Significant association of DRD2 and ANKK1 genes with rural heroin dependence and relapse in men.

INTRODUCTION: Substance abuse significantly influences human health and may induce problems with social functioning worldwide. Numerous genetic and environmental risk factors, as well as their interactions, accelerate the development of drug addiction. Etiologically, the dopaminergic mesocorticolimbic reward pathways are related to psychoactive substance addiction, and the reward properties of heroin are connected with changes in the mesolimbic dopaminergic system. OBJECTIVE: The aim of this study is a haplotypic analysis of subjects addicted to polysubstance. However, with the knowledge that this is not a homogenous subgroup, it was decided to separate and analyze homogenous subgroups of subjects in order to find specific haplotypic variants among them. The subjects in the subgroups were addicted to heroin, and subjects with more than two relapses in the past two years. MATERIAL AND METHODS: The study group comprised of 301 polysubstance addicted rural male subjects. From this group, 2 homogenous subgroups of subjects were isolated and additionally analyzed: (1) a group of heroin addicted subjects (n=61), and (2) a group of heroin-addicted subjects with at least two relapses in the last two years (n=21). The group consisting of all polysubstance addicted rural subjects and both homogenous subgroups were analyzed against a control group of non-addicted subjects (n=300), matching gender and age. Five polymorphisms in the DRD2/ANKK1 region were analyzed: rs1076560, rs1800498, rs1079597, rs6276 in the DRD2 gene, and rs1800497 in the ANKK1 gene. RESULTS: A statistically significant haplotype association was found in analysis of the heroin addicted subjects, compared to controls, and two possible trends - when comparing the whole group of addicted subjects to controls, and in relapse subgroups, compared to the controls. CONCLUSIONS: The results obtained showed that haplotypes indicate a part of the biological component of addiction.

Oxycodone's Unparalleled Addictive Potential: Is it Time for a Moratorium?

PURPOSE OF REVIEW: This study and literature review were carried out to investigate whether oxycodone is the most addictive prescription opioid. RECENT FINDINGS: This was a cross-sectional survey from a pain management practice in south-central Alaska and review of the literature involving 86 patients diagnosed with opioid dependence/opioid use disorder from 2013 to 2018. Patients were given a list of prescription opioids and asked to identify the one (1) most desirable to themselves, (2) most desirable among drug-using associates or community, and (3) they deemed most addictive. Patients with a history of heroin use were asked which, if any, served as their gateway drug to heroin. The literature was reviewed using a PubMed search for articles containing the words "oxycodone" and "abuse," "addiction," "dependence," "disorder," and "euphoria." Oxycodone was ranked most highly in all four questions (n = 50, 60.2%; n = 46, 75.4%; n = 38, 60.2%; n = 14, 77.8%, respectively) by a wide margin. Numerous observational studies performed over the past few decades have demonstrated the supreme "likability" and abuse and dependence liability/addictiveness of oxycodone, with more recent mechanistic studies illuminating biological underpinnings including markedly increased active transport across the blood-brain barrier, increased phasic dopaminergism in the ventral tegmental area, nucleus accumbens and related striatal reward centers, and possibly increased kappa opioid receptor-mediated withdrawal dysphoria. Oxycodone possesses pharmacologic qualities that render it disproportionately liable to abuse and addiction and the risks of any long-term prescription outweigh the benefits.

Prescription Drug Monitoring Programs and Opioid Overdoses: Exploring Sources of Heterogeneity.

