Tabernanthalog Reduces Motivation for Heroin and Alcohol in a Polydrug Use Model.

Background: The potential use of psychedelic drugs as therapeutics for neuropsychiatric disorders has been limited by their hallucinogenic properties. To overcome this limitation, we developed and characterized tabernanthalog (TBG), a novel analogue of the indole alkaloids ibogaine and 5-methoxy-N,N-dimethyltryptamine with reduced cardiac arrhythmogenic risk and a lack of classical psychedelic drugs-induced sensory alterations. We previously demonstrated that TBG has therapeutic efficacy in a preclinical model of opioid use disorder (OUD) in rats and in a binge model of alcohol drinking in mice. Alcohol is commonly co-used in ∼35-50% of individuals with OUD, and yet, preclinical models that recapitulate this comorbidity are lacking. Methodology: Here we employed a polydrug model of heroin and alcohol couse to screen the therapeutic efficacy of TBG on metrics of both opioid and alcohol seeking. We first exposed rats to alcohol (or control sucrose-fade solution) in the home-cage (HC), using a two-bottle binge protocol, over a period of 1 month. Rats were then split into two groups that underwent self-administration training for either intravenous heroin or oral alcohol, so that we could assess the impact of HC alcohol exposure on the self-administration of each substance separately. Thereafter, rats began self-administering both heroin and alcohol in the same sessions. Finally, we tested the effects of TBG on break points for heroin and alcohol in a progressive ratio test, where the number of lever presses required to obtain a single reward increased exponentially. Results and Conclusion: TBG effectively reduced motivation for heroin and alcohol in this test, indicating its efficacy is preserved in animals with a history of heroin and alcohol polydrug use.

Health technology assessment of diagnostic tests: a state of the art review of methods guidance from international organizations.

OBJECTIVES: To identify which international health technology assessment (HTA) agencies are undertaking evaluations of medical tests, summarize commonalities and differences in methodological approach, and highlight examples of good practice. METHODS: A methodological review incorporating: systematic identification of HTA guidance documents mentioning evaluation of tests; identification of key contributing organizations and abstraction of approaches to all essential HTA steps; summary of similarities and differences between organizations; and identification of important emergent themes which define the current state of the art and frontiers where further development is needed. RESULTS: Seven key organizations were identified from 216 screened. The main themes were: elucidation of claims of test benefits; attitude to direct and indirect evidence of clinical effectiveness (including evidence linkage); searching; quality assessment; and health economic evaluation. With the exception of dealing with test accuracy data, approaches were largely based on general approaches to HTA with few test-specific modifications. Elucidation of test claims and attitude to direct and indirect evidence are where we identified the biggest dissimilarities in approach. CONCLUSIONS: There is consensus on some aspects of HTA of tests, such as dealing with test accuracy, and examples of good practice which HTA organizations new to test evaluation can emulate. The focus on test accuracy contrasts with universal acknowledgment that it is not a sufficient evidence base for test evaluation. There are frontiers where methodological development is urgently required, notably integrating direct and indirect evidence and standardizing approaches to evidence linkage.

Neural circuits controlling choice behavior in opioid addiction.

As the opioid epidemic presents an ever-expanding public health threat, there is a growing need to identify effective new treatments for opioid use disorder (OUD). OUD is characterized by a behavioral misallocation in choice behavior between opioids and other rewards, as opioid use leads to negative consequences, such as job loss, family neglect, and potential overdose. Preclinical models of addiction that incorporate choice behavior, as opposed to self-administration of a single drug reward, are needed to understand the neural circuits governing opioid choice. These choice models recapitulate scenarios that humans suffering from OUD encounter in their daily lives. Indeed, patients with substance use disorders (SUDs) exhibit a propensity to choose drug under certain conditions. While most preclinical addiction models have focused on relapse as the outcome measure, our data suggest that choice is an independent metric of addiction severity, perhaps relating to loss of cognitive control over choice, as opposed to excessive motivational drive to seek drugs during relapse. In this review, we examine both preclinical and clinical literature on choice behavior for drugs, with a focus on opioids, and the neural circuits that mediate drug choice versus relapse. We argue that preclinical models of opioid choice are needed to identify promising new avenues for OUD therapy that are translationally relevant. Both forward and reverse translation will be necessary to identify novel treatment interventions. This article is part of the Special Issue on "Opioid-induced changes in addiction and pain circuits".

Oxytocin and orexin systems bidirectionally regulate the ability of opioid cues to bias reward seeking.

