ages. Separate groups of animals were trained to lever press for food before beginning 1-hour drug self-administration sessions for nicotine or CSE (15 μg/kg/infusion nicotine content). Once stable responding was reached, drug was removed, and behavior extinguished. Drug-seeking behavior was reinstated with yohimbine, cues, or a combination of yohimbine and cues.ResultsAlthough adolescents and adults showed different dose-responses for yohimbine-induced corticosterone release, a dose of 2.5 mg/kg increased stress hormone levels at both ages. Whereas both ages displayed similar responding for CSE and nicotine, adolescents self-administered more CSE and nicotine as compared to adults. Cues and cues + stress reinstated responding to a greater extent in animals that had self-administered CSE, regardless of age.DiscussionThese findings suggest that non-nicotine tobacco smoke constituents influence later but not earlier stages of addiction in both adolescent and adult male rats.

The incubation of cue-reinforced cocaine-seeking coincides with increased extracellular glutamate within the ventromedial prefrontal cortex (vmPFC). The vmPFC is comprised of two subregions that oppositely regulate drug-seeking, with infralimbic (IL) activity inhibiting, and prelimibic (PL) activity facilitating, drug-seeking. Thus, we hypothesized that increasing and decreasing endogenous glutamate within the IL would attenuate and potentiate, respectively, cue-reinforced drug-seeking behavior, with the converse effects observed upon manipulations of endogenous glutamate within the PL. Male Sprague-Dawley rats were trained to self-administer cocaine (0.25 mg/infusion; 6 h/day X 10 days), the delivery of which was signaled by a tone-light cue. Rats were then subdivided into 3 or 30 day withdrawal groups. For testing, rats were microinjected with vehicle, 20 mM of the mGlu2/3 agonist LY379268 (to lower endogenous glutamate), or 300 μM of the excitatory amino acid transporter inhibitor threo-β-benzyloxyaspartate (TBOA; to raise endogenous glutamate) into either the IL or PL (0.5 μl/side) and then given a 30-min test for cue-reinforced drug-seeking. Vehicle-infused rats exhibited incubated responding on the cocaine-associated lever. Neither LY379268 nor TBOA altered behavior at 3 days withdrawal, indicating that glutamate within neither subregion regulates cue-reinforced drug-seeking during early withdrawal. At 30 days withdrawal, intra-PL LY379268 microinjection significantly decreased drug-seeking behavior, while the effect was more modest when infused intra-IL. Interestingly, intra-IL TBOA attenuated incubated drug-seeking during protracted withdrawal, but did not affect behavior when infused intra-PL. These results argue that glutamate release within the PL in response to drug-seeking likely drives the manifestation of incubated cocaine-seeking during protracted withdrawal.

Drug abuse is considered a maladaptive pathology of emotional memory and is associated with craving and relapse induced by drug-associated stimuli or drugs. Reconsolidation is an independent memory process with a strict time window followed by the reactivation of drug-associated stimulus depending on the basolateral amygdala (BLA). Pharmacology or behavior treatment that disrupts the reconsolidation can effectively attenuate drug-seeking in addicts. Here, we hypothesized that heroin-memory reconsolidation requires cAMP-dependent protein kinase A (PKA) of BLA based on the fundamental effect of PKA in synaptic plasticity and memory process. After 10 days of acquisition, the rats underwent 11 days of extinction training and then received the intra-BLA infusions of the PKA inhibitor Rp-cAMPS at different time windows with/without a reactivation session. The results show that PKA inhibitor treatment in the reconsolidation time window disrupts the reconsolidation and consequently reduces cue-induced reinstatement, heroin-induced reinstatement, and spontaneous recovery of heroin-seeking behavior in the rats. In contrast, there was no effect on cue-induced reinstatement in the intra-BLA infusion of PKA inhibitor 6 h after reactivation or without reactivation. These data suggest that PKA inhibition disrupts the reconsolidation of heroin-associated memory, reduces subsequent drug seeking, and prevents relapse, which is retrieval-dependent, time-limited, and BLA-dependent.

Preclinical and human studies indicate psilocybin may reduce perseverant maladaptive behaviors, including nicotine and alcohol seeking. Such studies in the opioid field are lacking, though opioids are involved in more >50% of overdose deaths. Psilocybin is an agonist at the serotonin 2A receptor (5-HT 2A R), a well-documented target for modulation of drug seeking, and evidence suggests 5-HT 2A R agonists may dampen motivation for opioids. We sought to investigate the therapeutic efficacy of psilocybin in mediating cessation of opioid use and maintenance of long-lasting abstinence from opioid seeking behavior in a rat model of heroin self-administration (SA). Psilocybin or 5-HT 2A R antagonists ketanserin and volinanserin were administered systemically to rats prior to SA of 0.075 mg/kg/infusion of heroin, or relapse following forced abstinence. Psilocybin did not alter heroin taking, but a single exposure to 3.0 mg/kg psilocybin 4-24 hours prior to a relapse test blunted cue-induced heroin seeking. Conversely, 5-HT 2A R antagonists exacerbated heroin relapse. To begin to elucidate mechanisms of psilocybin, drug-naïve rats received psilocybin and/or ketanserin, and tissue was collected from the prefrontal cortex (PFC), a region critical for drug seeking and responsive to psilocybin, 24 hours later for RNA-sequencing. 3.0 mg/kg psilocybin regulated ~2-fold more genes in the PFC than 1.0 mg/kg, including genes involved in the cytoskeleton and cytokine signaling. Ketanserin blocked >90% of psilocybin-regulated genes, including the IL-17a cytokine receptor, Il17ra . Psychedelic compounds have reported anti-inflammatory properties, and therefore we performed a gene expression array to measure chemokine/cytokine molecules in the PFC of animals that displayed psilocybin-mediated inhibition of heroin seeking. Psilocybin regulated 4 genes, including Il17a , and a subset of genes correlated with relapse behavior. Selective inhibition of PFC IL-17a was sufficient to reduce heroin relapse. We conclude that psilocybin reduces heroin relapse and highlight IL-17a signaling as a potential downstream pathway of psilocybin that also reduces heroin seeking., Competing Interests: Competing Interests: We have no competing interests to disclose.

