Ghrelin receptor antagonist JMV2959 blunts cocaine and oxycodone drug-seeking, but not self-administration, in male rats.

The drug overdose crisis has spawned serious health consequences, including the increased incidence of substance use disorders (SUDs), conditions manifested by escalating medical and psychological impairments. While medication management is a key adjunct in SUD treatment, this crisis has crystallized the need to develop additional therapeutics to facilitate extended recovery from SUDs. The "hunger hormone" ghrelin acts by binding to the growth hormone secretagogue receptor 1α (GHS1αR) to control homeostatic and hedonic aspects of food intake and has been implicated in the mechanisms underlying SUDs. Preclinical studies indicate that GHS1αR antagonists and inverse agonists suppress reward-related signaling associated with cocaine and opioids. In the present study, we found that the GHS1αR antagonist JMV2959 was efficacious to suppress both cue-reinforced cocaine and oxycodone drug-seeking, but not cocaine or oxycodone self-administration in male Sprague-Dawley rats. These data suggest a role of the ghrelin-GHS1αR axis in mediating overlapping reward-related aspects of cocaine and oxycodone and premises the possibility that a GHS1αR antagonist may be a valuable therapeutic strategy for relapse vulnerability in SUDs.

A mobile addiction service for community-based overdose prevention.

Mainstays of opioid overdose prevention include medications for opioid use disorder (e.g., methadone or buprenorphine) and naloxone distribution. Inadequate access to buprenorphine limits its uptake, especially in communities of color, and people with opioid use disorders encounter multiple barriers to obtaining necessary medications including insurance, transportation, and consistent availability of telephones. UMass Memorial Medical Center and our community partners sought to alleviate these barriers to treatment through the deployment of a mobile addiction service, called the Road to Care. Using this approach, multidisciplinary and interprofessional providers deliver holistic addiction care by centering our patients' needs with respect to scheduling, location, and convenience. This program also extends access to buprenorphine and naloxone among people experiencing homelessness. Additional systemic and individualized barriers encountered are identified, as well as potential solutions for future mobile addiction service utilization. Over a two-year period, we have cared for 1,121 individuals who have accessed our mobile addiction service in over 4,567 encounters. We prescribed buprenorphine/naloxone (Suboxone®) to 330 individuals (29.4% of all patients). We have distributed nearly 250 naloxone kits directly on-site or and more than 300 kits via prescriptions to local pharmacies. To date, 74 naloxone rescue attempts have been reported back to us. We have demonstrated that a community-based mobile addiction service, anchored within a major medical center, can provide high-volume and high-quality overdose prevention services that facilitate engagement with additional treatment. Our experience is described as a case study below.

Discovery of Novel Oleamide Analogues as Brain-Penetrant Positive Allosteric Serotonin 5-HT2C Receptor and Dual 5-HT2C/5-HT2A Receptor Modulators.

The serotonin 5-HT2A receptor (5-HT2AR) and 5-HT2CR localize to the brain and share overlapping signal transduction facets that contribute to their roles in cognition, mood, learning, and memory. Achieving selective targeting of these receptors is challenged by the similarity in their 5-HT orthosteric binding pockets. A fragment-based discovery approach was employed to design and synthesize novel oleamide analogues as selective 5-HT2CR or dual 5-HT2CR/5-HT2AR positive allosteric modulators (PAMs). Compound 13 (JPC0323) exhibited on-target properties, acceptable plasma exposure and brain penetration, as well as negligible displacement to orthosteric sites of ∼50 GPCRs and transporters. Furthermore, compound 13 suppressed novelty-induced locomotor activity in a 5-HT2CR-dependent manner, suggesting 5-HT2CR PAM, but not 5-HT2AR, activity at the level of the whole organism at the employed doses of 13. We discovered new selective 5-HT2CR PAMs and first-in-class 5-HT2CR/5-HT2AR dual PAMs that broaden the pharmacological toolbox to explore the biology of these vital receptors.