As opioid-related fatalities continue to rise, the need for novel opioid use disorder (OUD) treatments could not be more urgent. Two separate hypothalamic neuropeptide systems have shown promise in preclinical OUD models. The oxytocin system, originating in the paraventricular nucleus (PVN), may protect against OUD severity. By contrast, the orexin system, originating in the lateral hypothalamus (LH), may exacerbate OUD severity. Thus, activating the oxytocin system or inhibiting the orexin system are potential therapeutic strategies. The specific role of these systems with regard to specific OUD outcomes, however, is not fully understood. Here, we probed the therapeutic efficacy of pharmacological interventions targeting the orexin or oxytocin system on two distinct metrics of OUD severity in rats-heroin choice (versus choice for natural reward, i.e., food) and cued reward seeking. Using a preclinical model that generates approximately equal choice between heroin and food reward, we examined the impact of exogenously administered oxytocin, an oxytocin receptor antagonist (L-368,899), and a dual orexin receptor antagonist (DORA-12) on opioid choice. Whereas these agents did not alter heroin choice when rewards (heroin and food) were available, oxytocin and DORA-12 each significantly reduced heroin seeking in the presence of competing reward cues when no rewards were available. In addition, the number of LH orexin neurons and PVN oxytocin neurons correlated with specific behavioral economic variables indicative of heroin versus food motivation. These data identify a novel bidirectional role of the oxytocin and orexin systems in the ability of opioid-related cues to bias reward seeking.

Mile high on heroin: Lessons on the opioid epidemic from the Mile High City.

This commentary discusses the novelty of the preclinical opioid choice model published in Heinsbroek et al., Nat Commun, 2021, and the potential influence of altitude on the reported findings. The studies were performed in the Mile High City of Denver, Colorado, where a unique subpopulation of heroin-choosing rats were noted.

Chemogenetic inhibition of corticostriatal circuits reduces cued reinstatement of methamphetamine seeking.

Methamphetamine (meth) causes enduring changes within the medial prefrontal cortex (mPFC) and the nucleus accumbens (NA). Projections from the mPFC to the NA have a distinct dorsal-ventral distribution, with the prelimbic (PL) mPFC projecting to the NAcore, and the infralimbic (IL) mPFC projecting to the NAshell. Inhibition of these circuits has opposing effects on cocaine relapse. Inhibition of PL-NAcore reduces cued reinstatement of cocaine seeking and IL-NAshell inhibition reinstates cocaine seeking. Meth, however, exhibits a different profile, as pharmacological inhibition of either the PL or IL decrease cued reinstatement of meth-seeking. The potentially opposing roles of the PL-NAcore and IL-NAshell projections remain to be explored in the context of cued meth seeking. Here we used an intersectional viral vector approach that employs a retrograde delivery of Cre from the NA and Cre-dependent expression of DREADD in the mPFC, in both male and female rats to inhibit or activate these parallel pathways. Inhibition of the PL-NAcore circuit reduced cued reinstatement of meth seeking under short and long-access meth self-administration and after withdrawal with and without extinction. Inhibition of the IL-NAshell also decreased meth cued reinstatement. Activation of the parallel circuits was without an effect. These studies show that inhibition of the PL-NAcore or the IL-NAshell circuits can inhibit reinstated meth seeking. Thus, the neural circuitry mediating cued reinstatement of meth seeking is similar to cocaine in the dorsal, but not ventral, mPFC-NA circuit.

Extinction blunts paraventricular thalamic contributions to heroin relapse.

Here, we use optogenetics and chemogenetics to investigate the contribution of the paraventricular thalamus (PVT) to nucleus accumbens (NAc) pathway in aversion and heroin relapse in two different heroin self-administration models in rats. In one model, rats undergo forced abstinence in the home cage prior to relapse testing, and in the other, they undergo extinction training, a procedure that is likened to cognitive behavioral therapy. We find that the PVT→NAc pathway is both sufficient and necessary to drive aversion and heroin seeking after abstinence, but not extinction. The ability of extinction to reduce this pathway's contribution to heroin relapse is accompanied by a loss of synaptic plasticity in PVT inputs onto a specific subset of NAc neurons. Thus, extinction may exert therapeutic reductions in opioid seeking by altering synaptic plasticity within the PVT→NAc pathway, resulting in reduced aversion during opioid withdrawal as well as reduced relapse propensity.

Engineering Safer Psychedelics for Treating Addiction.

