Availability and Opportunities for Expansion of Buprenorphine for the Treatment of Opioid Use Disorder.

There is an urgent need to expand access to treatment for persons with opioid use disorder (OUD). As neurologists may frequently encounter patients with chronic pain who have developed OUD, they are in a position to serve as advocates for treatment. Buprenorphine is the most scalable medication for OUD in the United States, yet expansion has plateaued in recent years despite growing treatment needs. Reluctance of providers to establish treatment with new patients, challenges with rural expansion, stigma related to buprenorphine-based care, and pharmacy pressures that incentivize low dispensing and inventories may have stalled expansion. This review introduces these challenges before outlining actionable and evidenced-based strategies that warrant investigation, including methods to improve patient access to care (remotely delivered care, mobile delivery programs, Bridge programs) and provider retention and confidence in prescribing (expert consults, Extension for Community Healthcare Outcomes, a telementoring model, hub-and-spoke services), as well as novel innovations (virtual reality, artificial intelligence, wearable technologies). Overall, fortifying existing delivery systems while developing new transformative models may be necessary to achieve more optimal levels of buprenorphine treatment expansion.

Restoration of Kv7 Channel-Mediated Inhibition Reduces Cued-Reinstatement of Cocaine Seeking.

Cocaine addicts display increased sensitivity to drug-associated cues, due in part to changes in the prelimbic prefrontal cortex (PL-PFC). The cellular mechanisms underlying cue-induced reinstatement of cocaine seeking remain unknown. Reinforcement learning for addictive drugs may produce persistent maladaptations in intrinsic excitability within sparse subsets of PFC pyramidal neurons. Using a model of relapse in male rats, we sampled >600 neurons to examine spike frequency adaptation (SFA) and afterhyperpolarizations (AHPs), two systems that attenuate low-frequency inputs to regulate neuronal synchronization. We observed that training to self-administer cocaine or nondrug (sucrose) reinforcers decreased SFA and AHPs in a subpopulation of PL-PFC neurons. Only with cocaine did the resulting hyperexcitability persist through extinction training and increase during reinstatement. In neurons with intact SFA, dopamine enhanced excitability by inhibiting Kv7 potassium channels that mediate SFA. However, dopamine effects were occluded in neurons from cocaine-experienced rats, where SFA and AHPs were reduced. Pharmacological stabilization of Kv7 channels with retigabine restored SFA and Kv7 channel function in neuroadapted cells. When microinjected bilaterally into the PL-PFC 10 min before reinstatement testing, retigabine reduced cue-induced reinstatement of cocaine seeking. Last, using cFos-GFP transgenic rats, we found that the loss of SFA correlated with the expression of cFos-GFP following both extinction and re-exposure to drug-associated cues. Together, these data suggest that cocaine self-administration desensitizes inhibitory Kv7 channels in a subpopulation of PL-PFC neurons. This subpopulation of neurons may represent a persistent neural ensemble responsible for driving drug seeking in response to cues.SIGNIFICANCE STATEMENT Long after the cessation of drug use, cues associated with cocaine still elicit drug-seeking behavior, in part by activation of the prelimbic prefrontal cortex (PL-PFC). The underlying cellular mechanisms governing these activated neurons remain unclear. Using a rat model of relapse to cocaine seeking, we identified a population of PL-PFC neurons that become hyperexcitable following chronic cocaine self-administration. These neurons show persistent loss of spike frequency adaptation, reduced afterhyperpolarizations, decreased sensitivity to dopamine, and reduced Kv7 channel-mediated inhibition. Stabilization of Kv7 channel function with retigabine normalized neuronal excitability, restored Kv7 channel currents, and reduced drug-seeking behavior when administered into the PL-PFC before reinstatement. These data highlight a persistent adaptation in a subset of PL-PFC neurons that may contribute to relapse vulnerability.

Social environment affects central distribution of estrogen receptor-α in Peromyscus californicus.