BACKGROUND: Prescription drug monitoring program are designed to reduce harms from prescription opioids; however, little is known about what populations benefit the most from these programs. We investigated how the relation between implementation of online prescription drug monitoring programs and rates of hospitalizations related to prescription opioids and heroin overdose changed over time, and varied across county levels of poverty and unemployment, and levels of medical access to opioids. METHODS: Ecologic county-level, spatiotemporal study, including 990 counties within 16 states, in 2001-2014. We modeled overdose counts using Bayesian hierarchical Poisson models. We defined medical access to opioids as the county-level rate of hospital discharges for noncancer pain conditions. RESULTS: In 2010-2014, online prescription drug monitoring programs were associated with lower rates of prescription opioid-related hospitalizations (rate ratio 2014 = 0.74; 95% credible interval = 0.69, 0.80). The association between online prescription drug monitoring programs and heroin-related hospitalization was also negative but tended to increase in later years. Counties with lower rates of noncancer pain conditions experienced a lower decrease in prescription opioid overdose and a faster increase in heroin overdoses. No differences were observed across different county levels of poverty and unemployment. CONCLUSIONS: Areas with lower levels of noncancer pain conditions experienced the smallest decrease in prescription opioid overdose and the faster increase in heroin overdose following implementation of online prescription drug monitoring programs. Our results are consistent with the hypothesis that prescription drug monitoring programs are most effective in areas where people are likely to access opioids through medical providers.

Increased use of heroin as an initiating opioid of abuse: Further considerations and policy implications.

INTRODUCTION: Previously, we reported a marked increase in the use of heroin as an initiating opioid in non-tolerant, first time opioid users. In the current paper, we sought to update and expand upon these results, with a discussion of the policy implications on the overall opioid epidemic. METHODS: Opioid initiation data from the original study were updated to include surveys completed through 2017 (N = 8382) from a national sample of treatment-seeking opioid users. In addition, past month abuse of heroin and prescription were analyzed as raw numbers of treatment program entrant in the last five years (2013-2017), drawing from only those treatment centers that participated every year in that time frame. RESULTS: The updated data confirm and extend the results of our original study: the use of heroin as an initiating opioid increased from 8.7% in 2005 to 31.6% in 2015, with increases in overall Ns per initiation year reflecting a narrowing of the "treatment gap", the time lag between opioid initiation from 2005 to 2015 and later treatment admission (up to 2017). Slight decreases were observed in treatment admissions, but this decline was totally confined to prescription opioid use, with heroin use continuing to increase in absolute numbers. CONCLUSIONS: Given that opioid novices have limited tolerance, the risk of fatal overdose for heroin initiates is elevated compared to prescription opioids, particularly given non-oral administration and often unknown purity/adulterants (i.e., fentanyl). Imprecision of titrating dose among opioid novices may explain observed increases opioid overdoses. Future policy decisions should note that prescription opioid-specific interventions may have little impact on a growing heroin epidemic.

The association of psychedelic use and opioid use disorders among illicit users in the United States.

BACKGROUND: Preliminary studies show psychedelic compounds administered with psychotherapy are potentially effective and durable substance misuse interventions. However, little is known about the association between psychedelic use and substance misuse in the general population. This study investigated the association between psychedelic use and past year opioid use disorders within illicit opioid users. METHODS: While controlling for socio-demographic covariates and the use of other substances, the relationship between classic psychedelic use and past year opioid use disorders was analyzed within 44,000 illicit opioid users who completed the National Survey on Drug Use and Health from 2008 to 2013. RESULTS: Among respondents with a history of illicit opioid use, psychedelic drug use is associated with 27% reduced risk of past year opioid dependence (weighted risk ratio = 0.73 (0.60-0.89) p = 0.002) and 40% reduced risk of past year opioid abuse (weighted risk ratio = 0.60 (0.41-0.86) p = 0.006). Other than marijuana use, which was associated with 55% reduced risk of past year opioid abuse (weighted risk ratio = 0.45 (0.30-0.66) p < 0.001), no other illicit drug was associated with reduced risk of past year opioid dependence or abuse. CONCLUSION: Experience with psychedelic drugs is associated with decreased risk of opioid abuse and dependence. Conversely, other illicit drug use history is largely associated with increased risk of opioid abuse and dependence. These findings suggest that psychedelics are associated with positive psychological characteristics and are consistent with prior reports suggesting efficacy in treatment of substance use disorders.