Background: α7 Nicotinic acetylcholine receptors are implicated in the reinstatement of drug-seeking, an important component of relapse. We showed previously that the α7 nicotinic acetylcholine receptor antagonist, methyllycaconitine, specifically attenuated morphine-primed reinstatement of conditioned place preference in rodents and this effect was mediated in the ventral hippocampus. Aims: The purpose of this study was to evaluate α7 nicotinic acetylcholine receptor antagonism in reinstatement of the conditioned place preference for the more widely abused opioid, heroin, and to compare the effect of α7 nicotinic acetylcholine receptor blockade on reinstatement of heroin-seeking and heroin self-administration in an intravenous self-administration model of addictive behaviour. Methods: Rats were trained to acquire heroin conditioned place preference or heroin self-administration; both followed by extinction of responding. Methyllycaconitine or saline was given prior to reinstatement of drug-primed conditioned place preference, or drug-prime plus cue-induced reinstatement of intravenous self-administration, using two protocols: without delivery of heroin in response to lever pressing to model heroin-seeking, or with heroin self-administration, using fixed and progressive ratio reward schedules, to model relapse. Results: Methyllycaconitine had no effect on acquisition of heroin conditioned place preference or lever-pressing for food rewards. Methyllycaconitine blocked reinstatement of heroin-primed conditioned place preference. Methyllycaconitine did not prevent drug-prime plus cue-induced reinstatement of heroin-seeking, reinstatement of heroin self-administration, or diminish the reinforcing effect of heroin. Conclusions: The α7 nicotinic acetylcholine receptor antagonist, methyllycaconitine, prevented reinstatement of the opioid conditioned place preference, consistent with a role for α7 nicotinic acetylcholine receptors in the retrieval of associative memories of drug liking. The lack of effect of methyllycaconitine in heroin-dependent rats in two intravenous self-administration models suggests that α7 nicotinic acetylcholine receptors do not play a role in later stages of heroin abuse. [ABSTRACT FROM AUTHOR]

Background: Alcohol and cigarettes are commonly used together, but little is known about their joint motivational impact. Cue reactivity studies have customarily examined alcohol and smoking cues in isolation, despite the potential for cues to elicit stronger motivational responses when combined. This study used a validated cue reactivity procedure (Choice Behavior Under Cued Conditions) systematically to disentangle the separate and joint effects of alcohol and cigarette cues on substance use motivation. Methods: Participants were 110 adults (Mage = 34.0, SD = 10.8) who consumed both cigarettes and alcohol. Participants completed 40 cue reactivity trials with four in vivo cue types: water, alcohol, cigarette, and combined cigarette and alcohol. Participants rated their craving prior to receiving opportunities to spend real money to gain access to the cues. Spending larger amounts of money increased the probability that the substance(s) would be available for consumption. When granted access, participants took one cigarette puff and/or sip of the beverage. A multimethod approach assessed three key motivational indices: craving, drug‐seeking (spending, latency to access the cue), and consumption (puff duration, alcohol consumed). Effects of cue type and rates of substance use (cigarettes per day, drinks per day, relative frequency of co‐use) were assessed using hierarchical linear models. Results: Both alcohol and smoking cues enhanced cue‐specific craving but not craving for the alternative substance. In a novel finding, combined cues elicited higher craving and greater spending than single‐drug cues. All drug cues elicited greater spending than water cues, and spending was moderated by the relative frequency of co‐use. Conclusions: We found that combined alcohol and cigarette cues provoke more powerful craving and drug‐seeking responses and, therefore, may be more motivationally potent among individuals who use multiple substances. [ABSTRACT FROM AUTHOR]

Rationale: Stress exposure has a lasting impact on motivated behavior and can exacerbate existing vulnerabilities for developing a substance use disorder. Several models have been developed to examine how stressful experiences shape drug reward. These range from locomotor sensitization and conditioned place preference to the propensity for drug self-administration or responding to drug-predictive cues. While self-administration studies are considered to have more translational relevance, most of the studies to date have been conducted in rats. Further, many self-administration studies are conducted in single-housed animals, adding the additional stressor of social isolation. Objectives: We sought to establish how chronic social defeat stress (CSDS) and social housing conditions impact cocaine self-administration and cocaine-seeking behaviors in C57BL/6 mice. Methods: We assessed self-administration behavior (cocaine or saline, 0.5 mg/kg/infusion) in C57BL/6 mice subjected to 10-day CSDS or in unstressed controls. Mice were housed either in pairs or in isolation during self-administration. We compared the effect of housing on acquisition of self-administration, seeking, extinction, drug-induced reinstatement, and after re-exposure to the social stressor. Results: Pair-housing during self-administration revealed increased social avoidance after CSDS is associated with decreased cocaine intake. In contrast, single-housing revealed stress-sensitive cocaine intake, with increased social avoidance after CSDS associated with increased early cocaine intake. Pair-, but not single-housed mice are susceptible to drug-induced reinstatement independent of CSDS history. Stress re-exposure sensitized cocaine-seeking in stressed single-housed mice. Conclusions: The social context surrounding cocaine intake can bidirectionally influence cocaine-related behaviors after psychosocial stress and should be considered when studying stress and drug cross-sensitization. [ABSTRACT FROM AUTHOR]

Introduction: Drug-seeking behavior (DSB) in the emergency department (ED) is a very common problem, yet there has been little quantitative study to date of such behavior.The goal of this study was to assess the frequency with which drug seeking patients in the ED use classic drug seeking behaviors to obtain prescription medication.Methods: We performed a retrospective chart review on patients in an ED case management program for DSB. We reviewed all visits by patients in the program that occurred during a 1-year period, and recorded the frequency of the following behaviors: complaining of headache, complaining of back pain, complaining of dental pain, requesting medication by name, requesting a refill of medication, reporting medications as having been lost or stolen, reporting 10/10 pain, reporting greater than 10/10 pain, reporting being out of medication, and requesting medication parenterally. These behaviors were chosen because they are described as “classic” for DSB in the existing literature.Results: We studied 178 patients from the case management program, who made 2,486 visits in 1 year. The frequency of each behavior was: headache 21.7%, back pain 20.8%, dental pain 1.8%, medication by name 15.2%, requesting refill 7.0%, lost or stolen medication 0.6%, pain 10/10 29.1%, pain greater than 10/10 1.8%, out of medication 9.5%, and requesting parenteral medication 4.3%. Patients averaged 1.1 behaviors per visit. Conclusion: Drug-seeking patients appear to exhibit “classically” described drug-seeking behaviors with only low to moderate frequency. Reliance on historical features may be inadequate when trying to assess whether or not a patient is drug-seeking. [West J Emerg Med. 2012;13(5):416-421.]

Inhalants, including volatile organic solvents such as toluene, continue to be one of the most prevalent, and often first substances abused by adolescents. Like other drugs of abuse, toluene affects the function of neurons within key brain reward circuits including the prefrontal cortex, ventral tegmental area, and nucleus accumbens. However, preclinical models used to study these toluene-induced adaptations generally employ passive exposure paradigms that do not mirror voluntary patterns of solvent exposure observed in humans. To address this shortcoming, we developed an inhalation chamber containing active and inactive nose pokes, cue lights, flow-through vaporizers, and software-controlled valves to test the hypothesis that rats will voluntarily self-administer toluene vapor. Following habituation and self-administration (SA) training rats achieve vapor concentrations associated with rewarding effects of toluene, and maintain responding for toluene vapor, but not for air. During extinction trials, rats showed an initial burst of drug-seeking behavior similar to that of other addictive drugs and then reduced responding to Air SA levels. Responding on the active nose poke recovered during cue-induced reinstatement but not following a single passive exposure to toluene vapor. The results from these studies establish a viable toluene SA protocol that will be useful in assessing toluene-induced changes in addiction neurocircuitry.