Isolation housing elevates amphetamine seeking independent of nucleus accumbens glutamate receptor adaptations.

Overdose death rates caused by psychostimulants have increased by 22.3% annually from 2008 to 2017. Cue-evoked drug craving progressively increases and contributes to perpetual relapse. Preclinical models have determined that glutamate receptor plasticity within the nucleus accumbens (NAc) drives amplified cue-evoked drug seeking after prolonged abstinence (>40 days). Isolated condition (IC) rearing increases cocaine and amphetamine (AMP) self-administration and cue-induced reinstatement. We tested the hypothesis that housing in the IC will augment AMP seeking after short and prolonged abstinence from AMP self-administration when compared with rats reared in the enrichment condition (EC). EC and IC male rats acquired stable AMP or SAL self-administration and were tested in a cue-induced AMP-seeking test after 1 and 40 days of abstinence. After the seeking test, the whole NAc was extracted and prepared for western blot analysis. Results indicate that IC rats had more active lever presses during a brief extinction interval and during the cue-induced seeking test. After 40 days of abstinence, IC rats had more active lever presses than EC rats during the cue-induced seeking test. Western blots indicated that the expression ratio between GluA1:mGlur5 was reduced only in IC-AMP-trained rats and the ratio between GluA1:mGlur1 was positively correlated with AMP seeking after prolonged abstinence in IC-AMP rats. These results indicate that IC housing engenders a vulnerable phenotype prone to persistent AMP seeking. The behavioural momentum of this vulnerable phenotype is further revealed when AMP-associated cues are presented following prolonged abstinence.

Discovery of 4-Phenylpiperidine-2-Carboxamide Analogues as Serotonin 5-HT2C Receptor-Positive Allosteric Modulators with Enhanced Drug-like Properties.

Targeting the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) allosteric site to potentiate endogenous 5-HT tone may provide novel therapeutics to alleviate the impact of costly, chronic diseases such as obesity and substance use disorders. Expanding upon our recently described 5-HT2CR-positive allosteric modulators (PAMs) based on the 4-alkylpiperidine-2-carboxamide scaffold, we optimized the undecyl moiety at the 4-position with variations of cyclohexyl- or phenyl-containing fragments to reduce rotatable bonds and lipophilicity. Compound 12 (CTW0415) was discovered as a 5-HT2CR PAM with improved pharmacokinetics and reduced off-target interactions relative to our previous series of molecules. The in vivo efficacy of compound 12 to potentiate the effects of a selective 5-HT2CR agonist was established in a drug discrimination assay. Thus, 12 is reported as a 5-HT2CR PAM with characteristics suitable for in vivo pharmacological studies to further probe the biological and behavioral mechanisms of allosteric modulation of a receptor important in several chronic diseases.

Environmental enrichment and a selective metabotropic glutamate receptor2/3 (mGluR2/3) agonist suppress amphetamine self-administration: Characterizing baseline differences.

A challenge for developing effective treatments for substance use disorders (SUDs) is understanding how environmental variables alter the efficacy of therapeutics. Environmental enrichment (EC) enhances brain development and protects against behaviors associated with drug abuse vulnerability when compared to rats reared in isolation (IC) or standard conditions (SC). EC rearing enhances the expression and function of metabotropic glutamate receptor2/3 (mGlurR2/3) and activating mGluR2/3 reduces psychostimulant self-administration (SA). However, the ability for mGluR2/3 activation to suppress amphetamine (AMP) SA in differentially reared rats is not determined. Therefore, we tested the hypothesis EC reduces AMP (SA) by augmenting mGluR2/3 function. At postnatal day 21, male Sprague-Dawley rats were assigned to EC, IC, or SC environments for 30 days. Then, they acquired AMP SA and were moved to a progressive ratio (PR) schedule of reinforcement. EC, IC, and SC rats were pretreated with LY379268 (vehicle, 0.3 and 1 mg/kg), a selective mGluR2/3 agonist, before PR behavioral sessions. Linear mixed effects analysis determined EC rats had reduced motivation for AMP SA when compared to IC or SC rats and that LY379268 dose-dependently suppressed AMP SA, but there was no evidence of an interaction. Cumming/Gardner-Altman estimation plots illustrate that the 0.3 mg/kg dose suppressed infusions in EC rats while the 1 mg/kg dose suppressed infusions in SC rats. LY379268 was incapable of suppressing the motivation for AMP SA in IC rats. Controlling for baseline differences in differentially reared rats remains a challenge. Normalizing to a baseline introduced error which is illustrated in the precision of the estimated effect size differences. The data indicate that environmental enrichment enhances the ability of a selective mGluR2/3 agonist to suppress AMP SA and indicates the functional status of the mGluR2/3 is formed during development. Therefore, environmental history must be considered when evaluating pharmacological therapeutics particularly those aimed at the mGluR2/3.