Factors Associated with Relapse among Heroin Addicts: Evidence from a Two-Year Community-Based Follow-Up Study in China.

BACKGROUND: Many countries including China are facing a serious opiate dependence problem. Anti-drug work effectiveness was affected by the high relapse rate all over the world. This study aims to analyze the factors influencing heroin addict relapse, and to provide evidence for generating relapse prevention strategies. METHODS: A community-based follow-up study was conducted in China between October 2010 and September 2012. A total of 554 heroin addicts in accordance with the inclusion criteria from 81 streets in 12 districts of Shanghai, China were divided into 4 groups: group 1--daily dosage taken orally of 60 mL of methadone or under combined with psychological counseling and social supports (n = 130); group 2--daily dosage taken orally of over 60 mL of methadone combined with psychological counseling and social supports (n = 50); group 3--JTT (Jitai tablets) combined with psychological counseling and social supports (n = 206); group 4--JTT combined with social supports (n = 168). RESULTS: Log-rank test results showed that the cumulative relapse rate differences among four groups during the two-year follow-up period were not statistically significant (χ² = 5.889, p = 0.117). Multivariate Cox regression analysis results showed that only three independent variables were still statistically significant, including compliance with participation in psychological counseling (OR = 3.563, p = 0.000), the years of drug use (OR = 1.078, p = 0.001)and intervention model. CONCLUSIONS: Using the detoxification medications combined with appropriate psychological counseling and social support measures will help improve the effectiveness of relapse prevention, which is a kind of alternative community detoxification pattern. Appropriate and standard psychological counseling is very important for anti-drug treatment. The longer the drug addiction lasts, the longer the anti-drug treatment takes.

Circumstances and contexts of heroin initiation following non-medical opioid analgesic use in New York City.

BACKGROUND: As the prevalence of opioid analgesic (OA) misuse and associated harms have increased in the United States, the prevalence of heroin use and rates of unintentional overdose have concurrently risen. Research has begun to identify connections between OA misuse and heroin use, although this relationship remains under explored. The present study explores the context of heroin initiation among persons with histories of OA misuse in New York City. METHODS: In-depth interviews were conducted with 31 individuals with histories of OA misuse who initiated heroin use within the past five years. Data were collected between August 2013 and January 2015. All participants' OA misuse temporally preceded their heroin use. Interviews were coded and analyzed utilizing thematic qualitative methods. RESULTS: Participants ranged in age from 18 to 44 years; 25 identified as male and 30 identified as non-Hispanic white and heterosexual. All participants had stable housing at the time of interview and all were high school graduates. Participants described several key points of transition along their trajectories from OA misuse to heroin initiation: dual- to single-entity OAs; oral to intranasal OA administration; and the development of physical opioid dependence. Participants described the breaking down of heroin-related stigma across social networks as new drug use permeated social groups. CONCLUSION: Several points of transition were identified in participants' trajectories from OA misuse to heroin initiation. In particular the development of physical dependence was a critical factor as existing heroin stigma was rapidly overcome in the face of opioid withdrawal. The relatively short time to heroin initiation documented among new user groups serves as an added challenge to the development of interventions.

Role of projections from ventral subiculum to nucleus accumbens shell in context-induced reinstatement of heroin seeking in rats.

