Fernando Boix

Background and Purpose: In some individuals, opioid use leads to decreased interest in socially relevant rewards. Recent studies showed that after extended‐access heroin self‐administration, rats strongly prefer social interaction over single unit‐dose heroin infusions. We hypothesized that this strong social preference results from access to a suboptimal heroin dose during testing, and individual differences in heroin versus social choice would emerge if rats were given access to their ‘preferred’ heroin dose. Experimental Approach: In Experiment 1, we trained male rats to lever‐press for social interaction, followed by heroin self‐administration under continuous‐access, no‐timeout schedule, which promotes burst‐patterned heroin taking. We then tested the rats for choice between single‐unit heroin dose and 1‐min full‐contact social interaction, or 5‐min heroin‐access (sufficient for burst‐patterned heroin taking) and 5‐min social interaction. In Experiment 2, we extended the 5‐min access procedure to female rats and tested heroin versus limited‐contact (screen‐based) social interaction. We also manipulated response requirements (effort) for heroin. Key Results: Rats given a single‐unit heroin dose during choice testing, strongly preferred social interaction. In rats given 5‐min heroin‐access, large individual differences in heroin preference emerged. These differences were independent of sex, social‐interaction conditions and effort manipulations. High heroin intake and burst‐patterned heroin taking during self‐administration, and high heroin seeking during abstinence predicted individual differences in heroin preference. Conclusion and Implications: Access to ‘preferred’ heroin doses during the choice tests leads to stable and effort‐independent individual differences in heroin preference. This procedure provides a platform to study mechanisms of resilience and vulnerability to opioid addiction.

Background and Purpose: Heroin and cocaine users tailor their dosage, frequency and administration route to maximise the drugs' effects or prevent withdrawal symptoms. Counterintuitively, preclinical self‐administration and choice experiments employ, almost invariably and regardless of the pharmacokinetic properties of the drug under examination, fixed unit‐doses and timeouts (after unit‐doses) largely resulting in uniform drug‐taking patterns. This uniformity contrasts with the large variability observed in humans, which serves as critical indicator of addiction severity and treatment success. Here, by combining behavioural and pharmacokinetics assessments, we revealed that drug self‐administration procedures without timeouts may overcome this limitation.Experimental Approach: We analysed heroin‐ and cocaine‐taking patterns and seeking and estimated drug‐brain levels in the presence or absence of timeout under different training conditions.Key Results: Removing timeouts had a profound effect on heroin‐taking patterns and seeking, promoting the emergence of burst‐like intake, yielding higher brain peak concentrations of heroin. In contrast, the removal of timeout had marginal impact on cocaine‐taking patterns and seeking.Conclusion and Implications: The removal of timeout during self‐administration revealed distinct cocaine and heroin patterns, with the latter closely resembling human heroin use patterns.

Background and Purpose. Heroin and cocaine users tailor their dosage, frequency, and method of administration, to maximize the drugs’ effects or prevent withdrawal symptoms. Counterintuitively, preclinical self-administration and choice experiments employ fixed unit-doses and timeouts (after doses) largely resulting in uniform drug-taking patterns. The application of these procedures also disregards the distinct pharmacokinetic properties of heroin and cocaine. This uniformity contrasts with the significantly different ways humans tailor their dosage and frequency of heroin and cocaine use. Here, by combining behavioral and pharmacokinetics assessments we revealed that self-administration procedures lacking the timeout may overcomes this limitation. Experimental Approach. We analyzed heroin and cocaine taking- and seeking-patterns and estimated drug-brain levels in the presence or absence of timeout. We further assessed how absence of timeout and the availability of drug or social peer (access time to the two rewards) affect drug preference in choice procedures. Key Results. Removing the timeout had a profound effect on heroin-taking patterns and seeking, promoting the emergence of burst-like intake, yielding higher brain peak concentrations of heroin. Timeout removal had marginal impact on cocaine taking patterns and seeking. Increasing the access time to the drug in the discrete choice procedure resulted in higher drug intake and increased preference for heroin, but it did not alter cocaine preference. Conclusion and Implications. Removing timeout during self-administration revealed distinct heroin and cocaine taking patterns. Self-administration without timeout and access to high heroin doses during choice more closely mimic human heroin taking patterns and related behaviors, including maladaptive choices.

Heroin and cocaine users tailor their dosage and frequency of use, as well as their method of administration, to maximize the drugs’ pleasurable effects and prevent withdrawal symptoms. On the other hand, many preclinical self-administration and choice experiments employ fixed unit doses and mandatory timeouts after doses (known as discrete dimension procedures). These restrictions fail to consider the distinct pharmacokinetic properties of heroin and cocaine, leading to uniform and comparable behaviors (including drug-taking patterns). This uniformity contrasts sharply with the significantly different ways humans use heroin and cocaine, which are characterized by highly individualized drug use behaviors. Here, we introduce a no-timeout procedure that overcomes this limitation (continuous dimension procedure). We analyzed the heroin and cocaine taking- and seeking-patterns and estimated drug-brain levels in the presence or absence of timeout between drug injections. We further assessed how absence of timeout and the availability of drug or social peer (access time to the two rewards) affect drug preference. Removing the timeout had a profound effect on pattern of heroin taking and seeking, promoting the emergence of burst-like drug intake and social withdrawal as revealed by a discrete choice procedure. On the other hand, timeout removal had a lesser impact on cocaine taking and seeking and did not impact social preference. By removing timeout during self-administration and increasing the access time during choice resulted in a self-administration procedure that more closely mimic human heroin intake, offering a platform to identify novel medications.

