Drug-evoked plasticity at excitatory synapses on medium spiny neurons (MSNs) of the nucleus accumbens (NAc) drives behavioral adaptations in addiction. MSNs expressing dopamine D1 (D1R-MSN) vs. D2 receptors (D2R-MSN) can exert antagonistic effects in drugrelated behaviors, and display distinct alterations in glutamate signaling following repeated exposure to psychostimulants; however, little is known of cell-type-specific plasticity induced by opiates. Here, we find that repeated morphine potentiates excitatory transmission and increases GluA2-lacking AMPA receptor expression in D1R-MSNs, while reducing signaling in D2-MSNs following 10-14 d of forced abstinence. In vivo reversal of this pathophysiology with optogenetic stimulation of infralimbic cortexaccumbens shell (ILC-NAc shell) inputs or treatment with the antibiotic, ceftriaxone, blocked reinstatement of morphine-evoked conditioned place preference. These findings confirm the presence of overlapping and distinct plasticity produced by classes of abused drugs within subpopulations of MSNs that may provide targetable molecular mechanisms for future pharmacotherapies.opiates | nucleus accumbens | plasticity | GluA2-lacking AMPARs | ceftriaxone O pioid-based drugs are mainstays for pain management (1). However, side effects such as euphoria and the development of tolerance and dependence contribute to an increasing diversion of these readily available compounds for nontherapeutic use (2). Opioid agonist-based treatments are known to reduce some aspects of opioid addiction. On the other hand, these therapies often lead to high relapse rates when discontinued because they fail to eliminate key aspects of addiction such as conditioned associations that can trigger intense drug craving (2). Currently, development of alternative treatments for opioid addiction is hampered by a distinct lack of knowledge of the cellular plasticity that underlies persistent opioid-induced changes in behavior.The nucleus accumbens (NAc) region of the ventral striatum is involved in attribution of salience to drug-paired cues that can in turn motivate reward-related behavior (3, 4). Medium spiny neurons (MSNs), the principal cells of the NAc, are GABAergic projection neurons that receive coordinated glutamatergic afferents arising from several cortical and limbic brain regions (5, 6). MSNs are divided into two subpopulations based on expression of the dopamine receptor 1 (D1R-MSN) or dopamine receptor 2 (D2-MSN), with a small fraction (∼6-17%) expressing both receptors (7). Importantly, these subpopulations have divergent projection targets and exert antagonistic effects in rewardrelated behaviors (8).Long-lasting alterations in excitatory synaptic strength and glutamate release at MSNs produced by repeated exposure to drugs of abuse is a driving factor behind drug seeking and relapse (9-11). Numerous studies have examined effects of repeated psychostimulant exposure on synaptic strength and AMPA receptor (AMPAR)-mediated transmission in MSN subpopulations, with a majority of adaptati...

Objectives Unpredictable fluctuations in the illicit drug market increase overdose risk. Drug checking, or the use of technology to provide insight into the contents of illicit drug products, is an overdose prevention strategy with an emerging evidence base. The use of portable spectrometry devices to provide point-of-service analysis of the contents of illicit drugs been adopted by harm reduction organizations internationally but is only emerging in the United States. This study aimed to identify barriers and facilitators of implementing drug checking services with spectrometry devices in an urban harm reduction organization and syringe service program serving economically marginalized people who use drugs in Boston, Massachusetts (USA). Methods In-vivo observations and semi-structured interviews with harm reduction staff and participants were conducted between March 2019 and December 2020. We used the consolidated framework for implementation research to identify implementation barriers and facilitators. Results This implementation effort was facilitated by the organization’s shared culture of harm reduction—which fostered shared implementation goals and beliefs about the intervention among staff persons—its horizontal organizational structure, strong identification with the organization among staff, and strong relationships with external funders. Barriers to implementation included the technological complexity of the advanced spectroscopy devices utilized for drug checking. Program staff indicated that commercially available spectroscopy devices are powerful but not always well-suited for drug checking efforts, describing their technological capacities as “the Bronze Age of Drug Checking.” Other significant barriers include the legal ambiguity of drug checking services, disruptive and oppositional police activity, and the responses and programmatic changes demanded by the COVID-19 pandemic. Conclusions For harm reduction organizations to be successful in efforts to implement and scale drug checking services, these critical barriers—especially regressive policing policies and prohibitive costs—need to be addressed. Future research on the impact of policy changes to reduce the criminalization of substance use or to provide explicit legal frameworks for the provision of this and other harm reduction services may be merited.

Background While nicotine is the primary addictive compound in tobacco, other tobacco constituents including minor alkaloids (e.g., nornicotine, anabasine) may also contribute to tobacco addiction by mimicking or enhancing the effects of nicotine. Further evaluating the behavioral effects of minor alkaloids is essential for understanding their impact on tobacco addiction and informing development of tobacco product standards by the FDA. Methods This study compared the addiction-related effects of nicotine and the minor alkaloids nornicotine, anabasine, myosmine, anatabine, and cotinine on intracranial self-stimulation (ICSS) thresholds in rats. Results Acute injection of nicotine produced reinforcement-enhancing (ICSS threshold-decreasing) effects at low to moderate doses, and reinforcement-attenuating/aversive (ICSS threshold-increasing) effects at high doses. Nornicotine and anabasine produced similar biphasic effects on ICSS thresholds, although with lower potency compared to nicotine. Myosmine only elevated ICSS thresholds at relatively high doses, while anatabine and cotinine did not influence ICSS thresholds at any dose. None of the alkaloids significantly influenced ICSS response latencies, indicating a lack of nonspecific motoric effects. Conclusions These findings indicate that some minor tobacco alkaloids can either fully (nornicotine, anabasine) or partially (myosmine) mimic nicotine’s addiction-related effects on ICSS, albeit at reduced potency. These findings emphasize the need for further study of the abuse potential of minor alkaloids, including evaluation of their effects when combined with nicotine and other tobacco constituents to better simulate tobacco exposure in humans. Such work is essential for informing FDA regulation of tobacco products and could also lead to the development of novel pharmacotherapies for tobacco addiction.

Mecamylamine elicited withdrawal-like signs in rats following a single dose of nicotine. The different effects of mecamylamine 1.5 mg/kg following acute versus chronic nicotine exposure supports the notion that these models simulate the early and more advanced stages of nicotine dependence, respectively. While further optimization and validation of these models is necessary, they may provide a novel approach for studying the earliest stages of nicotine dependence.