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ENeuro 2017Heroin use and overdose have increased in recent years as people transition from abusing prescription opiates to using the cheaper street drug. Despite a long history of...
Heroin use and overdose have increased in recent years as people transition from abusing prescription opiates to using the cheaper street drug. Despite a long history of research, many physiological effects of heroin and their underlying mechanisms remain unknown. Here, we used high-speed amperometry to examine the effects of intravenous heroin on oxygen and glucose levels in the nucleus accumbens (NAc) in freely-moving rats. Heroin within the dose range of human drug use and rat self-administration (100-200 μg/kg) induced a rapid, strong, but transient drop in NAc oxygen that was followed by a slower and more prolonged rise in glucose. Using oxygen recordings in the subcutaneous space, a densely-vascularized site with no metabolic activity, we confirmed that heroin-induced brain hypoxia results from decreased blood oxygen, presumably due to drug-induced respiratory depression. Respiratory depression and the associated rise in CO levels appear to drive tonic increases in NAc glucose via local vasodilation. Heroin-induced changes in oxygen and glucose were rapid and preceded the slow and prolonged increase in brain temperature and were independent of enhanced intra-brain heat production, an index of metabolic activation. A very high heroin dose (3.2 mg/kg), corresponding to doses used by experienced drug users in overdose conditions, caused strong and prolonged brain hypoxia and hyperglycemia coupled with robust initial hypothermia that preceded an extended hyperthermic response. Our data suggest heroin-induced respiratory depression as a trigger for brain hypoxia, which leads to hyperglycemia, both of which appear independent of subsequent changes in brain temperature and metabolic neural activity.
Topics: Animals; Body Temperature; Conditioning, Operant; Dose-Response Relationship, Drug; Electrochemical Techniques; Glucose; Heroin; Hyperglycemia; Hypoxia, Brain; Male; Narcotics; Nucleus Accumbens; Oxygen; Rats; Rats, Long-Evans; Self Administration; Wakefulness
PubMed: 28593192
DOI: 10.1523/ENEURO.0151-17.2017 -
The International Journal on Drug Policy May 2009Heroin coming into the United States historically comes from three widely dispersed geographical regions: Southwest Asia, Southeast Asia and Mexico. A fourth source of...
BACKGROUND
Heroin coming into the United States historically comes from three widely dispersed geographical regions: Southwest Asia, Southeast Asia and Mexico. A fourth source of US-bound heroin, from Colombia, originated in the early 1990s. The fact that the four heroin sources produce differing morphologies and qualities of heroin has not been critically examined. In addition, it is not well established how the contemporary competing dynamics of interdiction, or restriction of heroin flows across international boundaries, and neoliberal, e.g., global expansion of free trade, policies are affecting heroin markets. This paper will highlight changes in the US heroin market, including source trends, the political economy of the now dominant source and the resultant effects on the heroin risk environment by US region.
METHODS
Using a structural and historical framework this paper examines two decades of secondary data sources, including government and drug control agency documents, on heroin flows together with published work on the political and economic dynamics in Latin America.
RESULTS
Co-occurring neoliberal economic reforms may have contributed to paradoxical effects of US/Colombian interdiction efforts. Since entering the US market, heroin from Colombia has been distributed at a much higher quality and lower retail price. An increasingly exclusive market has developed with Mexican and Colombian heroin gaining market share and displacing Asian heroin. These trends have had dramatic effects on the risk environment for heroin consumers. An intriguing factor is that different global sources of heroin produce substantially different products. Plausible associations exist between heroin source/form and drug use behaviours and harms. For example, cold water-soluble powdered heroin (sources: Asia, Colombia) may be associated with higher HIV prevalence in the US, while low-solubility "black tar" heroin (BTH; source: Mexico) is historically used in areas with reduced HIV prevalence. BTH is associated with soft tissue infections caused by Clostridium bacteria.
CONCLUSION
Source and type of heroin are structural factors in the risk environment of heroin users: source dictates distribution and type predicts practice. How specific types of heroin are used and with what risk is therefore distributed geographically. Continued flux in the heroin market and its effects on the risk environment for drug users deserves further attention.