Addiction is best described as a disorder of maladaptive neuroplasticity involving the simultaneous strengthening of reward circuitry that drives compulsive drug seeking and weakening of circuits involved in executive control over harmful behaviors. Psychedelics have shown great promise for treating addiction, with many people attributing their therapeutic effects to insights gained while under the influence of the drug. However, psychedelics are also potent psychoplastogens-molecules capable of rapidly re-wiring the adult brain. The advent of non-hallucinogenic psychoplastogens with anti-addictive properties raises the intriguing possibility that hallucinations might not be necessary for all therapeutic effects of psychedelic-based medicines, so long as the underlying pathological neural circuitry can be remedied. One of these non-hallucinogenic psychoplastogens, tabernanthalog (TBG), appears to have long-lasting therapeutic effects in preclinical models relevant to alcohol and opioid addiction. Here, we discuss the implications of these results for the development of addiction treatments, as well as the next steps for advancing TBG and related non-hallucinogenic psychoplastogens as addiction therapeutics.

A common limiter circuit for opioid choice and relapse identified in a rodent addiction model.

Activity in numerous brain regions drives heroin seeking, but no circuits that limit heroin seeking have been identified. Furthermore, the neural circuits controlling opioid choice are unknown. In this study, we examined the role of the infralimbic cortex (IL) to nucleus accumbens shell (NAshell) pathway during heroin choice and relapse. This model yielded subpopulations of heroin versus food preferring rats during choice, and choice was unrelated to subsequent relapse rates to heroin versus food cues, suggesting that choice and relapse are distinct behavioral constructs. Supporting this, inactivation of the IL with muscimol produced differential effects on opioid choice versus relapse. A pathway-specific chemogenetic approach revealed, however, that the IL-NAshell pathway acts as a common limiter of opioid choice and relapse. Furthermore, dendritic spines in IL-NAshell neurons encode distinct aspects of heroin versus food reinforcement. Thus, opioid choice and relapse share a common addiction-limiting circuit in the IL-NAshell pathway.

Glutamatergic Systems and Memory Mechanisms Underlying Opioid Addiction.

Glutamate is the main excitatory neurotransmitter in the brain and is of critical importance for the synaptic and circuit mechanisms that underlie opioid addiction. Opioid memories formed over the course of repeated drug use and withdrawal can become powerful stimuli that trigger craving and relapse, and glutamatergic neurotransmission is essential for the formation and maintenance of these memories. In this review, we discuss the mechanisms by which glutamate, dopamine, and opioid signaling interact to mediate the primary rewarding effects of opioids, and cover the glutamatergic systems and circuits that mediate the expression, extinction, and reinstatement of opioid seeking over the course of opioid addiction.

A non-hallucinogenic psychedelic analogue with therapeutic potential.

The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine-like those of other psychedelic compounds-are long-lasting2, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling3,4. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog-a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.

Acute ovarian hormone treatment in freely cycling female rats regulates distinct aspects of heroin seeking.

Females are at higher risk for certain opioid addictive behaviors, but the influence of ovarian hormones is unknown. In our rat model of heroin self-administration, females exhibited higher relapse rates that correlated with rates of heroin seeking on the first extinction session. We administered estradiol alone, or in combination with progesterone, 30 min prior to the first extinction session in freely cycling, heroin-seeking female rats. Although neither treatment produced long-term effects on relapse, each treatment regulated distinct aspects of heroin seeking. Estradiol treatment enhanced extinction memory retention, whereas the combination treatment acutely reduced expression of heroin seeking.

Detrimental Effects of a Retrieval-Extinction Procedure on Nicotine Seeking, but Not Cocaine Seeking.

Retrieval-extinction memory reactivation procedures have been used to prevent the return of learned fear and drug seeking in preclinical models. These procedures first reactivate the original memory with a brief cue exposure (i.e., retrieval) session, and then disrupt memory reconsolidation by conducting extinction training within the reconsolidation window. The original memory is thought to be updated with the new information conveyed by extinction learning, resulting in a persistent therapeutic effect beyond that observed with extinction training alone (i.e., no retrieval). Here, we attempted to replicate the therapeutic effects on cocaine seeking reported by Xue et al. (2012), and extend these findings to nicotine seeking. Rats self-administered either cocaine or nicotine with contingent cues for weeks, and were then divided into two groups. The retrieval group underwent a 10-min retrieval session wherein drug cues were available, but drug was not. Ten minutes later, they were allowed to continue cue extinction training for an additional 60 min. The no retrieval group underwent a contiguous 70-min cue extinction session. These procedures continued for weeks, followed by a test for spontaneous recovery of drug seeking. No group differences were observed on any measure of cocaine seeking, although both groups exhibited extinction and spontaneous recovery. By contrast, for nicotine seeking, the retrieval group exhibited resistance to extinction, an effect that persisted on the spontaneous recovery test. These findings underscore the importance of drug type in the outcome of retrieval-extinction procedures and moreover indicate that retrieval-extinction procedures can be detrimental to nicotine seeking.