Abstract Pain physicians, more so than any other specialty, interact with a patient population that is significantly more likely to engage in violence. In this commentary on the article “Patient-on-Provider Violence in the Pain Clinic” by Judy George, we echo some of the points mentioned in the manuscript. There needs to be a better system in place to identify and to deal with problem patients seeking drugs. Although there has been a push recently to move away from opioids with a patient-specific multimodal analgesic treatment plan with a focus on interventional pain procedures, opioids are still a part of the pain physician’s practice. The medical community must stand behind ensuring these doctors and their staff can practice in an environment that is safe for them and the patients they are caring for. This response fully complies with ethical guidelines. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

Inhalants, including volatile organic solvents such as toluene, continue to be one of the most prevalent, and often first substances abused by adolescents. Like other drugs of abuse, toluene affects the function of neurons within key brain reward circuits including the prefrontal cortex, ventral tegmental area, and nucleus accumbens. However, preclinical models used to study these toluene-induced adaptations generally employ passive exposure paradigms that do not mirror voluntary patterns of solvent exposure observed in humans. To address this shortcoming, we developed an inhalation chamber containing active and inactive nose pokes, cue lights, flow-through vaporizers, and software-controlled valves to test the hypothesis that rats will voluntarily self-administer toluene vapor. Following habituation and self-administration (SA) training rats achieve vapor concentrations associated with rewarding effects of toluene, and maintain responding for toluene vapor, but not for air. During extinction trials, rats showed an initial burst of drug-seeking behavior similar to that of other addictive drugs and then reduced responding to Air SA levels. Responding on the active nose poke recovered during cue-induced reinstatement but not following a single passive exposure to toluene vapor. The results from these studies establish a viable toluene SA protocol that will be useful in assessing toluene-induced changes in addiction neurocircuitry. [ABSTRACT FROM AUTHOR]

Cocaine dependence is a psychiatric condition for which effective medications are still lacking. Published data indicate that an increase in nociceptin/orphanin FQ (N/OFQ) transmission by NOP receptor activation attenuates cocaine-induced place conditioning and the locomotor sensitization effects of cocaine. This suggests that the activation of the N/OFQ receptor (NOP) may attenuate the motivation for psychostimulants. To further explore this possibility, we investigated the effect of the potent and selective NOP receptor agonist Ro 64-6198 on cocaine intake under 1 h short access (ShA) and 6 h long access (LgA) operant self-administration conditions in rats. We used Marchigian Sardinian alcohol-preferring (msP) rats and Wistar control rats. msP rats were used because we recently found that this rat line, originally selected for excessive alcohol drinking and preference, exhibits a greater propensity to escalate cocaine self-administration following LgA training. msP rats are also characterized by innate overexpression of the N/OFQ-NOP system compared with Wistar rats. Wistar and msP rats both exhibited an increase in cocaine self-administration under LgA conditions, with a higher trend toward escalation in msP rats. In Wistar rats, the intraperitoneal administration of Ro 64-6198 (0. 1 and 3 mg/kg) significantly decreased ShA cocaine self-administration. In Wistar rats that underwent LgA cocaine self-administration training, Ro 64-6198 induced no significant effect either during the first hour of self-administration or after the entire 6 h session. In msP rats, Ro 64-6198 significantly reduced cocaine self-administration both under ShA conditions and in the first hour of the LgA session. At the end of the 6 h session, the effect of Ro 64-6198 was no longer observed in msP rats. The highest dose of Ro 64-6198 (3 mg/kg) did not affect saccharin self-administration in msP rats but reduced saccharin self-administration in Wistar rats. Altogether, these data suggest that NOP receptor activation attenuates cocaine self-administration, and this effect tends to be more pronounced in a rat line with innately higher NOP receptor expression and that more robustly escalates cocaine intake.

In abstinent drug addicts, cues formerly associated with drug-taking experiences gain relapse-inducing potency (‘incubate’) over time. Animal models of incubation may help develop treatments to prevent relapse, but these models have ubiquitously focused on the role of conditioned stimuli (CSs) signaling drug delivery. Discriminative stimuli (DSs) are unique in that they exert stimulus-control over both drug taking and drug seeking behavior and are difficult to extinguish. For this reason, incubation of the excitatory effects of DSs that signal drug availability, not yet examined in preclinical studies, could be relevant to relapse prevention. We trained rats to self-administer cocaine (or palatable food) under DS control, then investigated DS-controlled incubation of craving, in the absence of drug-paired CSs. DS-controlled cocaine (but not palatable food) seeking incubated over 60 days of abstinence and persisted up to 300 days. Understanding the neural mechanisms of this DS-controlled incubation holds promise for drug relapse treatments.

• IC and NAc core were activated following cue-induced morphine-seeking behavior. • Inhibition of IC→NAc core input blocked the reinstatement of expressed CPP. • Inhibition of glutamatergic IC→NAc core input suppressed CPP reinstatement. • Reinstatement of cue-associated drug-seeking require glutamatergic IC→NAc core input. Recently, the insular cortex (IC) was identified as part of the neuronal circuit responsible for the reward expectations in cue-triggered behaviours. Moreover, there are evidences that connections between the IC and the ventral striatum, particularly with the nucleus accumbens (NAc), may mediate the retrieval and performance of actions based on incentive memory. However, the precise role of the IC-NAc connections in cue-related drug-seeking behaviour remains unclear. We used the morphine-induced conditioned place preference (CPP) paradigm to assess the formation and relapse of cue-related drug-seeking. cFos immunostaining was used to determine the activation of the brain regions. Chemogenetic and optogenetic methods were used to manipulate the activity of IC-to-NAc projection neurons. The result showed that neurons in IC and NAc core but not NAc shell were activated following cue-induced morphine-seeking behaviour. Negligible effect of inhibition of IC-to-NAc core projection (IC→NAc core) on morphine CPP expression, whereas chemogenetic inactivation of this projection potently blocked the reinstatement of expressed morphine CPP. Furthermore, optogenetic inhibition of glutamatergic IC→NAc core inputs significant suppressed the CPP reinstatement without significant effect on CPP expression. We demonstrated here, for the first time, that IC→NAc core glutamatergic projection is required for the reinstatement of cue-associated drug seeking behaviour in mice. The present study provide insights into modulations of relapse of cue-associated drug-seeking behaviour following repeated overexposure to opioids in humans. [ABSTRACT FROM AUTHOR]

