Opioid abuse is now the most common cause of accidental death in the US. Although opioids and most other drugs of abuse acutely increase signaling mediated by midbrain dopamine (DA)-synthesizing neurons, little is known about long-lasting changes in DA cells that may contribute to continued opioid abuse, craving, and relapse. A better understanding of the molecular and cellular bases of opioid abuse could lead to advancements in therapeutics. This study comprises, to our knowledge, the first unbiased examination of genome-wide changes in midbrain gene expression associated with human opioid abuse. Our analyses identified differentially expressed genes and distinct gene networks associated with opioid abuse, specific genes with predictive capability for subject assignment to the opioid abuse cohort, and genes most similarly affected in chronic opioid and cocaine abusers. We also identified differentially expressed long noncoding RNAs capable of regulating known drug-responsive protein-coding genes. Opioid-regulated genes identified in this study warrant further investigation as potential biomarkers and/or therapeutic targets for human substance abuse.

Opioid-targeted vaccines represent an emerging treatment strategy for opioid use disorder. To determine whether concurrent vaccination against two commonly abused opioids (fentanyl and heroin) would confer broader spectrum opioid coverage, the current study evaluated dual fentanyl/heroin conjugate vaccine effectiveness using a warm water tail-withdrawal and a fentanyl/heroin-vs-food choice procedure in male and female rats across a 105-day observation period. Vaccine administration generated titers of high-affinity antibodies to both fentanyl and heroin sufficient to decrease the antinociceptive potency of fentanyl (25-fold), heroin (4.6-fold), and a 1:27 fentanyl/heroin mixture (7.5-fold). Vaccination did not alter the antinociceptive potency of the structurally dissimilar opioid agonist methadone. For comparison, continuous treatment with a naltrexone dose (0.032 mg/kg/h) shown previously to produce clinically relevant plasma-naltrexone levels decreased the antinociceptive potency of fentanyl, heroin, and the 1:27 fentanyl/heroin mixture by approximately 20-fold. Naltrexone treatment also shifted the potency of 1:27 fentanyl/heroin mixture in a drug-vs-food choice self-administration procedure 4.3-fold. In contrast, vaccination did not attenuate 1:27 fentanyl/heroin mixture self-administration in the drug-vs-food choice procedure. These data demonstrate that a vaccine can simultaneously attenuate the thermal antinociceptive effects of two structurally dissimilar opioids. However, the vaccine did not attenuate fentanyl/heroin mixture self-administration, suggesting a greater magnitude of vaccine responsiveness is required to decrease opioid reinforcement relative to antinociception.

Classical psychedelics represent a subgroup of serotonergic psychoactive substances characterized by their distinct subjective effects on the human psyche. Another unique attribute of this drug class is that such effects become less apparent after repeated exposure within a short time span. The classification of psychedelics as a subgroup within the serotonergic drug family and the tolerance to their effects are replicated by the murine head twitch response (HTR) behavioral paradigm. Here, we aimed to assess tolerance and cross-tolerance to HTR elicited by psychedelic and nonpsychedelic serotonin 2A receptor (5-HT 2A R) agonists in mice. We show that repeated (4 days) administration of the psychedelic 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induced a progressive decrease in HTR behavior. Tolerance to DOI-induced HTR was also observed 24 h after a single administration of this psychedelic. Pretreatment with the 5-HT 2A R antagonist M100907 reduced not only the acute manifestation of DOI-induced HTR, but also the development of tolerance to HTR. Additionally, cross-tolerance became apparent between the psychedelics DOI and lysergic acid diethylamide (LSD), whereas repeated administration of the nonpsychedelic 5-HT 2A R agonist lisuride did not affect the ability of these two psychedelics to induce HTR. At the molecular level, DOI administration led to down-regulation of 5-HT 2A R density in mouse frontal cortex membrane preparations. However, development of tolerance to the effect of DOI on HTR remained unchanged in β-arrestin-2 knockout mice. Together, these data suggest that tolerance to HTR induced by psychedelics involves activation of the 5-HT 2A R, is not observable upon repeated administration of nonpsychedelic 5-HT 2A R agonists, and occurs via a signaling mechanism independent of β-arrestin-2.

Psychedelic research across different disciplines and biological levels is growing at a remarkably fast pace. In the prospect of a psychedelic drug becoming again an approved treatment, much of these efforts have been oriented toward exploring the relationship between the actual psychedelic effects and those manifestations of therapeutic interest. Considering the central role of the serotonin 5‐HT2A receptor in the distinct effects of psychedelics in human psyche, neuropharmacology sits at the center of this debate and exploratory continuum. Here we discuss some of the most recent findings in human studies and contextualize them considering previous preclinical models studying phenomena related to synaptic plasticity. A special emphasis is placed on knowledge gaps, challenges, and limitations to evaluate the underpinnings of psychedelics’ potential antidepressant action.

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Known classic psychedelic serotonin 2A receptor (5-HT 2A R) agonists retain a tryptamine or phenethylamine at their structural core. However, activation of the 5-HT 2A R can be elicited by drugs lacking these fundamental scaffolds. Such is the case of the Nsubstituted piperazine quipazine. Here, we show that quipazine bound to and activated 5-HT 2A R as measured by [ 3 H]ketanserin binding displacement, Ca 2+ mobilization, and accumulation of the canonical G q/11 signaling pathway mediator inositol monophosphate (IP 1 ) in vitro and in vivo. Additionally, quipazine induced via 5-HT 2A R an expression pattern of immediate early genes (IEG) in the mouse somatosensory cortex consistent with that of classic psychedelics. In the mouse head-twitch response (HTR) model of psychedelic-like action, quipazine produced a lasting effect with high maximal responses during the peak effect that were successfully blocked by the 5-HT 2A R antagonist M100907 and absent in 5-HT 2A R knockout (KO) mice. The acute effect of quipazine on HTR appeared to be unaffected by serotonin depletion and was independent from 5-HT 3 R activation. Interestingly, some of these features were shared by its deaza bioisostere 2-NP, but not by other closely related piperazine congeners, suggesting that quipazine might represent a distinct cluster within the family of psychoactive piperazines. Together, our results add to the mounting evidence that quipazine's profile matches that of classic psychedelic 5-HT 2A R agonists at cellular signaling and behavioral pharmacology levels.