naloxone and Alcohol-Related-Disorders

We previously showed that, by activating innate immune receptors Toll-like 4 (TLR4), adolescent intermittent ethanol (EtOH) exposure causes neuroinflammation, myelin damage, and behavioral dysfunctions. Recent findings reveal that clinically used opioid antagonists naltrexone (NT) and naloxone (NX) inhibit opioid-induced TLR4 signaling and that NT, NX, and nalmefene (NF), the 6-methylene derivative of NX, are able to reduce alcohol drinking escalation.. NF (0.1 mg/kg, intraperitoneally) was injected 1 hour prior to EtOH (3 g/kg, intraperitoneally) following intermittent treatment in female (PND35) adolescent mice. Inflammatory molecules, myelin proteins, and apoptotic markers were assessed in the prefrontal cortex (PFC) and striatum/nucleus accumbens (STR/NAcc). The effect of NF on alcohol drinking preference was evaluated in both the wild-type and TLR4 knockout (KO) adolescent mice. Using astroglial cells, the inhibitory potential of NT, NX, and NF on lipopolysaccharide (LPS), or the EtOH-triggered TLR4 response, was compared.. Our findings indicate that NF prevents the up-regulation of cytokines (IL-1β, IL-17A, TNF-α), chemokines (MCP-1, MIP-1, KC), and pro-inflammatory mediators (iNOS, COX-2), along with myelin damage and apoptotic events, in both PFC and STR/NAcc. NF also abolishes EtOH-induced escalation of alcohol preference/consumption, but has no effect when administered to TLR4-KO mice. In vitro experiments indicate that NX and NF inhibit TLR4 activation upon LPS or EtOH stimulation. Immunofluorescence studies and lipid rafts isolation show that NF is able to prevent TLR4 translocation to lipid rafts/caveolae in astrocytes.. These results suggest that NF prevents neuroinflammation and brain damage by blocking the TLR4 response and also support the role of central pro-inflammatory immune signaling in the modulation of alcohol consumption/addiction.

Topics: Alcohol Drinking; Alcohol-Related Disorders; Animals; Astrocytes; Cell Death; Chemokines; Drug Evaluation, Preclinical; Ethanol; Female; Membrane Microdomains; Mice, Inbred C57BL; Mice, Knockout; Myelin Sheath; Naloxone; Naltrexone; Narcotic Antagonists; Primary Cell Culture; Toll-Like Receptor 4

Millions of people with substance use disorders (SUDs) need, but do not receive, treatment. Delivering SUD treatment in primary care settings could increase access to treatment because most people visit their primary care doctors at least once a year, but evidence-based SUD treatments are underutilized in primary care settings. We used an organizational readiness intervention comprised of a cluster of implementation strategies to prepare a federally qualified health center to deliver SUD screening and evidence-based treatments (extended-release injectable naltrexone (XR-NTX) for alcohol use disorders, buprenorphine/naloxone (BUP/NX) for opioid use disorders and a brief motivational interviewing/cognitive behavioral -based psychotherapy for both disorders). This article reports the effects of the intervention on key implementation outcomes.. To assess changes in organizational readiness we conducted pre- and post-intervention surveys with prescribing medical providers, behavioral health providers and general clinic staff (N = 69). We report on changes in implementation outcomes: acceptability, perceptions of appropriateness and feasibility, and intention to adopt the evidence-based treatments. We used Wilcoxon signed rank tests to analyze pre- to post-intervention changes.. After 18 months, prescribing medical providers agreed more that XR-NTX was easier to use for patients with alcohol use disorders than before the intervention, but their opinions about the effectiveness and ease of use of BUP/NX for patients with opioid use disorders did not improve. Prescribing medical providers also felt more strongly after the intervention that XR-NTX for alcohol use disorders was compatible with current practices. Opinions of general clinic staff about the appropriateness of SUD treatment in primary care improved significantly.. Consistent with implementation theory, we found that an organizational readiness implementation intervention enhanced perceptions in some domains of practice acceptability and appropriateness. Further research will assess whether these factors, which focus on individual staff readiness, change over time and ultimately predict adoption of SUD treatments in primary care.

Topics: Adult; Alcohol-Related Disorders; Attitude of Health Personnel; Buprenorphine; Cognitive Behavioral Therapy; Delayed-Action Preparations; Delivery of Health Care; Feasibility Studies; Female; Financing, Government; Humans; Los Angeles; Male; Middle Aged; Motivational Interviewing; Naloxone; Naltrexone; Narcotic Antagonists; Opioid-Related Disorders; Primary Health Care; United States

Opioid receptors are involved in reinstatement of alcohol seeking, yet there are no reports of their role in reacquisition of an extinguished alcohol seeking response. Here we investigated the effects of the opioid antagonist naloxone on reacquisition and compared these effects with those on acquisition. Rats were trained, extinguished, then retrained to respond for alcoholic beer. Upon retraining, a second group of rats with no prior experience with the contingency between response and reinforcer was trained under the same conditions. Reacquisition was faster than acquisition. Systemic injection of naloxone (1.25 or 5 mg/kg) reduced reacquisition but had no effect on acquisition. These results suggest that reacquisition and acquisition of alcohol seeking have dissociable neurochemical substrates.