Rationale: Evidence indicates that drug-paired stimuli can evoke drug-craving leading to drug-seeking and repeated relapse periods can influence drug-seeking behaviors. Objectives: The present study examined (1) the effect of an interaction between repeated deprivation cycles and excitatory conditioning stimuli (CS+) on ethanol (EtOH)-seeking; (2) the effects of EtOH-paired cue-exposure in a non-drug-paired environment on subsequent conditioning in a drug-paired environment; and (3) the temporal effects of conditioned cues on subsequent EtOH-seeking. Methods: Adult female alcohol-preferring (P) rats were exposed to three conditioned odor cues; CS+ associated with EtOH self-administration, CS− associated with the absence of EtOH (extinction training), and a neutral stimulus (CS0) presented in a neutral non-drug-paired environment. The rats underwent four deprivation cycles or were non-deprived, following extinction they were maintained in a home cage for an EtOH-free period, and then exposed to no cue, CS+, CS−, or CS0 to assess the effect of the conditioned cues on EtOH-seeking behavior. Results: Repeated deprivations enhanced and prolonged the duration of CS+ effects on EtOH-seeking. Presentation of the CS− in a non-drug-paired environment blocked the ability of a CS+ to enhance EtOH-seeking in a drug-paired environment. Presentation of the CS+ or CS− in a non-drug-paired environment 2 or 4 h earlier significantly altered EtOH-seeking. Conclusion: Results indicated an interaction between repeated deprivation cycles and CS+ resulted in a potentiation of CS+ evoked EtOH-seeking. In addition, a CS− may have therapeutic potential by providing prophylactic protection against relapse behavior in the presence of cues in the drug-using environment. [ABSTRACT FROM AUTHOR]

• We propose a "competitive" model to account for how striatal output pathways shape behavior. • This model draws on knowledge of synaptic plasticity to link action selection to reinforcement. • This model also provides insight into how imbalances in these pathways may contribute to compulsive and avoidant disorders. The direct and indirect pathway striatal medium spiny neurons (dMSNs and iMSNs) have long been linked to action selection, but the precise roles of these neurons in this process remain unclear. Here, we review different models of striatal pathway function, focusing on the classic " go/no-go " model which posits that dMSNs facilitate movement while iMSNs inhibit movement, and the " complementary " model, which argues that dMSNs facilitate the selection of specific actions while iMSNs inhibit potentially conflicting actions. We discuss the merits and shortcomings of these models and propose a " competitive " model to explain the contribution of these two pathways to behavior. The " competitive " model argues that rather than inhibiting conflicting actions, iMSNs are tuned to the same actions that dMSNs facilitate, and the two populations "compete" to determine the animal's behavioral response. This model provides a theoretical explanation for how these pathways work together to select actions. In addition, it provides a link between action selection and behavioral reinforcement, via modulating synaptic strength at inputs onto dMSNs and iMSNs. Finally, this model makes predictions about how imbalances in the activity of these pathways may underlie behavioral traits associated with psychiatric disorders. Understanding the roles of these striatal pathways in action selection may help to clarify the neuronal mechanisms of decision-making under normal and pathological conditions. [ABSTRACT FROM AUTHOR]

Abstract Kappa opioid receptor (KOPr) agonists have preclinical anti-cocaine and antinociceptive effects. However, adverse effects including dysphoria, aversion, sedation, anxiety and depression limit their clinical development. MP1104, an analogue of 3-iodobenzoyl naltrexamine, is a potent dual agonist at KOPr and delta opioid receptor (DOPr), with full agonist efficacy at both these receptors. In this study, we evaluate the ability of MP1104 to modulate cocaine-induced behaviors and side-effects preclinically. In male Sprague-Dawley rats trained to self-administer cocaine, MP1104 (0.3 and 1 mg/kg) reduced cocaine-primed reinstatement of drug-seeking behavior and caused significant downward shift of the dose-response curve in cocaine self-administration tests (0.3 and 0.6 mg/kg). The anti-cocaine effects exerted by MP1104 are in part due to increased dopamine (DA) uptake by the dopamine transporter (DAT) in the dorsal striatum (dStr) and nucleus accumbens (NAc). MP1104 (0.3 and 0.6 mg/kg) showed no significant anxiogenic effects in the elevated plus maze, pro-depressive effects in the forced swim test, or conditioned place aversion. Furthermore, pre-treatment with a DOPr antagonist, led to MP1104 producing aversive effects. This data suggests that the DOPr agonist actions of MP1104 attenuate the KOPr-mediated aversive effects of MP1104. The overall results from this study show that MP1104, modulates DA uptake in the dStr and NAc, and exerts potent anti-cocaine properties in self-administration tests with reduced side-effects compared to pure KOPr agonists. This data supports the therapeutic development of dual KOPr/DOPr agonists to reduce the side-effects of selective KOPr agonists. This article is part of the Special Issue entitled 'Opioid Neuropharmacology: Advances in treating pain and opioid addiction'. Highlights • MP1104 is a 3-Iodobenzoyl naltrexamine analogue with potent mixed kappa and delta opioid agonist activity in vivo. • MP1104 attenuates drug-primed reinstatement of drug-seeking via kappa opioid receptor dependent mechanisms. • MP1104 increases dopamine transporter uptake of dopamine in the dorsal striatum and nucleus accumbens. • Delta opioid receptor activity counteracts the kappa opioid side-effects of MP1104. [ABSTRACT FROM AUTHOR]

Cocaine dependence is a psychiatric condition for which effective medications are still lacking. Published data indicate that an increase in nociceptin/orphanin FQ (N/OFQ) transmission by NOP receptor activation attenuates cocaine-induced place conditioning and the locomotor sensitization effects of cocaine. This suggests that the activation of the N/OFQ receptor (NOP) may attenuate the motivation for psychostimulants. To further explore this possibility, we investigated the effect of the potent and selective NOP receptor agonist Ro 64-6198 on cocaine intake under 1 h short access (ShA) and 6 h long access (LgA) operant self-administration conditions in rats. We used Marchigian Sardinian alcohol-preferring (msP) rats and Wistar control rats. msP rats were used because we recently found that this rat line, originally selected for excessive alcohol drinking and preference, exhibits a greater propensity to escalate cocaine self-administration following LgA training. msP rats are also characterized by innate overexpression of the N/OFQ-NOP system compared with Wistar rats. Wistar and msP rats both exhibited an increase in cocaine self-administration under LgA conditions, with a higher trend toward escalation in msP rats. In Wistar rats, the intraperitoneal administration of Ro 64-6198 (0. 1 and 3 mg/kg) significantly decreased ShA cocaine self-administration. In Wistar rats that underwent LgA cocaine self-administration training, Ro 64-6198 induced no significant effect either during the first hour of self-administration or after the entire 6 h session. In msP rats, Ro 64-6198 significantly reduced cocaine self-administration both under ShA conditions and in the first hour of the LgA session. At the end of the 6 h session, the effect of Ro 64-6198 was no longer observed in msP rats. The highest dose of Ro 64-6198 (3 mg/kg) did not affect saccharin self-administration in msP rats but reduced saccharin self-administration in Wistar rats. Altogether, these data suggest that NOP receptor activation attenuates cocaine self-administration, and this effect tends to be more pronounced in a rat line with innately higher NOP receptor expression and that more robustly escalates cocaine intake. [ABSTRACT FROM AUTHOR]