Prefrontal cortex neuronal ensembles encoding fear drive fear expression during long-term memory retrieval.

The prefrontal cortex is an important regulator of fear expression in humans and rodents. Specifically, the rodent prelimbic (PL) prefrontal cortex drives fear expression during both encoding and retrieval of fear memory. Neuronal ensembles have been proposed to function as memory encoding units, and their re-activation is thought to be necessary for memory retrieval and expression of conditioned behavior. However, it remains unclear whether PL cortex neuronal ensembles that encode fear memory contribute to long-term fear expression during memory retrieval. To address this, we employed a viral-mediated TRAP (Targeted Recombination in Active Population) technology to target PL cortex ensembles active during fear conditioning and expressed the inhibitory Gi-DREADD in fear-encoding ensembles. Male and female rats were trained to lever press for food and subjected to Pavlovian delay fear conditioning, then 28 days later, they underwent a fear memory retrieval test. Chemogenetic inhibition of TRAPed PL cortex ensembles reduced conditioned suppression of food seeking in females, but not males. Neither context nor tone freezing behavior was altered by this manipulation during the same retrieval test. Thus, fear-encoding ensembles in PL cortex drive long-term fear expression in a sex and fear modality dependent manner.

Divergent Prelimbic Cortical Pathways Interact with BDNF to Regulate Cocaine-seeking.

A single BDNF microinfusion into prelimbic (PrL) cortex immediately after the last cocaine self-administration session decreases relapse to cocaine-seeking. The BDNF effect is blocked by NMDAR antagonists. To determine whether synaptic activity in putative excitatory projection neurons in PrL cortex is sufficient for BDNF's effect on relapse, the PrL cortex of male rats was infused with an inhibitory Designer Receptor Exclusively Activated by Designer Drugs (DREADD) viral vector driven by an αCaMKII promoter. Immediately after the last cocaine self-administration session, rats were injected with clozapine-N-oxide 30 min before an intra-PrL BDNF microinfusion. DREADD-mediated inhibition of the PrL cortex blocked the BDNF-induced decrease in cocaine-seeking after abstinence and cue-induced reinstatement after extinction. Unexpectedly, DREADD inhibition of PrL neurons in PBS-infused rats also reduced cocaine-seeking, suggesting that divergent PrL pathways affect relapse. Next, using a cre-dependent retroviral approach, we tested the ability of DREADD inhibition of PrL projections to the NAc core or the paraventricular thalamic nucleus (PVT) to alter cocaine-seeking in BDNF- and PBS-infused rats. Selective inhibition of the PrL-NAc pathway at the end of cocaine self-administration blocked the BDNF-induced decrease in cocaine-seeking but had no effect in PBS-infused rats. In contrast, selective inhibition of the PrL-PVT pathway in PBS-infused rats decreased cocaine-seeking, and this effect was prevented in BDNF-infused rats. Thus, activity in the PrL-NAc pathway is responsible for the therapeutic effect of BDNF on cocaine-seeking whereas inhibition of activity in the PrL-pPVT pathway elicits a similar therapeutic effect in the absence of BDNF.SIGNIFICANCE STATEMENT The major issue in cocaine addiction is the high rate of relapse. However, the neuronal pathways governing relapse remain unclear. Using a pathway-specific chemogenetic approach, we found that BDNF differentially regulates two key prelimbic pathways to guide long-term relapse. Infusion of BDNF in the prelimbic cortex during early withdrawal from cocaine self-administration decreases relapse that is prevented when neurons projecting from the prelimbic cortex to the nucleus accumbens core are inhibited. In contrast, BDNF restores relapse when neurons projecting from the prelimbic cortex to the posterior paraventricular thalamic nucleus are inhibited. This study demonstrates that two divergent cortical outputs mediate relapse that is regulated in opposite directions by infusing BDNF in the prelimbic cortex during early withdrawal from cocaine.

Chemogenetic activation of the perirhinal cortex reverses methamphetamine-induced memory deficits and reduces relapse.