Histone deacetylase inhibition differentially attenuates cue-induced reinstatement: An interaction of environment and acH3K9 expression in the dorsal striatum.

Substance use disorder is driven by complex gene-environment interactions. Epigenetic histone regulation is a significant contributor to several behavioral phenotypes of drug abuse. The primary epigenetic mechanisms that drive drug taking and drug seeking are still being investigated, and it is unclear how environmental conditions alter epigenetic histone acetylation to change behaviors geared toward drug reward. This study examined the effects of environmental condition on amphetamine self-administration, and whether drug-taking and drug-seeking behaviors could be influenced through inhibition of an epigenetic regulator, histone deacetylase (HDAC). Male rats reared for 30 days in enriched (EC), isolated (IC), or standard conditions (SC) prior to amphetamine (0.03, 0.05, 0.1 mg/kg/infusion, IV) self-administration, extinction, and reinstatement sessions. The HDAC inhibitor, Trichostatin A (TsA; 0.3 mg/kg, IV), was injected 30 min prior to operant sessions. After amphetamine-induced reinstatement (0.25 mg/kg, subcutaneous [s.c.]), tissue was extracted for Western blot analyses of acetylated histone H3 lysine 9 (acH3K9) in the nucleus accumbens (NAc) and dorsal striatum (DSt). While TsA did not significantly affect amphetamine self-administration or extinction, TsA decreased cue-, but not drug-induced reinstatement in IC rats only. In the DSt, but not in the NAc, IC rats exhibited significantly less acH3K9 expression than EC and SC rats, irrespective of TsA treatment. HDAC inhibition decreases cue-induced reinstatement of amphetamine seeking in IC rats. While IC rats exhibit less acH3K9 expression in the DSt, future studies are needed to elucidate the critical epigenetic factors that drive substance abuse, particularly in vulnerable populations. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Dynamic interactions of ceftriaxone and environmental variables suppress amphetamine seeking.

Extrasynaptic glutamate within the nucleus accumbens (NAc) is a driver of relapse. Cocaine, ethanol, and methamphetamine reduce the expression of cystine-glutamate antiporter (xCT) and primary glial glutamate transporter 1 (GLT1) leading to increased extrasynaptic glutamate. Ceftriaxone (CTX) restores xCT and GLT1 expression and effectively suppresses cocaine and ethanol reinstatement, however, the effects of CTX on amphetamine (AMP) reinstatement are not determined. Rodents were reared in an enriched condition (EC), isolated (IC), or standard condition (SC) and trained in AMP self-administration (0.1 mg/kg/infusion). EC, IC, and SC rats received injections of SAL or CTX (200 mg/kg) after daily extinction sessions. Then rats were tested in cue- and AMP-induced reinstatement tests. We hypothesized that EC rearing would reduce reinstatement by altering GLT1 or xCT expression in the NAc and medial prefrontal cortex (mPFC). In Experiment 2, pair-housed rats received once-daily AMP (1.0 mg/kg i.p.) or SAL for eight days followed by once-daily CTX (200 mg/kg i.p.) or SAL injections for 10 days. CTX treatment reduced cue-induced drug seeking in EC rats but not IC or SC rats. In an AMP-induced reinstatement test, CTX reduced AMP-induced drug seeking in EC and SC rats, but not IC rats. Western blot analyses revealed that AMP self-administration and non-contingent repeated AMP exposure did not downregulate GLT1 or xCT in the NAc or mPFC. Therefore, the ability for EC housing to reduce amphetamine seeking may work through other mechanisms.