Immunotherapeutic interventions that block drug effects by binding drug molecules to specific antibodies in the bloodstream have shown promising effects in animal studies. For heroin, which effects are mainly mediated by the metabolites 6‐acetylmorphine (6‐AM; also known as 6‐monoacetylmorphine or 6‐MAM) and morphine, the optimal antibody specificity has been discussed. In rodents, 6‐AM specific antibodies have been recommended based on the rapid metabolism of heroin to 6‐AM in the bloodstream. Since the metabolic rate of heroin in blood is unsettled in humans, we examined heroin metabolism with state‐of–the‐art analytical methodology (UHPLC–MS/MS) in freshly drawn human whole blood incubated with a wide range of heroin concentrations (1–500 μM). The half‐life of heroin was highly concentration dependent, ranging from 1.2–1.7 min for concentrations at or above 25 μM, and gradually increasing to approximately 20 min for 1 μM heroin. At concentrations that can be attained in the bloodstream shortly after an i.v. injection, approximately 70% was transformed into 6‐AM within 3 min, similar to previous observations in vivo. Our results indicate that blood enzymes play a more important role for the rapid metabolism of heroin in humans than previously assumed. This points to 6‐AM as an important target for an efficient immunotherapeutic approach to block heroin effects in humans.

Background and Purpose: Studies using intermittent‐access drug self‐administration show increased motivation to take and seek cocaine and fentanyl, relative to continuous access. In this study, we examined the effects of intermittent‐ and continuous‐access self‐administration on heroin intake, patterns of self‐administration and cue‐induced heroin‐seeking, after forced or voluntary abstinence, in male and female rats. We also modelled brain levels of heroin and its active metabolites.Experimental Approach: Rats were trained to self‐administer a palatable solution and then heroin (0.075 mg·kg⁻¹ per inf) either continuously (6 h·day⁻¹; 10 days) or intermittently (6 h·day⁻¹; 5‐min access every 30‐min; 10 days). Brain levels of heroin and its metabolites were modelled using a pharmacokinetic software. Next, heroin‐seeking was assessed after 1 or 21 abstinence days. Between tests, rats underwent either forced or voluntary abstinence. The oestrous cycle was measured using a vaginal smear test.Key Results: Intermittent access exacerbated heroin self‐administration and was characterized by a burst‐like intake, yielding higher brain peaks of heroin and 6‐monoacetylmorphine concentrations. Moreover, intermittent access increased cue‐induced heroin‐seeking during early, but not late abstinence. Heroin‐seeking was higher in females after intermittent, but not continuous access, and this effect was independent of the oestrous cycle.Conclusions and Implications: Intermittent heroin access in rats resembles critical features of heroin use disorder: a self‐administration pattern characterized by repeated large doses of heroin and higher relapse vulnerability during early abstinence. This has significant implications for refining animal models of substance use disorder and for better understanding of the neuroadaptations responsible for this disorder.LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc

03.05.2021: Kommentar - Man finner i artikkelen en høy korrelasjon mellom de variablene som har vært brukt som prediktorvariabler.

Aims To study whether the preparation procedure, and its acidic and heating conditions, used by heroin users to prepare heroin for intravenous administration affects the final composition of the fluid to be injected. Methods Samples from different seizures of illegal heroin provided by the Norwegian police were prepared by adding water and ascorbic acid before heating under controlled conditions in the laboratory. Further, three seizures were prepared with different amounts of ascorbic or citric acid relative to their diacetylmorphine content. Pure diacetylmorphine base or salt was also submitted to the procedure applying two different heating intensities. The seizures and the final product after preparation were analysed for diacetylmorphine, 6‐acetylmorphine, and morphine using liquid chromatography with tandem mass spectrometry (LC‐MS‐MS). Results After preparation, a decrease of 19.8% (25^th and 75^th percentiles: ‐29.2 and ‐15.3) in the initial diacetylmorphine content was observed. Both the 6‐acetylmorphine and morphine content increased but, due to their low content in the initial product, diacetylmorphine still represented 83.9% (25^th and 75^th percentiles: 77.3 and 88.0) of the sum of these three opioids in the final solution. The loss of water during preparation caused an increase in the concentration of diacetylmorphine, 6‐acetylmorphine, and morphine, depending on the heating intensity applied. The content of these opioids was affected by the quantity and type of acid added in relation to the heroin purity, the level of diacetylmorphine dissolved being proportional to the amount of ascorbic acid but not citric acid in the sample with high heroin purity. Conclusions Preparation of heroin for intravenous injection appears to change the amount or concentration of diacetylmorphine and its active metabolites, 6‐acetylmorphine and morphine, in the final product, depending on heroin purity, amount and type of acid used, or heating conditions. These circumstances can contribute to unintentional variations in the potency of the final injected solution, and therefore affect the outcome after injection.