RATIONALE AND OBJECTIVE: In humans, exposure to contexts previously associated with heroin use can provoke relapse. In rats, exposure to heroin-paired contexts after extinction of drug-reinforced responding in different contexts reinstates heroin seeking. We previously demonstrated that the projections from ventral medial prefrontal cortex (vmPFC) to nucleus accumbens (NAc) shell play a role in this reinstatement. The ventral subiculum (vSub) sends glutamate projections to NAc shell and vmPFC. Here, we determined whether these projections contribute to context-induced reinstatement. METHODS: We trained rats to self-administer heroin (0.05-0.1 mg/kg/infusion) for 3 h per day for 12 days; drug infusions were paired with a discrete tone-light cue. Lever pressing in the presence of the discrete cue was subsequently extinguished in a different context. We then tested the rats for reinstatement in the heroin- and extinction-associated contexts under extinction conditions. We combined Fos with the retrograde tracer Fluoro-Gold (FG) to determine projection-specific activation during the context-induced reinstatement tests. We also used anatomical disconnection procedures to determine whether the vSub → NAc shell and vSub → vmPFC projections are functionally involved in this reinstatement. RESULTS: Exposure to the heroin but not the extinction context reinstated lever pressing. Context-induced reinstatement of heroin seeking was associated with increased Fos expression in vSub neurons, including those projecting to NAc shell and vmPFC. Anatomical disconnection of the vSub → NAc shell projection, but not the vSub → vmPFC projection, decreased this reinstatement. CONCLUSIONS: Our data indicate that the vSub → NAc shell glutamatergic projection, but not the vSub → vmPFC projection, contributes to context-induced reinstatement of heroin seeking.

Reasons for recent marijuana use in relation to use of other illicit drugs among high school seniors in the United States.

OBJECTIVES: Studies show that illicit cannabis (marijuana) use is related to use of other illicit drugs and that reasons for use are related to frequency of marijuana use. However, research is needed to examine whether specific reasons for marijuana use are associated with use of other illicit drugs. METHODS: Data from recent marijuana-using high school seniors were examined from 12 cohorts of Monitoring the Future (Weighted n = 6481) to examine whether reasons for recent marijuana use are associated with use of eight other illicit drugs. RESULTS: Using "to experiment" decreased odds of reporting use of each drug and using to decrease effects of other drugs increased odds of reporting use of each drug. In multivariable models, using marijuana "to experiment" decreased the odds for reporting use of hallucinogens other than LSD and narcotics other than heroin. Using marijuana for "insight" increased the odds for use of hallucinogens other than LSD, and use due to "boredom" increased the odds for reporting use of powder cocaine and hallucinogens other than LSD. Using marijuana to increase effects of other drugs increased odds of reporting use of each of the eight drugs, and using it to decrease other drug effects increased odds of reporting use of crack, hallucinogens other than LSD, and amphetamine/stimulants. CONCLUSIONS: This study helped identify illicit marijuana users who are more likely to report use of other illicit drugs. Prevention efforts need to focus on students who report certain reasons for marijuana use as they may be at risk for use of other illicit drugs.

The epidemic of prescription opioid abuse, the subsequent rising prevalence of heroin use, and the federal response.

Opioids are a mainstay in the treatment of pain both chronically and acutely. In the past 20 years, the prescribing of opioids has increased exponentially. As the population for whom opioids are indicated has grown, with the number of opioid prescriptions written increased, so have indicators of opioid misuse, abuse, morbidity, and mortality. The purpose of this article is to review and explore the combination of factors of events that led to the current "epidemic" of prescription opioid abuse and overdose deaths, as well as the subsequent resurgence of heroin use among opioid addicts. Federal initiatives to mount war on prescription opioid abuse are reviewed, including responses from the White House, Drug Enforcement Agency (DEA), Food and Drug Administration (FDA), and interagency initiatives. Many initiatives are currently in place to combat the rising rates of morbidity and mortality associated with opioids, and those involved are hopeful in their efforts to curb the epidemic of this deadly phenomenon.

Failure to identify or effectively manage prescription opioid dependence acted as a gateway to heroin use-buprenorphine/naloxone treatment and recovery in a surgical patient.

The prescribing of opioid pain medication has increased markedly in recent years, with strong opioid dispensing increasing 18-fold in Tayside, Scotland since 1995. Despite this, little data is available to quantify the problem of opioid pain medication dependence (OPD) and until recently there was little guidance on best-practice treatment. We report the case of a young mother prescribed dihydrocodeine for postoperative pain relief who became opioid dependent. When her prescription was stopped without support, she briefly used heroin to overcome her withdrawal. After re-exposure to dihydrocodeine following surgery 9 years later and treatment with methadone for dependency, she was transferred to buprenorphine/naloxone. In our clinical experience and in agreement with Department of Health and Royal College of General Practitioner guidance, buprenorphine/naloxone is the preferred opioid substitution treatment for OPD. Our patient remains within her treatment programme and has returned to work on buprenorphine 16 mg/naloxone 4 mg in conjunction with social and psychological support.