Why I'm Not a Cognitive Psychologist... or a Behaviorist... or a Biologist.

"Science" is under increasing amounts of scrutiny. Concerns about reproducibility, reduced institutional support, and intensified competition has been highlighted in recent years, but segregated science endangers scientific discovery above all. Segregated science can be interdisciplinary (biology vs psychology) or intradisciplinary (behaviorism vs cognitive psychology). The advancement of science and public knowledge depends on the unification of all disciplines to better understand the phenomena scientists study. We suggest that engendering collaborations across scientific disciplines produces better-designed research and appropriate interpretations, and increases career-long success. I am not a cognitive psychologist, behaviorist, or biologist because I am a neuroscientist.

Differential housing and novelty response: Protection and risk from locomotor sensitization.

High novelty seeking increases the risk for drug experimentation and locomotor sensitization. Locomotor sensitization to psychostimulants is thought to reflect neurological adaptations that promote the transition to compulsive drug taking. Rats reared in enrichment (EC) show less locomotor sensitization when compared to rats reared in isolation (IC) or standard conditions (SC). The current research study was designed to test if novelty response contributed locomotor sensitization and more importantly, if the different housing environments could change the novelty response to protect against the development of locomotor sensitization in both adolescence and adulthood. Experiment 1: rats were tested for their response to novelty using the inescapable novelty test (IEN) and pseudorandomly assigned to enriched (EC), isolated (IC), or standard (SC) housing conditions for 30days. After housing, they were tested with IEN. Rats were then administered amphetamine (0.5mg/kg) or saline and locomotor activity was measured followed by a sensitization test 14days later. Experiment 2: rats were tested in the IEN test early adulthood and given five administrations of amphetamine (0.3mg/kg) or saline and then either stayed in or switched housing environments for 30days. Rats were then re-tested in the IEN test in late adulthood and administered five more injections of their respective treatments and tested for locomotor sensitization. Results indicate that IC and SC increased the response to novelty. EC housing decreased locomotor response to amphetamine and saline, and SC housing increased the locomotor response to amphetamine. Mediation results indicated that the late adult novelty response fully mediates the locomotor response to amphetamine and saline, while the early adulthood novelty response did not. CONCLUSIONS: Differential housing changes novelty and amphetamine locomotor response. Novelty response is altered into adulthood and provides evidence that enrichment can be used to reduce drug vulnerability.

Voluntary ethanol consumption changes anticipatory ultrasonic vocalizations but not novelty response.

Novelty and sensation seeking (NSS) and affective disorders are correlated with earlier ethanol (ETOH) consumption, and sustained drinking into adulthood. Understanding the NSS response and affective response before and after voluntary ETOH consumption could elucidate important individual differences promoting sustained ETOH consumption. This study determined that NSS and affective response to rewarding stimulation-measured by ultrasonic vocalizations (USVs)-change after adolescent ETOH voluntary drinking. Rats were tested for their NSS response using the inescapable novelty test. Then rats were tested for their affective response to a natural reward and USVs were measured. The natural reward was experimenter-induced play behavior. Rats were exposed to ETOH for 8 weeks using an intermittent two bottle paradigm. After 8 weeks of voluntary consumption, rats were retested for their response to NSS and affective response to natural reward. Results indicate that voluntary ETOH consumption did not change the response to novelty. Control and ETOH exposed rats decreased their novelty response equally after ETOH consumption, suggesting the decrease was due to age. Importantly, voluntary ETOH consumption changed affective USVs. Compared to water-drinking control rats, ETOH-consuming rats elicited greater anticipatory trill USVs to a natural reward-associated context during a post-drinking probe test. Tickle-induced trill USVs did not change differently between ETOH and control rats. These results provide evidence that voluntary intermittent ETOH exposure increases the anticipation of reward and may represent a form of incentive salience. We postulate these diverging effects could be due to differences in incentive salience or reward processing. Together, these results suggest that voluntary ETOH consumption changes the affective response to conditioned and unconditioned natural rewards and offers a behavioral mechanism for studying affective reward processing after ETOH consumption.