Social environment has well-established effects on an animal's social behavior and associated neuroendocrine responses. The presence of estrogen receptor alpha (ERα) in limbic system brain regions is related to the expression of a variety of social, reproductive and aggressive behaviors. We hypothesized that alterations to the social environment, specifically social isolation, would cause changes in ERα throughout the limbic system. The number of ERα immunoreactive (ERα-ir) cells within specific limbic system brain regions was quantified in male and female California mice (Peromyscus californicus), isolated or same sex pair-housed for 4 or 24 days. Peromyscus californicus is a highly social rodent species (monogamous and bi-parental) and therefore, may be particularly sensitive to manipulations of its social environment. Isolated males had a significantly greater number of ERα-ir cells in the ventromedial nucleus of the hypothalamus (VMH) and similar patterns within the bed nucleus of the stria terminalis (BST) and medial preoptic area (MPOA). Males housed for 24 days had a significantly greater number of ERα-ir cells in the BST, VMH, MPOA when compared with males housed for 4 days. Females housed for 24 days had significantly greater ERα-ir in the dentate gyrus of the hippocampus (DG) when compared with females housed for 4 days. No differences were found in the medial amygdala (MeA). These data demonstrate that social environment has region and sex specific effects on ERα-ir cells in this species. These results add to the comparative evidence regarding ERα, demonstrating a consistent role for ERα in species specific responsiveness to changes in the social environment.

The Paraventricular Thalamic Nucleus and Its Projections in Regulating Reward and Context Associations.

The paraventricular thalamic nucleus (PVT) is a brain region that mediates aversive and reward-related behaviors as shown in animals exposed to fear conditioning, natural rewards, or drugs of abuse. However, it is unknown whether manipulations of the PVT, in the absence of external factors or stimuli (e.g., fear, natural rewards, or drugs of abuse), are sufficient to drive reward-related behaviors. Additionally, it is unknown whether drugs of abuse administered directly into the PVT are sufficient to drive reward-related behaviors. Here, using behavioral as well as pathway and cell-type specific approaches, we manipulate PVT activity as well as the PVT-to-nucleus accumbens shell (NAcSh) neurocircuit to explore reward phenotypes. First, we show that bath perfusion of morphine (10 µM) caused hyperpolarization of the resting membrane potential, increased rheobase, and decreased intrinsic membrane excitability in PVT neurons that project to the NAcSh. Additionally, we found that direct injections of morphine (50 ng) in the PVT of mice were sufficient to generate conditioned place preference (CPP) for the morphine-paired chamber. Mimicking the inhibitory effect of morphine, we employed a chemogenetic approach to inhibit PVT neurons that projected to the NAcSh and found that pairing the inhibition of these PVT neurons with a specific context evoked the acquisition of CPP. Lastly, using brain slice electrophysiology, we found that bath-perfused morphine (10 µM) significantly reduced PVT excitatory synaptic transmission on both dopamine D1 and D2 receptor-expressing medium spiny neurons in the NAcSh, but that inhibiting PVT afferents in the NAcSh was not sufficient to evoke CPP.

The IMPOWR Network Divided or Single Exposure Study (DOSE) Protocol: A Randomized Controlled Comparison of Once Versus Split Dosing of Methadone for the Treatment of Comorbid Chronic Pain and Opioid Use Disorder.

BACKGROUND: The Divided or Single Exposure (DOSE) trial is a double-blind, placebo-controlled examination of once versus split dosing of methadone for comorbid pain and opioid use disorder (OUD) among persons receiving methadone for OUD treatment. METHODS: This multisite trial consists of a 12-week active intervention phase and 6-month follow-up period. Persons receiving methadone who endorse clinically-significant chronic pain are randomized into once-daily dosing or split dosing that is managed remotely via an electronic pillbox. Clinical pain is assessed weekly and using ecological momentary assessments. Experimentally-evoked pain is assessed using a quantitative sensory testing battery. Additional outcomes related to OUD, including withdrawal and craving, are also collected. RESULTS: The study hypothesizes that persons assigned to the split dosing condition will report lower pain and opioid withdrawal relative to persons assigned to the traditional once-daily dosing strategy. CONCLUSIONS: Split dosing is a relatively common technique in OUD treatments; therefore, if data support this hypothesis, there is high potential for implementation.

Anterior cingulate cortex and its projections to the ventral tegmental area regulate opioid withdrawal, the formation of opioid context associations and context-induced drug seeking.

