Dynamic vaccine blocks relapse to compulsive intake of heroin

Abstract

Heroin addiction, a chronic relapsing disorder characterized by excessive drug taking and seeking, requires constant psychotherapeutic and pharmacotherapeutic interventions to minimize the potential for further abuse. Vaccine strategies against many drugs of abuse are being developed that generate antibodies that bind drug in the bloodstream, preventing entry into the brain and nullifying psychoactivity. However, this strategy is complicated by heroin's rapid metabolism to 6-acetylmorphine and morphine. We recently developed a "dynamic" vaccine that creates antibodies against heroin and its psychoactive metabolites by presenting multihaptenic structures to the immune system that match heroin's metabolism. The current study presents evidence of effective and continuous sequestration of brain-permeable constituents of heroin in the bloodstream following vaccination. The result is efficient blockade of heroin activity in treated rats, preventing various features of drugs of abuse: heroin reward, drug-induced reinstatement of drug seeking, and reescalation of compulsive heroin selfadministration following abstinence in dependent rats. The dynamic vaccine shows the capability to significantly devalue the reinforcing and motivating properties of heroin, even in subjects with a history of dependence. In addition, targeting a less brainpermeable downstream metabolite, morphine, is insufficient to prevent heroin-induced activity in these models, suggesting that heroin and 6-acetylmorphine are critical players in heroin's psychoactivity. Because the heroin vaccine does not target opioid receptors or common opioid pharmacotherapeutics, it can be used in conjunction with available treatment options. Thus, our vaccine represents a promising adjunct therapy for heroin addiction, providing continuous heroin antagonism, requiring minimal medical monitoring and patient compliance.immunotherapy | antinociception | progressive ratio

Hypocretin Receptor 2 Antagonism Dose-Dependently Reduces Escalated Heroin Self-Administration in Rats

“…In this escalation phase, all groups were allowed to nose poke for food and water on an FR1 schedule while in the test chambers. Rats were allowed 15 days of daily escalation sessions, at the end of which ShA rats displayed stable levels of heroin self-administration, whereas LgA rats displayed an escalation of heroin intake as repeatedly reported by our laboratory (data not shown; Ahmed et al, 2000b;Barbier et al, 2013;Greenwell et al, 2009a,b;Schlosburg et al, 2013;Vendruscolo et al, 2011;Walker et al, 2000).…”

“…The escalation of heroin intake observed in LgA animals contrasts with the lower, more stable intake levels observed in ShA animals (Ahmed et al, 2000b;Barbier et al, 2013;Greenwell et al, 2009a, b;Schlosburg et al, 2013;Vendruscolo et al, 2011;Walker et al, 2000). It is hypothesized that escalated heroin taking is mediated, in part, by the dysregulation of brain reward and stress systems (eg, HCRT, dynorphin, substance P and corticotropin-releasing factor; CRF) particularly within subregions of the extended amygdala via negative reinforcement mechanisms (for review, see Koob et al, 2014) Effects of acute heroin withdrawal on Hcrtr2 mRNA expression levels in reward/stress-related brain regions of heroin-naive, short access (ShA) and long access (LgA) to heroin rats.…”

Opioid Dose- and Route-Dependent Efficacy of Oxycodone and Heroin Vaccines in Rats

“…Therapeutic vaccines for heroin and prescription opioid abuse have shown efficacy in a wide range of preclinical models, demonstrating that immunization can reduce opioid distribution to the brain and attenuate opioid-related behaviors including self-administration, locomotor activation, and analgesia in mice, rats, and non-human primates (Bonese et al, 1974;Anton and Leff, 2006;Li et al, 2011Li et al, , 2014Stowe et al, 2011;Pravetoni et al, 2012bPravetoni et al, ,c, 2013Pravetoni et al, , 2014aKosten et al, 2013;Raleigh et al, 2013Raleigh et al, , 2014Schlosburg et al, 2013;Laudenbach et al, 2015;Bremer et al, 2017). However, vaccine efficacy is often tested in animals using immunization protocols involving routes of administration (e.g., intraperitoneal) and adjuvants (e.g., Freund's complete adjuvant) that are not used in humans, or at opioid doses that are suitable for the animal models chosen but are at the lower end of the range that may be abused by humans.…”

Vaccine-driven pharmacodynamic dissection and mitigation of fenethylline psychoactivity

“…21 A ‘dynamic’ variant of this general approach was recently developed to blunt heroin self-administration, wherein a single chemically-labile hapten was used to induce antibodies directed against multiple opioid metabolites. 22 These foundational studies inspired us to pursue a generalizable ‘dissection through vaccination’ method that could isolate the effects of single compounds within a structurally- and pharmacologically-diverse chemical system, such as that generated by fenethylline. 7–9 We termed the resulting approach “Determining the Identities of Species Supporting Expression of CNS-activity Through Incremental Vaccination”, or DISSECTIV (Extended Data Figure 1).…”