Novelty response and 50 kHz ultrasonic vocalizations: Differential prediction of locomotor and affective response to amphetamine in Sprague-Dawley rats.

RATIONALE: Novelty and sensation seeking (NSS) predisposes humans and rats to experiment with psychostimulants. In animal models, different tests of NSS predict different phases of drug dependence. Ultrasonic vocalizations (USVs) are evoked by psychomotor stimulants and measure the affective/motivation response to stimuli, yet the role NSS has on USVs in response to amphetamine is not determined. OBJECTIVES: The aim of the present study was to determine if individual differences in NSS and USVs can predict locomotor and USV response to amphetamine (0.0, 0.3, and 1.0 mg/kg) after acute and chronic exposure. METHODS: Thirty male rats were tested for their response to novelty (IEN), choice to engage in novelty (NPP), and heterospecific play (H-USV). Rats were administered non-contingent amphetamine or saline for seven exposures, and USVs and locomotor activity were measured. After a 14-day rest, rats were administered a challenge dose of amphetamine. RESULTS: Regression analyses indicated that amphetamine dose-dependently increased locomotor activity and the NPP test negatively predicted treatment-induced locomotor activity. The H-USV test predicted treatment-induced frequency-modulated (FM) USVs, but the strength of prediction depended on IEN response. CONCLUSIONS: Results provide evidence that locomotor activity and FM USVs induced by amphetamine represent different behavioral responses. The prediction of amphetamine-induced FM USVs by the H-USV screen was changed by the novelty response, indicating that the affective value of amphetamine-measured by FM USVs-depends on novelty response. This provides evidence that higher novelty responders may develop a tolerance faster and may escalate intake faster.

Harmonic and frequency modulated ultrasonic vocalizations reveal differences in conditioned and unconditioned reward processing.

Novelty and sensation seeking (NSS) and ultrasonic vocalizations (USVs) are both used as measures of individual differences in reward sensitivity in rodent models. High responders in the inescapable novelty screen have a greater response to low doses of amphetamine and acquire self-administration more rapidly, while the novelty place preference screen is positively correlated with compulsive drug seeking. These screens are uncorrelated and implicated in separate drug abuse models. 50 kHz USVs measure affective state in rats and are evoked by positive stimuli. NSS and USVs are each implicated in drug response, self-administration, and reveal differences in individual behavior, yet their relationship with each other is not understood. The present study screened rats for their response to novelty and measured USVs of all call types in response to heterospecific play to determine the relationships between these individual difference traits. Generally, we hypothesized that 50k Hz USVs would be positively correlated with the NPP screen, and that 22 kHz would be positively correlated with the IEN screen. Results indicate none of the screens were correlated indicating they are measuring different individual difference traits. However, examination of the subtypes of USVs indicated harmonic USVs and the novelty place preference were positively correlated. Harmonic 50 kHz USVs increased in response to reward associated context, suggesting animals conditioned to the heterospecific tickle arena and anticipated rewarding stimuli, while FM only increased in response to tickling. USV subtypes can be used to elucidate differences in attribution of incentive value across conditioned stimuli and receipt of rewarding stimuli. These data provide strong support that harmonic and FM USVs can be used to understand reward processing in addition to NSS.