Clinical evidence suggests that there are correlations between activity within the anterior cingulate cortex (ACC) following re-exposure to drug-associated contexts and drug craving. However, there are limited data contributing to our understanding of ACC function at the cellular level during re-exposure to drug-context associations as well as whether the ACC is directly related to context-induced drug seeking. Here, we addressed this issue by employing our novel behavioral procedure capable of measuring the formation of drug-context associations as well as context-induced drug-seeking behavior in male mice (8-12 weeks of age) that orally self-administered oxycodone. We found that mice escalated oxycodone intake during the long-access training sessions and that conditioning with oxycodone was sufficient to evoke conditioned place preference (CPP) and drug-seeking behaviors. Additionally, we found that thick-tufted, but not thin-tufted pyramidal neurons (PyNs) in the ACC as well as ventral tegmental area (VTA)-projecting ACC neurons had increased intrinsic membrane excitability in mice that self-administered oxycodone compared to controls. Moreover, we found that global inhibition of the ACC or inhibition of VTA-projecting ACC neurons was sufficient to significantly reduce oxycodone-induced CPP, drug seeking, and spontaneous opioid withdrawal. These results demonstrate a direct role of ACC activity in mediating context-induced opioid seeking among other behaviors, including withdrawal, that are associated with the DSM-V criteria of opioid use disorder.

Anterior cingulate cortex is necessary for spontaneous opioid withdrawal and withdrawal-induced hyperalgesia in male mice.

The anterior cingulate cortex (ACC) is implicated in many pathologies, including depression, anxiety, substance-use disorders, and pain. There is also evidence from brain imaging that the ACC is hyperactive during periods of opioid withdrawal. However, there are limited data contributing to our understanding of ACC function at the cellular level during opioid withdrawal. Here, we address this issue by performing ex vivo electrophysiological analysis of thick-tufted, putative dopamine D2 receptor expressing, layer V pyramidal neurons in the ACC (ACC L5 PyNs) in a mouse model of spontaneous opioid withdrawal. We found that escalating doses of morphine (20, 40, 60, 80, and 100 mg/kg, i.p. on days 1-5, respectively) injected twice daily into male C57BL/6 mice evoked withdrawal behaviors and an associated withdrawal-induced mechanical hypersensitivity. Brain slices prepared 24 h following the last morphine injection showed increases in ACC L5 thick-tufted PyN-intrinsic membrane excitability, increases in membrane resistance, reductions in the rheobase, and reductions in HCN channel-mediated currents (IH). We did not observe changes in intrinsic or synaptic properties on thin-tufted, dopamine D1-receptor-expressing ACC L5 PyNs recorded from male Drd1a-tdTomato transgenic mice. In addition, we found that chemogenetic inhibition of the ACC blocked opioid-induced withdrawal and withdrawal-induced mechanical hypersensitivity. These results demonstrate that spontaneous opioid withdrawal alters neuronal properties within the ACC and that ACC activity is necessary to control behaviors associated with opioid withdrawal and withdrawal-induced mechanical hypersensitivity. The ability of the ACC to regulate both withdrawal behaviors and withdrawal-induced mechanical hypersensitivity suggests overlapping mechanisms between two seemingly distinguishable behaviors. This commonality potentially suggests that the ACC is a locus for multiple withdrawal symptoms.

Drug-Induced Conditioned Place Preference and Its Practical Use in Substance Use Disorder Research.

The conditioned place preference (CPP) paradigm is a well-established model utilized to study the role of context associations in reward-related behaviors, including both natural rewards and drugs of abuse. In this review article, we discuss the basic history, various uses, and considerations that are tied to this technique. There are many potential takeaway implications of this model, including negative affective states, conditioned drug effects, memory, and motivation, which are all considered here. We also discuss the neurobiology of CPP including relevant brain regions, molecular signaling cascades, and neuromodulatory systems. We further examine some of our prior findings and how they integrate CPP with self-administration paradigms. Overall, by describing the fundamentals of CPP, findings from the past few decades, and implications of using CPP as a research paradigm, we have endeavored to support the case that the CPP method is specifically advantageous for studying the role of a form of Pavlovian learning that associates drug use with the surrounding environment.

Acute and chronic bupropion treatment does not prevent morphine-induced conditioned place preference in mice.

