The dopamine D3 receptor (D3R) is a target for developing medications to treat substance use disorders. D3R-selective compounds with high affinity and varying efficacies have been discovered, providing critical research tools for cell-based studies that have been translated to in vivo models of drug abuse. D3R antagonists and partial agonists have shown especially promising results in rodent models of relapse-like behavior, including stress-, drug-, and cue-induced reinstatement of drug seeking. However, to date, translation to human studies has been limited. Herein, we present an overview and illustrate some of the pitfalls and challenges of developing novel D3R-selective compounds toward clinical utility, especially for treatment of cocaine abuse. Future research and development of D3R-selective antagonists and partial agonists for substance abuse remains critically important but will also require further evaluation and development of translational animal models to determine the best time in the addiction cycle to target D3Rs for optimal therapeutic efficacy.

Background Recent epidemiological data suggest a resurgence in cocaine use (CU) and cocaine-related problems in the United States. Demographic trends and correlates of problem CU are needed to determine potential factors that may be influencing the increased trend and to inform targeted prevention and intervention strategies. Methods Trends in any past-year CU, weekly CU, and cocaine use disorder (CUD) were examined among persons aged ≥12 years using the National Survey on Drug Use and Health from 2011 to 2015. Logistic regression analyses were used to determine correlates of past-year and weekly CU and CUD among adolescents and adults. Results The prevalence of past-year CU from 2011 to 2015 increased among females, ages 18–25, ages ≥50, non-Hispanic Blacks, and persons reporting low income, past-year tobacco use, past-year alcohol use, and past-month binge and heavy alcohol use. The prevalence of weekly CU increased among persons aged ≥50 years and persons reporting past-month heavy alcohol use. A significant increase in the prevalence of CUD was only found among persons aged ≥50 years. Adjusted logistic regression showed that older age, large metropolitan residence, past-year tobacco, alcohol, cannabis, and heroin use, and major depressive episode were associated with increased odds of CU or CUD among both adolescents and adults; however, sex and race/ethnicity correlates differed among adolescents and adults. Conclusions Findings have implications for increased monitoring of CU-related indicators among some high-risk groups, such as females, older adults, Blacks, and polysubstance users. Targeted screening and intervention strategies among these population subgroups may be needed.

Rationale The dopamine (DA) D2 and D3 receptors have been associated with cocaine abuse. A recent study with the D3 receptor (D3R) partial agonist PG619 found that it attenuated cocaine-induced reinstatement and the D2-like receptor antagonist buspirone has shown positive outcomes in two studies of cocaine abuse in monkeys. However, a recent clinical trial indicated that buspirone did not improve abstinence in treatment-seeking cocaine abusers. Objective The objective of the study was to examine PG619 and buspirone under a food-drug choice paradigm in order to better model the clinical findings. In addition, we extended the characterization of both compounds to include methamphetamine (MA) self-administration (SA). Methods Six adult male rhesus monkeys were trained to respond under a concurrent food (1.0-g pellets) and drug (0.01–0.3 mg/kg/injection cocaine or MA) choice paradigm in which complete SA dose-response curves were determined each session (N=3/group). Monkeys received 5 days of treatment with either PG619 (0.1–3.0 mg/kg, i.v.) or buspirone (0.01–1.0 mg/kg, i.m.). In a follow-up study, the SA doses were reduced (0.003–0.1 mg/kg/injection) to increase reinforcement frequency and buspirone was retested. Results PG619 did not affect cocaine or MA choice, while buspirone increased low-dose cocaine choice. Changing the SA doses increased the number of reinforcers received each session, but buspirone did not decrease drug choice. Conclusions Consistent with clinical findings, these results do not support the use of buspirone for psychostimulant abuse and suggest that food-drug choice paradigms may have greater predictive validity than the use of other schedules of reinforcement.

Findings suggest that primary care physicians should be aware of multiple SUDs when planning treatment, especially among adults who are male, younger, less educated, or unemployed. Interventions that target multiple SUDs warrant future investigation.

Background and Aims Physician and pharmacist collaboration may help address the shortage of buprenorphine-waivered physicians and improve care for patients with opioid use disorder (OUD). This study investigated the feasibility and acceptability of a new collaborative care model involving buprenorphine-waivered physicians and community pharmacists. Design Nonrandomized, single-arm, open-label feasibility trial. Setting Three office-based buprenorphine treatment (OBBT) clinics and three community pharmacies in the United States. Participants Six physicians, six pharmacists, and 71 patients aged ≥18 years with Diagnostic and Statistical Manual of Mental Disorders, FifthEdition (DSM-5) OUD on buprenorphine maintenance. Intervention After screening, eligible patients' buprenorphine care was transferred from their OBBT physician to a community pharmacist for 6 months. Measurements Primary outcomes included recruitment, treatment retention and adherence, and opioid use. Secondary outcomes were intervention fidelity, pharmacists' use of prescription drug monitoring program (PDMP), participant safety, and satisfaction with treatment delivery. Findings A high proportion (93.4%, 71/76) of eligible participants enrolled into the study. There were high rates of treatment retention (88.7%) and adherence (95.3%) at the end of the study. The proportion of opioid-positive urine drug screens (UDSs) among complete cases (i.e. those with all six UDSs collected during 6 months) at month 6 was (4.9%, 3/61). Intervention fidelity was excellent. Pharmacists used PDMP at 96.8% of visits. There were no opioid-related safety events. Over 90% of patients endorsed that they were "very satisfied with their experience and the quality of treatment offered," that "treatment transfer from physician's office to the pharmacy was not difficult at all," and that "holding buprenorphine visits at the same place the medication is dispensed was very or extremely useful/convenient." Similarly, positive ratings of satisfaction were found among physicians/pharmacists. Conclusions A collaborative care model for people with opioid use disorder that involves buprenorphine-waivered physicians and community pharmacists appears to be feasible to operate in the United States and have high acceptability to patients.