Prolonged use of methamphetamine (meth) has been associated with episodic memory deficits in humans, and preclinical rat models of meth self-administration indicate the memory deficits are a consequence of meth use. Others have suggested that the meth-induced memory deficits may promote a cyclical pattern of drug use, abstinence, and relapse, although preclinical evidence for this relationship is somewhat lacking. The memory deficits in preclinical models manifest as a loss of novel object recognition (NOR) memory. These deficits occur one to two weeks after cessation of meth use and involve the perirhinal cortex, a parahippocampal region essential to NOR memory. We hypothesized that a loss of perirhinal cortex function contributes to both the NOR memory deficits and increased vulnerability to relapse in a novel-cue reinstatement model. To test this, we attempted to restore NOR memory in meth rats using an excitatory Gq-DREADD in perirhinal neurons. Activation of these neurons not only reversed the meth-induced deficit in NOR memory, but also restored novelty salience in a novel-cue reinstatement model. Thus, perirhinal cortex functionality contributes to both memory deficits in relapse in a long-access model of meth self-administration in rats, and chemogenetic restoration of perirhinal function restores memory and reduces relapse.

A single, extinction-based treatment with a kappa opioid receptor agonist elicits a long-term reduction in cocaine relapse.

Kappa opioid receptor (KOR) agonists have known anti-addiction properties and can reduce drug seeking. Their potential for clinical use has largely been daunted by their aversive properties mediated through p38 MAPK signaling. Here we examined the therapeutic potential of the KOR agonist U50,488 (U50) to reduce cocaine seeking in a self-administration model. Following cocaine self-administration and 7 days of forced home-cage abstinence, rats were administered a single dose of U50 (5 mg/kg, i.p.) 30 min prior to the first extinction training session, wherein cocaine and the discrete cocaine-paired cues were no longer available. U50 reduced cocaine seeking on this first extinction session, but did not alter extinction training over subsequent days. 2 weeks after U50 treatment, rats underwent a test of cue-induced reinstatement, and rats that had received U50 reinstated less than controls. Central inhibition of p38 MAPK at the time of U50 administration prevented its long-term therapeutic effect on reinstatement, but not its acute reduction in drug seeking on extinction day 1. The long-term therapeutic effect of U50 required operant extinction during U50 exposure, extended to cocaine-primed reinstatement, and was not mimicked by another aversive drug, lithium chloride (LiCl). These data suggest U50 elicits its long-term anti-relapse effects through a KOR-p38 MAPK-specific aversive counterconditioning of the operant cocaine-seeking response. A single, albeit aversive treatment that is able to reduce relapse long-term warrants further consideration of the therapeutic potential of KOR agonists in the treatment of addiction.

Chemogenetic Activation of an Extinction Neural Circuit Reduces Cue-Induced Reinstatement of Cocaine Seeking.

UNLABELLED: The ventromedial prefrontal cortex (vmPFC) has been shown to negatively regulate cocaine-seeking behavior, but the precise conditions by which vmPFC activity can be exploited to reduce cocaine relapse are currently unknown. We used viral-mediated gene transfer of designer receptors (DREADDs) to activate vmPFC neurons and examine the consequences on cocaine seeking in a rat self-administration model of relapse. Activation of vmPFC neurons with the Gq-DREADD reduced reinstatement of cocaine seeking elicited by cocaine-associated cues, but not by cocaine itself. We used a retro-DREADD approach to confine the Gq-DREADD to vmPFC neurons that project to the medial nucleus accumbens shell, confirming that these neurons are responsible for the decreased cue-induced reinstatement of cocaine seeking. The effects of vmPFC activation on cue-induced reinstatement depended on prior extinction training, consistent with the reported role of this structure in extinction memory. These data help define the conditions under which chemogenetic activation of extinction neural circuits can be exploited to reduce relapse triggered by reminder cues. SIGNIFICANCE STATEMENT: The ventromedial prefrontal cortex (vmPFC) projection to the nucleus accumbens shell is important for extinction of cocaine seeking, but its anatomical proximity to the relapse-promoting projection from the dorsomedial prefrontal cortex to the nucleus accumbens core makes it difficult to selectively enhance neuronal activity in one pathway or the other using traditional pharmacotherapy (e.g., systemically administered drugs). Viral-mediated gene delivery of an activating Gq-DREADD to vmPFC and/or vmPFC projections to the nucleus accumbens shell allows the chemogenetic exploitation of this extinction neural circuit to reduce cocaine seeking and was particularly effective against relapse triggered by cocaine reminder cues.