A substantial barrier to the treatment of Opioid Use Disorder (OUD) is the elevated relapse rates in affected patients, and a significant contributor to these events of relapse is exposure to cues and contexts that are intensely associated with prior drug abuse. The neurotransmitter dopamine plays a key role in reward-related behaviors, and previous studies have illustrated that dopamine hypofunction in periods of abstinence serves to prompt drug craving and seeking. We hypothesized that restoration of dopaminergic signaling could attenuate drug-seeking behaviors. Therefore, we investigated whether use of an FDA-approved drug, bupropion, an inhibitor of the dopamine transporter (DAT), or a dopamine uptake inhibitor with high affinity for DAT, JHW 007, was able to decrease preference for a drug-paired context. In these experiments, mice underwent 5 days of non-contingent morphine (10 mg/kg) exposure in a conditioned place preference (CPP) paradigm. We found that systemic injection of bupropion (20 mg/kg, i. p.) or intracranial injection of JHW 007 into the nucleus accumbens shell did not prevent the expression of morphine CPP. We then investigated whether chronic bupropion treatment (via implanted osmotic pumps) would influence morphine CPP. We observed that chronic bupropion treatment for 21 days following morphine conditioning did not attenuate the prolonged preference for morphine-paired contexts. Overall, with our dose and paradigm, neither acute nor chronic bupropion diminishes morphine CPP. Continued studies should address FDA-approved medications and their potential for recovery in OUD patients.

A novel method to study reward-context associations and drug-seeking behaviors.

Animal models have significantly contributed to the understanding of reward-related behaviors, such as in Substance Use Disorder research. One of the most heavily utilized paradigms to date is conditioned place preference (CPP). However, CPP is limited by non-contingent exposure. Our new method advances this classic method by utilizing its benefits and simultaneously diminishing its limitations. We used a traditional 3-compartment CPP apparatus, where each chamber differs by both visual and tactile contexts. We restructured the apparatus allowing for insertion of bottles so that mice could orally self-administer sucrose or morphine-containing solutions in a specific context. Our results show that mice who self-administer sucrose or morphine show a place preference for the sucrose- or morphine-paired chamber. This place preference lasts for 21 d in sucrose-treated, but not morphine-treated mice. Additionally, we found that that mice will drink more water in the morphine-paired context during extinction tests. This model combines the distinct contextual cues associated with conditioned place preference and combines them with voluntary self-administration, thus enabling researchers to measure behavior using a model that incorporates spatial memory involved in affective states, while also providing a quantifiable readout of context/environment-specific drug seeking. In conclusion, we combined CPP and voluntary intake to establish a novel technique to assess not only preference for a context associated with rewarding stimuli (natural or drug), but also seeking, retention, and locomotor activity. This model can be further utilized to examine other drugs of abuse, extinction training, other learning models, or to allow for the assessment of neurobiological manipulations.

Ketamine Blocks Morphine-Induced Conditioned Place Preference and Anxiety-Like Behaviors in Mice.

Patients suffering from opioid use disorder often relapse during periods of abstinence, which is posited to be caused by negative affective states that drive motivated behaviors. Here, we explored whether conditioning mice with morphine in a conditioned place preference (CPP) training paradigm evoked anxiety-like behavior during morphine abstinence. To do this, mice were conditioned with morphine (10 mg/kg, i.p.) for 5 days. Twenty-four hours following conditioning, anxiety levels were tested by measuring time in the open arms of the elevated plus-maze. The next day, mice were placed in the three-compartment chamber to measure morphine-induced CPP. Our results show that following morphine conditioning, mice spent significantly less time in the open arm of the elevated plus-maze and expressed robust morphine CPP on CPP test day. Furthermore, we found that an acute treatment with (R,S)-ketamine (10 mg/kg, i.p.), a medication demonstrating promise for preventing anxiety-related phenotypes, 30 min before testing on post-conditioning day 1, increased time spent in the open arm of the elevated plus-maze in saline- and morphine-conditioned mice. Additionally, we found that the second injection of ketamine 30 min before CPP tests on post-conditioning day 2 prevented morphine-induced CPP, which lasted for up to 28 days post-conditioning. Furthermore, we found that conditioning mice with 10% (w/v) sucrose using an oral self-administration procedure did not evoke anxiety-like behavior, but elicited robust CPP, which was attenuated by ketamine treatment 30 min before CPP tests. Overall, our results suggest that the ketamine-induced block of morphine CPP may not be attributed solely to alleviating negative affective states, but potentially through impaired memory of morphine-context associations.