Topics: Clostridium Infections; Commerce; Crime; Drug and Narcotic Control; HIV Infections; Heroin; Heroin Dependence; History, 20th Century; History, 21st Century; Humans; Illicit Drugs; Politics; Public Policy; Risk; Risk-Taking; United States
PubMed: 18945606
DOI: 10.1016/j.drugpo.2008.08.003 -
Molecular Neurobiology Jun 2021There is significant comorbidity of opioid use disorder (OUD) and post-traumatic stress disorder (PTSD) in clinical populations. However, the neurobiological mechanisms...
There is significant comorbidity of opioid use disorder (OUD) and post-traumatic stress disorder (PTSD) in clinical populations. However, the neurobiological mechanisms underlying the relationship between chronic opioid use and withdrawal and development of PTSD are poorly understood. Our previous work identified that chronic escalating heroin administration and withdrawal can produce enhanced fear learning, an animal model of hyperarousal, and is associated with an increase in dorsal hippocampal (DH) interleukin-1β (IL-1β). However, other cytokines, such as TNF-α, work synergistically with IL-1β and may have a role in the development of enhanced fear learning. Based on both translational rodent and clinical studies, TNF-α has been implicated in hyperarousal states of PTSD, and has an established role in hippocampal-dependent learning and memory. The first set of experiments tested the hypothesis that chronic heroin administration followed by withdrawal is capable of inducing alterations in DH TNF-α expression. The second set of experiments examined whether DH TNF-α expression is functionally relevant to the development of enhanced fear learning. We identified an increase of TNF-α immunoreactivity and positive cells at 0, 24, and 48 h into withdrawal in the dentate gyrus DH subregion. Interestingly, intra-DH infusions of etanercept (TNF-α inhibitor) 0, 24, and 48 h into heroin withdrawal prevented the development of enhanced fear learning and mitigated withdrawal-induced weight loss. Overall, these findings provide insight into the role of TNF-α in opioid withdrawal and the development of anxiety disorders such as PTSD.
Topics: Animals; Etanercept; Fear; Heroin; Hippocampus; Learning; Male; Rats, Sprague-Dawley; Signal Transduction; Substance Withdrawal Syndrome; Tumor Necrosis Factor-alpha; Weight Loss; Rats
PubMed: 33580871
DOI: 10.1007/s12035-021-02322-z -
Neuroendocrinology 2023There are numerous pharmacologic treatments for opioid use disorder (OUD), but none that directly target the underlying addictive effects of opioids. Oxytocin, a peptide...
INTRODUCTION
There are numerous pharmacologic treatments for opioid use disorder (OUD), but none that directly target the underlying addictive effects of opioids. Oxytocin, a peptide hormone produced in the paraventricular nucleus (PVN) of the hypothalamus, has been investigated as a potential therapeutic for OUD. Promising preclinical and clinical results have been reported, but the brain region(s) and mechanism(s) by which oxytocin impacts reward processes remain undetermined.
METHODS
Here, we assess peripherally administered oxytocin's impacts on cued reinstatement of heroin seeking following forced abstinence and its effects on neuronal activation in the PVN and key projection regions. We also examine how designer receptors exclusively activated by designer drug (DREADD)-mediated activation or inhibition of oxytocinergic PVN neurons alters cued heroin seeking and social interaction.
RESULTS
As predicted, peripheral oxytocin administration successfully decreased cued heroin seeking on days 1 and 30 of abstinence. Oxytocin administration also led to increased neuronal activity within the PVN and the central amygdala (CeA). Activation of oxytocinergic PVN neurons with an excitatory (Gq) DREADD did not impact cued reinstatement or social interaction. In contrast, suppression with an inhibitory (Gi) DREADD reduced heroin seeking on abstinence day 30 and decreased time spent interacting with a novel conspecific.
DISCUSSION
These findings reinforce oxytocin's therapeutic potential for OUD, the basis for which may be driven in part by increased PVN-CeA circuit activity. Our results also suggest that oxytocin has distinct signaling and/or other mechanisms of action to produce these effects, as inhibition, but not activation, of oxytocinergic PVN neurons did not recapitulate the suppression in heroin seeking.