Pain physicians, more so than any other specialty, interact with a patient population that is significantly more likely to engage in violence. In this commentary on the article "Patient-on-Provider Violence in the Pain Clinic" by Judy George, we echo some of the points mentioned in the manuscript. There needs to be a better system in place to identify and to deal with problem patients seeking drugs. Although there has been a push recently to move away from opioids with a patient-specific multimodal analgesic treatment plan with a focus on interventional pain procedures, opioids are still a part of the pain physician's practice. The medical community must stand behind ensuring these doctors and their staff can practice in an environment that is safe for them and the patients they are caring for. This response fully complies with ethical guidelines. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors. [ABSTRACT FROM AUTHOR]

Introduction: Over 50 years of approaching drug use from the "War on Drugs" has led to ignoring the systemic structural and social determinants of health, enforced drug use stigma, and damaging stereotypes of people who use drugs or are labeled as "drug-seeking," and sorely failed to support those needing assistance., On Philosophy of Harm Reduction and Power: People who use drugs are often disenfranchised and pathologized by being labeled as "a drug addict," which then serves as a rationalization for mistreatment by healthcare providers. This is in opposition to a harm-reduction approach. Harm reduction philosophy is an epistemic valuation necessary for drug use stigma and our moral obligation to reduce harm from interlocking systems of power that perpetuate harm., On Drug-Seeking Mistrust and Human Rights: We have encountered many clients who use drugs that report harmful interactions with healthcare providers. Harm reduction is an issue of health equity, social justice, and fundamental human rights. This paper presents three vignettes, the author's experiences of being labeled as-and advocating for family members labeled as "drug-seeking.", Discussion: To better serve as healthcare providers, workers must be equipped to work with people who use drugs and reinforce the social justice commitment against medical stigma, neglect, racism, and inadequate pain coverage and withdrawal treatment. Nurses and our epistemic lens can meet the challenge of complex intersectional issues affecting our use of power to develop more just and equitable health systems and advance our rebuilding of a trusting relationship with the people we serve., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor JC declared a shared affiliation with the authors at the time of review., (Copyright © 2023 Febres-Cordero, Shasanmi-Ellis and Sherman.)

The incubation of cue-reinforced cocaine-seeking coincides with increased extracellular glutamate within the ventromedial prefrontal cortex (vmPFC). The vmPFC is comprised of two subregions that oppositely regulate drug-seeking, with infralimbic (IL) activity inhibiting, and prelimibic (PL) activity facilitating, drug-seeking. Thus, we hypothesized that increasing and decreasing endogenous glutamate within the IL would attenuate and potentiate, respectively, cue-reinforced drug-seeking behavior, with the converse effects observed upon manipulations of endogenous glutamate within the PL. Male Sprague-Dawley rats were trained to self-administer cocaine (0.25 mg/infusion; 6 h/day X 10 days), the delivery of which was signaled by a tone-light cue. Rats were then subdivided into 3 or 30 day withdrawal groups. For testing, rats were microinjected with vehicle, 20 mM of the mGlu2/3 agonist LY379268 (to lower endogenous glutamate), or 300 μM of the excitatory amino acid transporter inhibitor threo -β-benzyloxyaspartate (TBOA; to raise endogenous glutamate) into either the IL or PL (0.5 μl/side) and then given a 30-min test for cue-reinforced drug-seeking. Vehicle-infused rats exhibited incubated responding on the cocaine-associated lever. Neither LY379268 nor TBOA altered behavior at 3 days withdrawal, indicating that glutamate within neither subregion regulates cue-reinforced drug-seeking during early withdrawal. At 30 days withdrawal, intra-PL LY379268 microinjection significantly decreased drug-seeking behavior, while the effect was more modest when infused intra-IL. Interestingly, intra-IL TBOA attenuated incubated drug-seeking during protracted withdrawal, but did not affect behavior when infused intra-PL. These results argue that glutamate release within the PL in response to drug-seeking likely drives the manifestation of incubated cocaine-seeking during protracted withdrawal. [ABSTRACT FROM AUTHOR]

Background: Most variants of negative reinforcement theory predict that acute depressed mood can promote alcohol-seeking behaviour, but the precise mechanisms underpinning this effect remain contested. One possibility is that mood-induced alcohol-seeking is due to the formation of a stimulus-response (S-R) association, enabling depressed mood to elicit alcohol-seeking automatically. A second possibility is that depressed mood undergoes incentive learning, enabling it to enhance the expected value of alcohol and thus promote goal-directed alcohol-seeking. Objectives: These two explanations were distinguished using a human outcome-revaluation procedure. Methods: One hundred and twenty-eight alcohol drinkers completed questionnaires of alcohol use disorder, drinking to cope with negative affect and depression symptoms. Participants then learned that two responses earned alcohol and food points respectively (baseline) in two alternative forced choice trials. At test, participants rated the valence of randomly sampled negative and positive mood statements and, after each statement, chose between the alcohol- and food-seeking responses in extinction. Results: The percentage of alcohol- versus food-seeking responses was increased significantly in trials containing negative statements compared to baseline and positive statement trials, in individuals who reported drinking to cope with negative affect ( p = .004), but there was no such interaction with indices of alcohol use disorder ( p = .87) or depression symptoms ( p = .58). Conclusions: Individuals who drink to cope with negative affect are more sensitive to the motivational impact of acute depressed mood statements priming goal-directed alcohol-seeking. Negative copers' vulnerability to alcohol dependence may be better explained by excessive affective incentive learning than by S-R habit formation. [ABSTRACT FROM AUTHOR]

Prior studies have shown that drug-seeking behaviors increase, rather than dissipate, over weeks to months after withdrawal from drug self-administration. This phenomenon - termed incubation - suggests that drug-craving responses elicited by conditioned environmental or discrete cues may intensify over pronged abstinence. While most of this work is conducted in rats with intravenous drug self-administration models, there is less evidence for incubation in mice that have greater utility for molecular genetic analysis and perturbation. We tested whether incubation of cocaine-seeking behavior is evident in C57BL/6J mice following 3 weeks (5 days/week) of cocaine self-administration in 2 h self-administration sessions. We compared cocaine-seeking (drug-paired lever) responses 1, 7, or 28 days after withdrawal from cocaine self-administration, and over similar times following sucrose pellet self-administration. We found that the initial re-exposure to the self-administration test chambers elicited increased reward-seeking behavior in both sucrose and cocaine self-administering mice, with maximal responses found at 7 days compared to 1 or 28 days after self-administration with either reinforcer. However, following extinction training, reinstatement of cocaine seeking reinforced by response-contingent presentation of reward-associated cues (tone/light) was significantly higher after 28 days compared to 1 or 7 days following cocaine self-administration. In contrast, cue-induced reinstatement of sucrose-paired lever pressing did not increase over this time frame, demonstrating a drug-specific incubation effect not seen with a natural reward. Thus, C57BL/6J mice display incubation of cue-induced reinstatement of cocaine seeking similar to findings with rats, but only show a transient incubation of context-induced cocaine seeking. [ABSTRACT FROM AUTHOR]