How is acceptance of the brain disease model of addiction related to Australians' attitudes towards addicted individuals and treatments for addiction?

BACKGROUND: We investigated whether beliefs about addiction being a 'disease' or 'brain disease', and holding certain beliefs about addiction aetiology, are associated with public views about addicted persons and support for different types of treatment, coerced treatment and punishment for addiction. METHODS: Data were collected as part of the 2012 Queensland Social Survey, a computer assisted telephone interview of 1263 residents of Queensland, Australia. Participants were presented with scenarios of two addicted males, one who was addicted to heroin and the other addicted to alcohol. Participants were then asked a series of questions for both characters. RESULTS: There was widespread support for all treatment modalities (alcohol: 80.8-98.0%, heroin: 89.9-97.2%). There was less support for coerced treatment for alcohol than heroin addiction (alcohol: 41%, heroin: 71%, χ(2) = 273.90, p < 0.001). Being 35 years of age or older (alcohol: OR = 0.58 (0.37-0.91), heroin: OR = 0.49 (0.28-0.85)) and having 15 or more years of education (alcohol: OR = 0.60 (0.44-0.81), heroin: 0.55 (0.40-0.75)) predicted less support for coerced treatment. 31.7% of respondents agreed heroin use should be punished by imprisonment and being 35 years of age or older (OR = 0.51 (0.33-0.80)) predicted lack of support. The sample agreed that an alcohol or heroin dependent person would suffer career damage (alcohol: 96.2%, heroin: 98.9%), marriage breakdown (alcohol: 92.2%, heroin: 97.3%) and get in trouble with the law (alcohol: 92.3%, heroin: 98.9%). Respondents expressed more comfort with encountering alcohol rather than heroin addicted persons in the workplace or at a dinner party. Beliefs that addiction was a 'brain disease' or a 'disease' did not predict any of these attitudes. Beliefs about addiction aetiology were inconsistent predictors of outcomes measured. CONCLUSIONS: Age and educational attainment were the most consistent predictors of stigmatising beliefs and beliefs about coercion and punishment. Beliefs that addiction is a 'disease' or a 'brain disease' were not associated with an overall reduction in beliefs about stigma, coercion or punishment. Beliefs in different causes of addiction were not consistent predictors of beliefs about stigma, coercion or punishment.

Synaptic glutamate spillover due to impaired glutamate uptake mediates heroin relapse.

Reducing the enduring vulnerability to relapse is a therapeutic goal in treating drug addiction. Studies with animal models of drug addiction show a marked increase in extrasynaptic glutamate in the core subcompartment of the nucleus accumbens (NAcore) during reinstated drug seeking. However, the synaptic mechanisms linking drug-induced changes in extrasynaptic glutamate to relapse are poorly understood. Here, we discovered impaired glutamate elimination in rats extinguished from heroin self-administration that leads to spillover of synaptically released glutamate into the nonsynaptic extracellular space in NAcore and investigated whether restoration of glutamate transport prevented reinstated heroin seeking. Through multiple functional assays of glutamate uptake and analyzing NMDA receptor-mediated currents, we show that heroin self-administration produced long-lasting downregulation of glutamate uptake and surface expression of the transporter GLT-1. This downregulation was associated with spillover of synaptic glutamate to extrasynaptic NMDA receptors within the NAcore. Ceftriaxone restored glutamate uptake and prevented synaptic glutamate spillover and cue-induced heroin seeking. Ceftriaxone-induced inhibition of reinstated heroin seeking was blocked by morpholino-antisense targeting GLT-1 synthesis. These data reveal that the synaptic glutamate spillover in the NAcore results from reduced glutamate transport and is a critical pathophysiological mechanism underling reinstated drug seeking in rats extinguished from heroin self-administration.