Topics: Paraventricular Hypothalamic Nucleus; Oxytocin; Heroin; Hypothalamus; Brain
PubMed: 36709749
DOI: 10.1159/000529358 -
Psychopharmacology Jun 2009Dependence can develop during chronic opioid use, and the emergence of withdrawal might promote drug taking.
RATIONALE
Dependence can develop during chronic opioid use, and the emergence of withdrawal might promote drug taking.
OBJECTIVE
This study examined how chronic morphine administration or withdrawal modified self administration of heroin or cocaine.
METHODS
Four monkeys responded under a fixed ratio 10 schedule to receive i.v. infusions of heroin (0.56-560 microg/kg/infusion) or cocaine (1-100 microg/kg/infusion). Monkeys received morphine twice daily; the final dose was 10 mg/kg/12 h. Dose-effect curves for heroin or cocaine were determined in 150-min sessions throughout morphine administration and during temporary suspension when withdrawal signs were also monitored. Heroin dose-effect curves and withdrawal signs were determined daily following termination of morphine administration.
RESULTS
Before monkeys received morphine, heroin, and cocaine maintained responding with unit doses of 1.78 microg/kg of heroin and 10 microg/kg/injection of cocaine resulting in, on average, 13.4 and 20.8 infusions, respectively. When monkeys received morphine daily, self administration of heroin and cocaine decreased to, on average, 3.1 and 11.3 infusions, respectively. Responding for heroin or cocaine recovered following temporary (17-53 h) suspension of morphine administration. The number of heroin infusions and total withdrawal signs increased when morphine administration was terminated. Withdrawal signs peaked 3-4 days after morphine; however, the number of infusions remained elevated for 8 weeks.
CONCLUSIONS
Changes in self administration responding did not precisely covary with signs of withdrawal and responding for small doses of heroin persisted long after discontinuation of morphine, suggesting that non-pharmacologic (e.g., conditioned reinforcing) effects might contribute to the maintenance of lever pressing under these conditions.
Topics: Animals; Cocaine; Conditioning, Operant; Dose-Response Relationship, Drug; Female; Heroin; Macaca mulatta; Male; Morphine Dependence; Narcotics; Reinforcement Schedule; Self Administration; Substance Withdrawal Syndrome
PubMed: 19194694
DOI: 10.1007/s00213-009-1471-1 -
Biochemistry Sep 2013The pharmacological function of heroin requires an activation process that transforms heroin into 6-monoacetylmorphine (6-MAM), which is the most active form. The...
The pharmacological function of heroin requires an activation process that transforms heroin into 6-monoacetylmorphine (6-MAM), which is the most active form. The primary enzyme responsible for this activation process in human plasma is butyrylcholinesterase (BChE). The detailed reaction pathway of the activation process via BChE-catalyzed hydrolysis has been explored computationally, for the first time, in this study via molecular dynamics simulation and first-principles quantum mechanical/molecular mechanical free energy calculations. It has been demonstrated that the whole reaction process includes acylation and deacylation stages. The acylation consists of two reaction steps, i.e., the nucleophilic attack on the carbonyl carbon of the 3-acetyl group of heroin by the hydroxyl oxygen of the Ser198 side chain and the dissociation of 6-MAM. The deacylation also consists of two reaction steps, i.e., the nucleophilic attack on the carbonyl carbon of the acyl-enzyme intermediate by a water molecule and the dissociation of the acetic acid from Ser198. The calculated free energy profile reveals that the second transition state (TS2) should be rate-determining. The structural analysis reveals that the oxyanion hole of BChE plays an important role in the stabilization of rate-determining TS2. The free energy barrier (15.9 ± 0.2 or 16.1 ± 0.2 kcal/mol) calculated for the rate-determining step is in good agreement with the experimentally derived activation free energy (~16.2 kcal/mol), suggesting that the mechanistic insights obtained from this computational study are reliable. The obtained structural and mechanistic insights could be valuable for use in the future rational design of a novel therapeutic treatment of heroin abuse.