Introduction: Drug-seeking behavior (DSB) in the emergency department (ED) is a very commonproblem, yet there has been little quantitative study to date of such behavior.The goal of this study wasto assess the frequency with which drug seeking patients in the ED use classic drug seeking behaviorsto obtain prescription medication.Methods: We performed a retrospective chart review on patients in an ED case management programfor DSB. We reviewed all visits by patients in the program that occurred during a 1-year period, andrecorded the frequency of the following behaviors: complaining of headache, complaining of backpain, complaining of dental pain, requesting medication by name, requesting a refill of medication,reporting medications as having been lost or stolen, reporting 10/10 pain, reporting greater than 10/10pain, reporting being out of medication, and requesting medication parenterally. These behaviors werechosen because they are described as “classic” for DSB in the existing literature.Results: We studied 178 patients from the case management program, who made 2,486 visits in 1year. The frequency of each behavior was: headache 21.7%, back pain 20.8%, dental pain 1.8%,medication by name 15.2%, requesting refill 7.0%, lost or stolen medication 0.6%, pain 10/10 29.1%,pain greater than 10/10 1.8%, out of medication 9.5%, and requesting parenteral medication 4.3%.Patients averaged 1.1 behaviors per visit.Conclusion: Drug-seeking patients appear to exhibit “classically” described drug-seeking behaviorswith only low to moderate frequency. Reliance on historical features may be inadequate when trying toassess whether or not a patient is drug-seeking.

Studies presented in this chapter show that: (1) in the brain, ethanol is metabolized by catalase to acetaldehyde, which condenses with dopamine forming salsolinol; (2) acetaldehyde-derived salsolinol increases the release of dopamine mediating, via opioid receptors, the reinforcing effects of ethanol during the acquisition of ethanol consumption, while (3) brain acetaldehyde does not influence the maintenance of chronic ethanol intake, it is suggested that a learned cue-induced hyperglutamatergic system takes precedence over the dopaminergic system. However, (4) following a prolonged ethanol deprivation, the generation of acetaldehyde in the brain again plays a role, contributing to the increase in ethanol intake observed during ethanol re-access, called the alcohol deprivation effect (ADE), a model of relapse behavior; (5) naltrexone inhibits the high ethanol intake seen in the ADE condition, suggesting that acetaldehyde-derived salsolinol via opioid receptors also contributes to the relapse-like drinking behavior. The reader is referred to glutamate-mediated mechanisms that trigger the cue-associated alcohol-seeking and that also contribute to triggering relapse., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Introduction: Given the rapid increase in teen vaping over recent years it is critical to understand mechanisms underlying addiction and relapse to tobacco use at this age. To evaluate the role of non-nicotine constituents in cigarette smoke, our lab has previously established a model of intravenous self-administration of aqueous cigarette smoke extract (CSE). We now compare the sensitivity of male adolescent and adult rats who have self-administered CSE or nicotine to reinstatement with the pharmacological stressor, yohimbine, with and without cues., Methods: Adolescents and adults, aged postnatal day (P) 34 and 84, were tested for the effect of yohimbine (0-2.5 mg/kg) on plasma corticosterone levels to establish a dose that was an effective stressor at both ages. Separate groups of animals were trained to lever press for food before beginning 1-hour drug self-administration sessions for nicotine or CSE (15 μg/kg/infusion nicotine content). Once stable responding was reached, drug was removed, and behavior extinguished. Drug-seeking behavior was reinstated with yohimbine, cues, or a combination of yohimbine and cues., Results: Although adolescents and adults showed different dose-responses for yohimbine-induced corticosterone release, a dose of 2.5 mg/kg increased stress hormone levels at both ages. Whereas both ages displayed similar responding for CSE and nicotine, adolescents self-administered more CSE and nicotine as compared to adults. Cues and cues + stress reinstated responding to a greater extent in animals that had self-administered CSE, regardless of age., Discussion: These findings suggest that non-nicotine tobacco smoke constituents influence later but not earlier stages of addiction in both adolescent and adult male rats., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gellner, Carreño, Belluzzi and Leslie.)

Metabotropic glutamate (mGlu) receptors are expressed throughout the central nervous system and act as important regulators of drug-induced neuroplasticity and behavior. Preclinical research suggests that mGlu receptors play a critical role in a spectrum of neural and behavioral consequences arising from methamphetamine (meth) exposure. However, an overview of mGlu-dependent mechanisms linked to neurochemical, synaptic, and behavioral changes produced by meth has been lacking. This chapter provides a comprehensive review of the role of mGlu receptor subtypes (mGlu1-8) in meth-induced neural effects, such as neurotoxicity, as well as meth-associated behaviors, such as psychomotor activation, reward, reinforcement, and meth-seeking. Additionally, evidence linking altered mGlu receptor function to post-meth learning and cognitive deficits is critically evaluated. The chapter also considers the role of receptor-receptor interactions involving mGlu receptors and other neurotransmitter receptors in meth-induced neural and behavioral changes. Taken together, the literature indicates that mGlu5 regulates the neurotoxic effects of meth by attenuating hyperthermia and possibly through altering meth-induced phosphorylation of the dopamine transporter. A cohesive body of work also shows that mGlu5 antagonism (and mGlu2/3 agonism) reduce meth-seeking, though some mGlu5-blocking drugs also attenuate food-seeking. Further, evidence suggests that mGlu5 plays an important role in extinction of meth-seeking behavior. In the context of a history of meth intake, mGlu5 also co-regulates aspects of episodic memory, with mGlu5 stimulation restoring impaired memory. Based on these findings, we propose several avenues for the development of novel pharmacotherapies for Methamphetamine Use Disorder based on the selective modulation mGlu receptor subtype activity., Competing Interests: Conflict of interest The authors have no conflict of interest to report., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Two theories explain how negative mood primes smoking behaviour. The stimulus-response (S-R) account argues that in the negative mood state, smoking is experienced as more reinforcing, establishing a direct (automatic) association between the negative mood state and smoking behaviour. By contrast, the incentive learning account argues that in the negative mood state smoking is expected to be more reinforcing, which integrates with instrumental knowledge of the response required to produce that outcome. Objectives: One differential prediction is that whereas the incentive learning account anticipates that negative mood induction could augment a novel tobacco-seeking response in an extinction test, the S-R account could not explain this effect because the extinction test prevents S-R learning by omitting experience of the reinforcer. Methods: To test this, overnight-deprived daily smokers ( n = 44) acquired two instrumental responses for tobacco and chocolate points, respectively, before smoking to satiety. Half then received negative mood induction to raise the expected value of tobacco, opposing satiety, whilst the remainder received positive mood induction. Finally, a choice between tobacco and chocolate was measured in extinction to test whether negative mood could augment tobacco choice, opposing satiety, in the absence of direct experience of tobacco reinforcement. Results: Negative mood induction not only abolished the devaluation of tobacco choice, but participants with a significant increase in negative mood increased their tobacco choice in extinction, despite satiety. Conclusions: These findings suggest that negative mood augments drug-seeking by raising the expected value of the drug through incentive learning, rather than through automatic S-R control. [ABSTRACT FROM AUTHOR]