Purchase and use patterns of heroin users at an inner-city emergency department.

BACKGROUND: Many consider heroin abuse a problem of the inner city, but suburban patients may also be at risk. OBJECTIVE: To characterize the demographics and purchase/use patterns of heroin users in an inner-city emergency department (ED). METHODS: The study was conducted in one of the most impoverished and crime-ridden cities in the United States. Demographics and substance use habits of ED patients were prospectively collected. Patients who were<18 years of age, cognitively impaired, or did not speak English were excluded. Participants were further categorized as homeless, inner-city, and suburban residents. RESULTS: Of 3947 participants, 608 (15%) used an illicit substance in the past year, with marijuana (9%) and cocaine (6%) the most commonly used. Heroin ranked third, used by 180 (5%) participants, with 61% male, 31% black, and 20% Hispanic. There were 64 homeless, 60 suburban, and 56 inner-city heroin users. The most common route of use was injection (68%), with the highest rate in the homeless (84%). The majority of homeless and inner-city users bought (73%, both groups) and used (homeless 74%, inner city 88%) in the inner city. Of suburban users, 58% purchased and 61% used heroin in the inner city. Prescription narcotic use was more common in homeless (20%) and suburban (23%) heroin users than in inner-city users (9%) (p<0.001). CONCLUSIONS: Heroin is the third most commonly used illicit substance by ED patients, and a significant amount of inner-city purchase and use activity is conducted by suburban heroin users.

A pilot study of life events and mood disorders: self-report survey in chinese heroin-dependent individuals.

An understanding of the relationship among life events, anxiety, depression, and heroin abuse may benefit the prevention and early treatment of heroin dependence. The objective of this study was to assess self-reported life events, anxiety, and depression in patients with heroin dependence. In this survey, Chinese heroin-dependent patients (n = 139) were asked to conduct a battery of self-reported questionnaires. A total of 76.26% of heroin-dependent patients reported the occurrence of major lifestyle pattern (dietary and sleep) changes as negative life events. Financial problems from family, unemployment, and poor interpersonal relationships were also frequently reported as negative events. Heroin-dependent patients experienced overwhelmingly more negative life events than positive life events. Those negative life events positively correlated with depression and anxiety. They also exhibited high levels of anxiety (Self-Rating Anxiety Scale, mean 44.42 ± 8.27) and depression (Self-Rating Depression Scale, mean 47.28 ± 8.54). Although preliminary, findings from this study suggest the need for further investigation of life events, anxiety, and depression in a generalized large sample, which may benefit community-based psychosocial intervention and prevention of relapse in heroin-dependent subjects.

Escalation patterns of varying periods of heroin access.

The prevalence of opioid abuse and dependence has been on the rise in just the past few years. Animal studies indicate that extended access to heroin produces escalation of intake over time, whereas stable intake is observed under limited-access conditions. Escalation of drug intake has been suggested to model the transition from controlled drug use to compulsive drug seeking and taking. Here, we directly compared the pattern of heroin intake in animals with varying periods of heroin access. Food intake was also monitored over the course of escalation. Rats were allowed to lever press on a fixed-ratio 1 schedule of reinforcement to receive intravenous infusions of heroin for 1, 6, 12, or 23h per day for 14 sessions. The results showed that heroin intake in the 12 and 23h groups markedly increased over time, whereas heroin intake in the 1h group was stable. The 6h group showed a significant but modest escalation of intake. Total heroin intake was similar in the 12 and 23h groups, but the rate of heroin self-administration was two-fold higher in the 12h group compared with the 23h group. Food intake decreased over sessions only in the 12h group. The 12 and 23h groups showed marked physical signs of naloxone-precipitated withdrawal. These findings suggest that 12h heroin access per day may be the optimal access time for producing escalation of heroin intake. The advantages of this model and the potential relevance for studying drug addiction are discussed.