Background: Current data suggest that opioid misuse or opioid use disorder (OUD) may be over represented among tobacco users. However, this association remains understudied in primary care settings. A better understanding of the extent of heterogeneity in opioid misuse among primary care patients who use tobacco may have implications for improved primary care-based screening, prevention, and intervention approaches. Methods: Data were derived from a sample of 2,000 adult (aged ≥18) primary care patients across 5 distinct clinics. Among past-year tobacco users (n=882), we assessed the prevalence of opioid misuse and OUD by sociodemographic characteristics and past-year polysubstance use. Latent class analysis (LCA) was used to identify heterogeneous subgroups of tobacco users according to past-year polysubstance use patterns. Multinomial logistic regression was used to examine variables associated with LCA-defined class membership. Results: Past-year tobacco use was reported by >84% of participants who reported past-year opioid misuse or OUD. Among those reporting past-year tobacco use, the prevalence of past-year opioid misuse and OUD was 14.0% and 9.5%, respectively. The prevalence of opioid misuse or OUD was highest among tobacco users who were male or unemployed. Three LCA-defined classes among tobacco users were identified including a tobacco-minimal drug use group (78.0%), a tobacco-cannabis use group (10.1%), and a tobacco-opioid/polydrug use group (11.9%). Class membership differed by sociodemographic characteristics. Conclusions: Results from this study support the benefit of more comprehensive assessment of and/or monitoring for opioid misuse among primary care patients who use tobacco, particularly for those who are male, unemployed, or polydrug users.

Background The emergency department (ED) and hospital settings represent crucial opportunities for engaging treatment for cannabis use disorder (CUD). Thus, there is a need to identify factors associated with healthcare utilization among persons with CUD to improve screening and intervention approaches. Problematic alcohol use may be a salient risk factor. Methods Using data from the 2005–2013 National Surveys on Drug Use and Health, we determined factors, including different patterns of alcohol use, associated with past-year ED admission and inpatient hospitalization among persons aged 12 years or older meeting criteria for CUD in the past year (N=16,757). We also determined the prevalence and correlates of problem alcohol use among persons with CUD to further inform its association with healthcare utilization. Results Among persons with CUD, 40.15% and 10.04% reported past-year ED admission and inpatient hospitalization, respectively. Severe alcohol use disorder (AUD) (≥ 6 AUD symptoms), female sex, Black race, low income, major depressive episode (MDE), and other substance use disorders were associated with increased odds of healthcare utilization; current (i.e., last month) alcohol use patterns were not. Persons with CUD that were males, ages 18–25 (vs. ages 12–17), Hispanic (vs. White), and with low income, other drug use disorders, or MDE had increased odds of AUD. Conclusions Findings suggest that screening and intervention efforts for improving treatment initiation or engagement for CUD may target cannabis-using women, blacks, low-income adults or those with severe AUD in the past year, another substance use disorder, or MDE.

The dopamine (DA) D 3 receptor (D3R) has been associated with impulsivity, pathologic gambling, and drug addiction, making it a potential target for pharmacotherapy development. Positron emission tomography studies using the D3R-preferring radioligand [ 11 C]PHNO ([ 11 C](+)-propyl-hexahydro-naphtho-oxazin) have shown higher binding potentials in drug abusers compared with control subjects. Preclinical studies have examined D3R receptor activation using the DA agonist quinpirole and the unconditioned behavior of yawning. However, the relationship between quinpirole-elicited yawning and D3R receptor availability has not been determined. In Experiment 1, eight drug-naive male rhesus monkeys were scanned with [ 11 C]PHNO, and the ability of quinpirole (0.01-0.3 mg/kg i.m.) to elicit yawning was examined. Significant positive (globus pallidus) and negative (caudate nucleus, putamen, ventral pallidum, and hippocampus) relationships between D3R receptor availability and quinpirole-induced yawns were noted. Experiment 2 replicated earlier findings that a history of cocaine self-administration (n = 11) did not affect quinpirole-induced yawning and extended this to examine monkeys (n = 3) with a history of methamphetamine (MA) selfadministration and found that monkeys with experience selfadministering MA showed greater potency and significantly higher quinpirole-elicited yawning compared with controls. Finally, quinpirole-elicited yawning was studied in drug-naive female monkeys (n = 6) and compared with drug-naive male monkeys (n = 8). Sex differences were noted, with quinpirole being more potent and eliciting significantly more yawns in males compared with females. Taken together these findings support the use of quinpirole-elicited yawning as a behavioral tool for examining D3R activation in monkeys and that both drug history and sex may influence individual sensitivity to the behavioral effects of D3R compounds.