The incubation of cocaine craving describes the time-dependent augmentation of cue-induced cocaine seeking during withdrawal from prolonged cocaine self-administration and requires time-dependent changes in neuroplasticity at the level of glutamatergic synapses in the nucleus accumbens (NAc). In contrast to most studies that use multiple cocaine-cue conditioning sessions, the present study tested mice with limited cocaine experience (i.e., a single conditioning session) in the incubation of cue-mediated cocaine seeking and its associated changes in the glutamate system. Mice that self-administered cocaine during a single session exhibited a time-dependent increase in their response for the drug-associated cue as compared to mice that self-administered saline. This behavior was associated with changes in AMPA and NMDA receptor binding characteristics. Furthermore, Group I metabotropic glutamate receptor (mGluR1) mRNA levels were altered in several brain regions, including the NAc. Because of the pivotal role of mGluR1 in the control of cocaine-induced plasticity, we investigated the role of mGluR1 in the formation of drug cue-mediated cocaine seeking. After prolonged with-drawal, mice in which an mGluR1 antagonist was administered following cocaine self-administration displayed increased cocaine seeking compared to vehicle-treated mice. These results suggest that limited cocaine experience is sufficient to induce neurobiological changes that enable an initially neutral cue to acquire motivational value that increases over time, an effect that likely involves glutamate signaling through mGluR1. [ABSTRACT FROM AUTHOR]

ABSTRACT Baclofen, a gamma-aminobutyric acidB receptor agonist, is currently under investigation as a potential treatment to prevent relapse to drinking in alcohol-dependent persons. In the current study, two groups of baboons were trained under a chained schedule of reinforcement (CSR), with three linked components, which were each correlated with different response requirements and cues. Fulfilling the requirement in the second link initiated the third link where either alcohol ( n = 4) or a preferred non-alcoholic beverage (Tang, n = 5) was available for self-administration; failure to complete the response requirement in Link 2 ended the session (no access to alcohol or Tang). Seeking responses in Link 2 were used as indices of the motivational processes thought to be involved in relapse. The effects of baclofen (0.1-2.4 mg/kg) were examined under conditions with alcohol or Tang access and under extinction. Under the CSR, baclofen (1.8 and 2.4 mg/kg) significantly decreased ( P < 0.05) alcohol self-administration responses and total g/kg alcohol intake. In contrast, only the highest dose of baclofen (2.4 mg/kg) reduced Tang self-administration and consumption. Under within-session extinction conditions, baclofen (1.8 and 2.4 mg/kg) facilitated extinction of responding for both alcohol and Tang, particularly during the first 10 minutes of extinction. Baclofen may be effective in reducing craving and alcohol drinking, although the facilitation of extinction and suppression of both alcohol and Tang self-administration by baclofen suggests these effects may be related to a more general suppression of consummatory and conditioned behaviors. [ABSTRACT FROM AUTHOR]

Abstract: Exposure to drug-associated cues evokes drug-seeking behavior and is regarded as a major cause of relapse. Cues evoke burst firing of ventral tegmental area (VTA) dopamine (DA) neurons and phasic DA release in the nucleus accumbens (NAc). Cholinergic and glutamatergic input to the VTA is suggested to gate phasic DA activity. However, the role of VTA cholinergic and glutamatergic receptors in regulating phasic dopamine release and cue-induced drug-seeking in cocaine experienced subjects is not known. In male Sprague–Dawley rats, we found that VTA inactivation strongly inhibited, while VTA stimulation promoted, cocaine-seeking behavior during early withdrawal. Blockade of phasic activated D1 receptors in the NAc core also strongly inhibited cue-induced cocaine-seeking – suggesting an important role of phasic DA activity in the VTA to NAc core circuit. Next, we examined the role of VTA acetylcholine receptors (AChRs) and N-methyl-d-aspartate receptors (NMDARs) in regulating both NAc core phasic DA release and cue-induced cocaine-seeking. In cocaine naïve subjects, VTA infusion of the nicotinic acetylcholine receptor (AChR) antagonist mecamylamine, the muscarinic AChR antagonist scopolamine, or the NMDAR antagonist AP-5, led to robust attenuation of phasic DA release in the NAc core. During early cocaine withdrawal, VTA infusion of AP-5 had limited effects on NAc phasic DA release and cue-induced cocaine-seeking while VTA infusion of mecamylamine or scopolamine robustly inhibited both phasic DA release and cocaine-seeking. The results demonstrate that VTA AChRs, but not NMDARs, strongly regulate cue-induced cocaine-seeking and phasic DA release during early cocaine withdrawal. [Copyright &y& Elsevier]

Orexins (hypocretins) are neuropeptides synthesized in neurons located in the lateral, perifornical and dorsomedial hypothalamus. These neurons innervate many regions in the brain and modulate multiple other neurotransmitter systems. As a result of these extensive projections and interactions orexins are involved in numerous functions, such as feeding behavior, neuroendocrine regulation, the sleep-wake cycle and reward-seeking. This review will summarise the literature to date which has evaluated a role of orexins in the behavioral effects of alcohol, with a focus on understanding the importance of this peptide and its potential as a potential therapeutic target for alcohol use disorders.

The idea of ‘receptor mosaics’ suggests that proteins can form complex and dynamic networks, with respect to time and protein make up, which has the potential to make significant contributions to the diversity and specificity of GPCR signalling, particularly in neuropharmacology, where a few key receptors have been implicated in multiple neurological and psychiatric disorders such as addiction. Metabotropic glutamate type 5 receptors (mGlu5) have been shown to heterodimerise and form complexes with other GPCRs including adenosine A2A and dopamine D2 receptors. mGlu5-containing complexes are found in the striatum, a region of the brain known to be critical for mediating the rewarding and incentive motivational properties of drugs of abuse. Indeed, initial studies indicate a role for mGlu5-containing complexes in rewarding and conditioned effects of drugs, as well as drug-seeking behaviour. This is consistent with the substantial influence that mGlu5 complexes appear to have on striatal function, regulating both GABAergic output of striatopallidal neurons and glutamatergic input from corticostriatal afferents. Given their discrete localization, mGlu5-containing complexes represent a novel way in which to minimize the off-target effects and therefore provide us with an exciting therapeutic avenue for drug discovery efforts. Indeed, the therapeutic targeting of receptor mosaics in a tissue specific or temporal manner (for example, a sub-population of receptors in a ‘pathological state’) has the potential to dramatically reduce detrimental side effects that may otherwise impair vital brain function.