Childhood sexual abuse, post-traumatic stress disorder, and use of heroin among female clients in Israeli methadone maintenance treatment programs (MMTPS).

This study investigated association between post-traumatic stress disorder (PTSD) and a 1-year follow-up heroin use among female clients in methadone clinics in Israel. Participants were 104 Israeli female clients from four methadone clinics (Mean age = 39.09, SD = 8.61) who reported victimization to childhood sexual abuse. We tested traces in urine of these female clients for heroin a year preceding and a year following the assessment of their PTSD. Results show that 54.2% reported symptoms that accedes the DSM-IV criteria for PTSD. We found that among childhood victimized women PTSD is associated with more frequent use of heroin at a 1-year follow-up even after controlling for duration of the stay at the clinic, background, other traumatic experiences and heroin use a year prior the assessment of their PTSD. This study shows the potential long-run negative consequences of childhood sexual abuse. Not only are these sexually abused women trapped into drug dependence and addiction, they cannot break the vicious cycle of continuing the use of illicit drugs even when treated for their addiction. One major practice implication is that treatment for PTSD proven efficacious will be provided in the methadone and other drug treatment services.

Extracellular matrix plasticity and GABAergic inhibition of prefrontal cortex pyramidal cells facilitates relapse to heroin seeking.

Successful treatment of drug addiction is hampered by high relapse rates during periods of abstinence. Neuroadaptation in the medial prefrontal cortex (mPFC) is thought to have a crucial role in vulnerability to relapse to drug seeking, but the molecular and cellular mechanisms remain largely unknown. To identify protein changes that contribute to relapse susceptibility, we investigated synaptic membrane fractions from the mPFC of rats that underwent 21 days of forced abstinence following heroin self-administration. Quantitative proteomics revealed that long-term abstinence from heroin self-administration was associated with reduced levels of extracellular matrix (ECM) proteins. After extinction of heroin self-administration, downregulation of ECM proteins was also present in the mPFC, as well as nucleus accumbens (NAc), and these adaptations were partially restored following cue-induced reinstatement of heroin seeking. In the mPFC, these ECM proteins are condensed in the perineuronal nets that exclusively surround GABAergic interneurons, indicating that ECM adaptation might alter the activity of GABAergic interneurons. In support of this, we observed an increase in the inhibitory GABAergic synaptic inputs received by the mPFC pyramidal cells after the re-exposure to heroin-conditioned cues. Recovering levels of ECM constituents by metalloproteinase inhibitor treatment (FN-439; i.c.v.) prior to a reinstatement test attenuated subsequent heroin seeking, suggesting that the reduced synaptic ECM levels during heroin abstinence enhanced sensitivity to respond to heroin-conditioned cues. We provide evidence for a novel neuroadaptive mechanism, in which heroin self-administration-induced adaptation of the ECM increased relapse vulnerability, potentially by augmenting the responsivity of mPFC GABAergic interneurons to heroin-associated stimuli.

Initial experience of heroin use under a two-chained operant schedule influences drug-seeking behavior after one month of abstinence.

AIM: To evaluate the influence of an initial heroin experience under a modified two-chained training schedule on drug-seeking behavior after a long abstinence period. METHODS: Rats were trained to respond for intravenous heroin (120 microg/kg) under a heterogeneous chained schedule of reinforcement using different responses in the first and second links of the chain. Animals received low-frequency drug administration training for four days and were then subjected to one month of abstinence in their home cages. Heroin-seeking behavior induced by re-exposure to the first chain associated context or discriminative stimuli was assessed after abstinence. RESULTS: Almost all animals could acquire operant skills quickly under the two-chained schedule training for four days, as measured in first active response latency, travel speed and goal-box enter latency. Both first chain associated context and discriminative stimulus could reinstate heroin-seeking behavior after one month abstinence. CONCLUSION: These observations suggest that an early experience of drug use is sufficient to maintain heroin-seeking behavior even after a one month abstinence.