Topics: Acylation; Butyrylcholinesterase; Heroin; Humans; Hydrolysis; Metabolic Networks and Pathways; Molecular Dynamics Simulation; Quantum Theory; Thermodynamics
PubMed: 23992153
DOI: 10.1021/bi400709v -
Psychopharmacology Oct 2018Drug addiction is a complex disease that is impacted by numerous factors. One such factor, time of day, influences drug intake, but there have been no investigations of...
RATIONALE
Drug addiction is a complex disease that is impacted by numerous factors. One such factor, time of day, influences drug intake, but there have been no investigations of how time of day affects the amount of drug taken and the development of addiction-like behavior. Previous data from our group show circadian disruption in rats given access to heroin during the light phase, which is important because circadian disruption, itself, can increase drug intake. Thus, the goal of this experiment was to determine how time of day of access affects heroin self-administration and the development of addiction-like behaviors including escalation of heroin intake, willingness to work for heroin on a progressive ratio schedule of reinforcement, seeking during extinction, incubation of seeking, and reinstatement of heroin-seeking behavior.
MATERIALS AND METHODS
Male Sprague Dawley rats were given the opportunity to self-administer heroin for 6 h per trial during the second half of either the light or dark phase for 18 trials, including one progressive ratio challenge. Rats then underwent 14 days of abstinence, with a 5-h extinction test occurring on both the first and the 14th days of abstinence. The second extinction test was followed by a heroin prime and 1 h of reinstatement testing. On the following day, a subset of rats were tested in an additional extinction test where rats were tested either at the same time of the day as their previous self-administration sessions or during the opposite light/dark phase.
RESULTS
Relative to Light Access rats, Dark Access rats took more heroin, exhibited more goal-directed behavior, exhibited more seeking during the dark phase, failed to extinguish seeking during the 5-h extinction test in the dark phase, and exhibited greater incubation of heroin seeking following abstinence. However, Dark Access rats did not escalate drug taking over trials, work harder for drug, or seek more during drug-induced reinstatement than Light Access rats.
CONCLUSIONS
These results show that time of access to heroin affects overall heroin intake and seeking in extinction, but does not affect other addiction-like behaviors in rats.
Topics: Animals; Behavior, Addictive; Circadian Rhythm; Disease Models, Animal; Extinction, Psychological; Heroin; Heroin Dependence; Male; Rats; Rats, Sprague-Dawley; Reinforcement, Psychology; Self Administration
PubMed: 30178302
DOI: 10.1007/s00213-018-4990-9 -
The Journal of Adolescent Health :... Aug 2019Although estimates of heroin and injection drug use (IDU) among U.S. adolescents have remained low and stable, national data may mask local variation in use. Adolescent...
PURPOSE
Although estimates of heroin and injection drug use (IDU) among U.S. adolescents have remained low and stable, national data may mask local variation in use. Adolescent use may be higher in urban areas, many of which have historically high rates of heroin use and IDU. We investigate trends in heroin use and IDU among 9th-12th grade students in major urban centers in the U.S.
METHODS
We used local Youth Risk Behavior Survey data from all large, urban school districts (n = 9) with at least 5 years of weighted, publicly available data. We used time series mean estimation to estimate the prevalence of heroin use and IDU among high school students from 1999 to 2017 and used logistic regression to test for linear and quadratic trends.
RESULTS
We observed statistically significant linear increases in (1) lifetime heroin use in New York (β = .43, 1%-3.9%), Chicago (β = .15, 3.1%-4.6%), and Milwaukee (β = .35, 2.8%-7.4%); and (2) lifetime IDU in New York (β = .34, .8%-2.7%), Orange County (β = .17, 2.2%-3.5%), and Miami-Dade County (β = .16, 2.7%-3.9%). Only San Bernardino experienced significant decreases in heroin use (β = -.34, 4.6%-1.6%) and IDU (β = -.20, 2.5%-1.9%) over the time period.
CONCLUSIONS
In contrast to national trends, the prevalence of heroin use is increasing among adolescents in certain urban centers in the U.S. Our results illustrate that national averages mask local variation in adolescent heroin use. Further research with locally representative samples is needed to inform public health policy and practice, especially in cities where heroin problems have been historically endemic and continue to rise.