Complex neuroadaptations within key nodes of the brain’s ‘reward circuitry’ are thought to underpin long-term vulnerability to relapse. A more comprehensive understanding of the molecular and cellular signalling events that subserve relapse vulnerability may lead to pharmacological treatments that could improve treatment outcomes for psychostimulant-addicted individuals. Recent advances in this regard include findings that drug-induced perturbations to neurotrophin, metabotropic glutamate receptor and dopamine receptor signalling pathways perpetuate plasticity impairments at excitatory glutamatergic synapses on ventral tegmental area (VTA) and nucleus accumbens (NAC) neurons. In the context of addiction, much previous work, in terms of downstream effectors to these receptor systems, has centered on the extracellular-regulated MAP kinase (ERK) signalling pathway. The purpose of the present review is to highlight the evidence of an emerging role for another downstream effector of these addiction-relevant receptor systems - the mammalian target of rapamycin complex 1 (mTORC1). mTORC1 functions to regulate synaptic protein translation and is a potential critical link in our understanding of the neurobiological processes that drive addiction and relapse behavior. The precise cellular and molecular changes that are regulated by mTORC1 and contribute to relapse vulnerability are only just coming to light. Therefore, we aim to highlight evidence that mTORC1 signalling may be dysregulated by drug-exposure and that these changes may contribute to aberrant translation of synaptic proteins that appear critical to increased relapse vulnerability, including AMPARs. The importance of understanding the role of this signalling pathway in the development of addiction vulnerability is underscored by the fact that the mTORC1 inhibitor rapamycin reduces drug-seeking in preclinical models and preliminary evidence indicating that rapamycin suppresses drug craving in humans.

Rationale: Accumulating evidence indicates that brain kappa-opioid receptors (KORs) and dynorphin, the endogenous ligand that binds at these receptors, are involved in regulating states of motivation and emotion. These findings have stimulated interest in the development of KOR-targeted ligands as therapeutic agents. As one example, it has been suggested that KOR antagonists might have a wide range of indications, including the treatment of depressive, anxiety, and addictive disorders, as well as conditions characterized by co-morbidity of these disorders (e.g., post-traumatic stress disorder) A general effect of reducing the impact of stress may explain how KOR antagonists can have efficacy in such a variety of animal models that would appear to represent different disease states. Objective: Here, we review evidence that disruption of KOR function attenuates prominent effects of stress. We will describe behavioral and molecular endpoints including those from studies that characterize the effects of KOR antagonists and KOR ablation on the effects of stress itself, as well as on the effects of exogenously delivered corticotropin-releasing factor, a brain peptide that mediates key effects of stress. Conclusion: Collectively, available data suggest that KOR disruption produces anti-stress effects and under some conditions can prevent the development of stress-induced adaptations. As such, KOR antagonists may have unique potential as therapeutic agents for the treatment and even prevention of stress-related psychiatric illness, a therapeutic niche that is currently unfilled. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) Val(66)Met genotype has been associated with neurobehavioral deficits. To examine its relevance for addiction, we examined BDNF genotype differences in drug-seeking behavior. Heroin-dependent volunteers (n = 128) completed an interview that assessed past-month naturalistic drug-seeking/use behaviors. In African Americans (n = 74), the Met allele was uncommon (carrier frequency 6.8%); thus, analyses focused on European Americans (n = 54), in whom the Met allele was common (carrier frequency 37.0%). In their natural setting, Met carriers (n = 20) reported more time- and cost-intensive heroin-seeking and more cigarette use than Val homozygotes (n = 34). BDNF Val(66)Met genotype predicted 18.4% of variance in 'weekly heroin investment' (purchasing time × amount × frequency). These data suggest that the BDNF Met allele may confer a 'preferred drug-invested' phenotype, resistant to moderating effects of higher drug prices and non-drug reinforcement. These preliminary hypothesis-generating findings require replication, but are consistent with pre-clinical data that demonstrate neurotrophic influence in drug reinforcement. Whether this genotype is relevant to other abused substances besides opioids or nicotine, or treatment response, remains to be determined. [ABSTRACT FROM AUTHOR]

ABSTRACT Brain-derived neurotrophic factor (BDNF) Val66Met genotype has been associated with neurobehavioral deficits. To examine its relevance for addiction, we examined BDNF genotype differences in drug-seeking behavior. Heroin-dependent volunteers ( n = 128) completed an interview that assessed past-month naturalistic drug-seeking/use behaviors. In African Americans ( n = 74), the Met allele was uncommon (carrier frequency 6.8%); thus, analyses focused on European Americans ( n = 54), in whom the Met allele was common (carrier frequency 37.0%). In their natural setting, Met carriers ( n = 20) reported more time- and cost-intensive heroin-seeking and more cigarette use than Val homozygotes ( n = 34). BDNF Val66Met genotype predicted 18.4% of variance in 'weekly heroin investment' (purchasing time × amount × frequency). These data suggest that the BDNF Met allele may confer a 'preferred drug-invested' phenotype, resistant to moderating effects of higher drug prices and non-drug reinforcement. These preliminary hypothesis-generating findings require replication, but are consistent with pre-clinical data that demonstrate neurotrophic influence in drug reinforcement. Whether this genotype is relevant to other abused substances besides opioids or nicotine, or treatment response, remains to be determined. [ABSTRACT FROM AUTHOR]

Abstract: Despite decades of research on treatments for cocaine dependence, relapse rates following many behavioral and drug-based therapies remain high. This may be in part because cocaine-associated cues and contexts can invoke powerful drug cravings years after quitting. Recent studies suggest that drugs that promote cognitive function can enhance the formation of memories involving cocaine and other substances. One target of these drugs is facilitating histone acetylation to promote learning by increasing gene transcription that supports memory formation. Here, we investigate the effects of the histone deacetylase (HDAC) inhibitor sodium butyrate (NaBut) on cocaine-induced conditioned place preference (CPP) in C57BL/6 mice. After establishing a graded dose–response curve (2, 5, & 20mg/kg) for cocaine-induced CPP, we examined the effects of different doses of NaBut (0, 0.3, 0.6, & 1.2g/kg) on conditioning, extinction, and post-extinction reconditioning of CPP. A high dose of NaBut (1.2g/kg) enhanced initial acquisition of cocaine CPP, but there were no effects of NaBut on reconditioning of extinguished CPP. Effects of NaBut on extinction were more complex, with a low-dose (0.3g/kg) facilitating extinction and a high dose (1.2g/kg) weakening extinction evident by preference at a retention test. These findings suggest that HDAC inhibition may have dose dependent effects on different components of cocaine CPP, with implications for (1) involvement of histone acetylation in context-drug learning, (2) interpretation of acute and chronic drug effects, and (3) the targeting of different types of learning in therapeutic application of HDAC inhibitors. [Copyright &y& Elsevier]