Topics: Alcohol-Related Disorders; Analysis of Variance; Animals; Conditioning, Operant; Disease Models, Animal; Dose-Response Relationship, Drug; Extinction, Psychological; Male; Naloxone; Narcotic Antagonists; Rats; Rats, Long-Evans; Reaction Time; Self Administration

Topics: Alcohol Deterrents; Alcohol-Related Disorders; Alcoholism; Humans; Mental Disorders; Naloxone; Patient Compliance; Practice Guidelines as Topic; Psychotherapy; Thiamine; Vitamin B Complex

Contexts associated with the availability of alcohol can induce craving in humans and alcohol seeking in rats. The opioid antagonist naltrexone attenuates context-induced reinstatement (renewal) of alcohol seeking and suppresses neuronal activation in the basolateral amygdaloid complex and dorsal hippocampus induced by such reinstatement. The objective of this study was to determine whether pharmacological blockade of opioid receptors in the basolateral amygdala or dorsal hippocampus would attenuate the context-induced reinstatement of alcohol seeking. Rats were trained to self-administer alcohol in one context (Context A), extinguished in a distinct context (Context B) and then tested for reinstatement of alcohol seeking in A and B contexts. Prior to the test session, rats were bilaterally microinjected with 0, 333 or 1000ng (total) naloxone methiodide into the basolateral amygdala or dorsal hippocampus. Naloxone methiodide in the amygdala, but not the hippocampus, dose dependently suppressed context-induced reinstatement. This suggests that opioid transmission in the basolateral amygdaloid complex is an important mediator of context-induced alcohol seeking.

Topics: Alcohol-Related Disorders; Amygdala; Animals; Appetitive Behavior; Association Learning; Dose-Response Relationship, Drug; Environment; Ethanol; Hippocampus; Male; Motivation; Naloxone; Narcotic Antagonists; Quaternary Ammonium Compounds; Rats; Rats, Wistar; Receptors, Opioid; Self Administration

Ethanol and the neuroactive steroids have interactive neuropharmacological effects and chronic ethanol administration blunts the ethanol-induced increase in neuroactive steroid levels in rodent plasma and brain. Few studies have explored neuroactive steroid regulation in alcohol-dependent human subjects. In fact, the regulation of adrenal neuroactive steroids has not been well defined in healthy controls. We thus explored the regulation of two neuroactive steroids, pregnenolone sulfate (PREG-S) and deoxycorticosterone, by pharmacological challenges to the hypothalamic-pituitary-adrenal (HPA) axis in healthy controls and 1-month abstinent alcohol-dependent patients with co-occurring nicotine dependence. Plasma levels of PREG-S and deoxycorticosterone were measured by radioimmunoassay in controls and alcohol-dependent patients after challenges of naloxone, ovine corticotrophin releasing hormone (oCRH), dexamethasone, cosyntropin, and cosyntropin following high-dose dexamethasone. In addition, basal diurnal measures of both hormones were obtained. PREG-S plasma levels in healthy controls were increased by cosyntropin challenge (with and without dexamethasone pretreatment) and decreased by dexamethasone challenge. However, PREG-S concentrations were not altered by naloxone or oCRH challenges, suggesting that PREG-S is not solely regulated by hypothalamic or pituitary stimulation. Deoxycorticosterone, in contrast, is regulated by HPA challenge stimulation in a manner similar to cortisol. Alcohol-dependent patients had a blunted PREG-S response to cosyntropin (with and without dexamethasone pretreatment). Furthermore, the time to peak deoxycorticosterone response following oCRH was delayed in alcohol-dependent patients compared to controls. These results indicate that plasma PREG-S and deoxycorticosterone levels are differentially regulated by HPA axis modulation in human plasma. Further, alcohol-dependent patients show a blunted PREG-S response to adrenal stimulation and a delayed deoxycorticosterone response to oCRH challenge.

Topics: Adult; Alcohol-Related Disorders; Analysis of Variance; Animals; Case-Control Studies; Corticotropin-Releasing Hormone; Cosyntropin; Desoxycorticosterone; Dexamethasone; Drug Synergism; Feedback, Physiological; Hormones; Humans; Hypothalamo-Hypophyseal System; Male; Matched-Pair Analysis; Middle Aged; Naloxone; Narcotic Antagonists; Pituitary-Adrenal System; Pregnenolone; Reference Values; Sheep; Stimulation, Chemical; Tobacco Use Disorder

To examine the relationship between key patient variables and variation in naloxone dose (from the standard dose of 1.6 mg IMI) administered by ambulance paramedics in the prehospital management of heroin overdose.. A retrospective analysis of 7985 ambulance patient care records of non-fatal heroin overdose cases collected in greater metropolitan Melbourne. The main outcome measure was the dose of intramuscular naloxone required to increase the level of consciousness and the respiratory rate in patients presenting with suspected heroin overdose. Key patient variables influencing the dose that were recorded included: age, sex, initial patient presentation and reported concurrent alcohol use.. Multinomial logistic regression revealed that patients with higher levels of consciousness and respiratory rates on arrival of the paramedic crew were more likely to receive a less than standard dose of naloxone. Conversely, patients with lower levels of consciousness and low respiratory rates received greater than standard doses of naloxone for resuscitation. Patients who received greater than the standard dose of naloxone were 2.25 (95% CI, 1.83-2.77) times more likely to have been under the influence of alcohol when consuming the heroin that resulted in overdose.. The concurrent use of alcohol with heroin resulted in the use of greater than standard doses of naloxone by paramedics in resuscitating overdose patients. It is possible that the higher dose of naloxone is required to reverse the combined effects of alcohol and heroin. There was also a link between initial patient presentation and the dose of naloxone required for resuscitation. In light of these findings, it would appear that initial patient presentation and evidence of alcohol use might be useful guides as to providing the most effective dose of naloxone in the prehospital setting.

Topics: Adolescent; Adult; Aged; Alcohol-Related Disorders; Dose-Response Relationship, Drug; Drug Overdose; Emergency Medical Services; Female; Heroin; Heroin Dependence; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Retrospective Studies