Topics: Adolescent; Female; Health Surveys; Heroin; Humans; Male; Prevalence; Risk-Taking; Schools; Students; Substance Abuse, Intravenous; United States; Urban Population
PubMed: 31331542
DOI: 10.1016/j.jadohealth.2019.03.026 -
Bioconjugate Chemistry Nov 2021Opioid use disorders and fatal overdose due to consumption of fentanyl-laced heroin remain a major public health menace in the United States. Vaccination may serve as a...
Opioid use disorders and fatal overdose due to consumption of fentanyl-laced heroin remain a major public health menace in the United States. Vaccination may serve as a promising potential remedy to combat accidental overdose and to mitigate the abuse potential of opioids. We previously reported the heroin and fentanyl monovalent vaccines carrying, respectively, a heroin hapten, 6-AmHap, and a fentanyl hapten, AmFenHap, conjugated to tetanus toxoid (TT). Herein, we describe the mixing of these antigens to formulate a bivalent vaccine adjuvanted with liposomes containing monophosphoryl lipid A (MPLA) adsorbed on aluminum hydroxide. Immunization of mice with the bivalent vaccine resulted in IgG titers of >10 against both haptens. The polyclonal sera bound heroin, 6-acetylmorphine, morphine, and fentanyl with dissociation constants () of 0.25 to 0.50 nM. Mice were protected from the anti-nociceptive effects of heroin, fentanyl, and heroin +9% (w/w) fentanyl. No cross-reactivity to methadone and buprenorphine was observed . Naloxone remained efficacious in immunized mice. These results highlighted the potential of combining TT-6-AmHap and TT-AmFenHap to yield an efficacious bivalent vaccine that could ablate heroin and fentanyl effects. This vaccine warrants further testing to establish its potential translatability to humans.
Topics: Heroin
PubMed: 34076427
DOI: 10.1021/acs.bioconjchem.1c00179 -
The International Journal of... Dec 2023There is a strong link between chronic stress and vulnerability to drug abuse and addiction. Corticotropin releasing factor (CRF) is central to the stress response that...
BACKGROUND
There is a strong link between chronic stress and vulnerability to drug abuse and addiction. Corticotropin releasing factor (CRF) is central to the stress response that contributes to continuation and relapse to heroin abuse. Chronic heroin exposure can exacerbate CRF production, leading to dysregulation of the midbrain CRF-dopamine-glutamate interaction.
METHODS
Here we investigated the role of midbrain CRF1 receptors in heroin self-administration and assessed neuroplasticity in CRF1 receptor expression in key opioid addiction brain regions.
RESULTS
Infusions of antalarmin (a CRF1 receptor antagonist) into the ventral tegmental area (VTA) dose dependently reduced heroin self-administration in rats but had no impact on food reinforcement or locomotor activity in rats. Using RNAscope in situ hybridization, we found that heroin, but not saline, self-administration upregulated CRF1 receptor mRNA in the VTA, particularly on dopamine neurons. AMPA GluR1 and dopamine reuptake transporter mRNA in VTA neurons were not affected by heroin. The western-blot assay showed that CRF1 receptors were upregulated in the VTA and nucleus accumbens. No significant changes in CRF1 protein expression were detected in the prefrontal cortex, insula, dorsal hippocampus, and substantia nigra. In addition, we found that 15 days of environmental enrichment implemented after heroin self-administration does not reverse upregulation of VTA CRF1 receptor mRNA but it downregulates dopamine transporter mRNA.
CONCLUSIONS
Overall, these data suggest that heroin self-administration requires stimulation of VTA CRF1 receptors and upregulates their expression in brain regions involved in reinforcement. Such long-lasting neuroadaptations may contribute to continuation of drug use and relapse due to stress exposure and are not easily reversed by EE exposure.
Topics: Rats; Animals; Corticotropin-Releasing Hormone; Heroin; Dopamine; Ventral Tegmental Area; Self Administration; Recurrence; RNA, Messenger
PubMed: 37864842
DOI: 10.1093/ijnp/pyad060