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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, Fifth Edition (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.

Marijuana and other cannabinoid compounds are widely used by cocaine users. Preclinical animal studies suggest that these compounds can increase the reinforcing effects of cocaine under some schedules of cocaine self-administration and reinstatement, but not in all cases. To date, no studies have used a food-cocaine concurrent choice procedure, which allows for assessment of drug effects on response allocation, not just changes in cocaine self-administration. The goal of the present study was to examine the effects of compounds differing in their efficacy at the cannabinoid receptor (CBR) on cocaine self-administration using a food-drug choice procedure in monkeys. Four adult male rhesus monkeys were trained to self-administer cocaine in the context of an alternative food (1.0-g banana-flavored pellets) reinforcer, such that complete cocaine dose-response curves (0, 0.003–0.1 mg/kg per injection) were determined each session. Monkeys were tested acutely with the CBR full agonist CP 55,940 (0.001–0.01 mg/kg); the CBR partial agonist Δ(9)-tetrahydrocannabinol (THC; 0.03–0.3 mg/kg), which is also the primary active ingredient in marijuana and the CBR antagonist rimonabant (0.3–3.0 mg/kg). Cocaine choice increased in a dose-dependent manner. Acute treatment with CP 55,940 decreased cocaine choice, whereas THC and rimonabant enhanced the reinforcing effects of cocaine. Chronic (7-day) treatment with CP 55,940 resulted in tolerance to the decreases in cocaine choice. These findings with Δ(9)-THC provide support for a potential mechanism for co-abuse of marijuana and cocaine. Additional research with chronic treatment with full CBR agonists on attenuating the reinforcing strength of cocaine is warranted. SIGNIFICANCE STATEMENT: Co-abuse of tetrahydrocannabinol and cocaine is a significant public health problem. The use of animal models allows for the determination of how cannabinoid receptor stimulation or blockade influences the reinforcing strength of cocaine.

Background Primary care settings provide salient opportunities for identifying patients with problematic substance use and addressing unmet treatment need. The aim of this study was to examine the extent and correlates of problematic substance use by substance-specific risk categories among primary care patients to inform screening/intervention efforts. Methods Data were analyzed from 2000 adult primary care patients aged ≥18 years (56% female) across 5 clinics in the eastern U.S. Participants completed the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST). Prevalence and ASSIST-defined risk-level of tobacco use, alcohol use, and nonmedical/illicit drug use was examined. Multinomial logistic regression models analyzed the demographic correlates of substance use risk-levels. Results Among the total sample, the prevalence of any past 3-month use was 53.9% for alcohol, 42.0% for tobacco, 24.2% for any illicit/Rx drug, and 5.3% for opioids; the prevalence of ASSIST-defined moderate/high-risk use was 45.1% for tobacco, 29.0% for any illicit/Rx drug, 14.2% for alcohol, and 9.1% for opioids. Differences in the extent and risk-levels of substance use by sex, race/ethnicity, and age group were observed. Adjusted logistic regression showed that male sex, white race, not being married, and having less education were associated with increased odds of moderate/high-risk use scores for each substance category; older ages (versus ages 18–25 years) were associated with increased odds of moderate/high-risk opioid use. Conclusions Intervention need for problematic substance use was prevalent in this sample. Providers should maintain awareness and screen for problematic substance use more consistently in identified high risk populations.

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 2000 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 Addressing multiple substance use disorders (SUDs) in primary care-based screening and intervention may improve SUD treatment access, engagement, and outcomes. To inform such efforts, research is needed on the prevalence and patterns of multiple SUDs among primary care patients. Methods Data were analyzed from a sample of 2000 adult (aged ≥ 18) primary care patients recruited for a multisite National Drug Abuse Treatment Clinical Trials Network (CTN) study (CTN-0059). Past-year DSM-5 SUDs (tobacco, alcohol, and drug) were assessed by the modified Composite International Diagnostic Interview. Prevalence and correlates of multiple versus single SUDs were examined. Latent class analysis (LCA) was used to explore patterns of multiple SUDs. Results Multiple SUDs were found among the majority of participants with SUD for alcohol, cannabis, prescription opioids, cocaine, and heroin. Participants who were male, ages 26–34, less educated, and unemployed had increased odds of multiple SUDs compared to one SUD. Having multiple SUDs was associated with greater severity of tobacco or alcohol use disorder. LCA of the sample identified three classes: class 1 (83.7%) exhibited low prevalence of all SUDs; class 2 (12.0%) had high-moderate prevalence of SUDs for tobacco, alcohol, and cannabis; class 3 (4.3%) showed high prevalence of SUD for tobacco, opioids, and cocaine. LCA-defined classes were distinguished by sex, age, race, education, and employment status. Conclusions 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.

Characterization of the effects of long-term alcohol consumption on the brain would be aided by the development of behavioral assays that are relatively easy to implement in animal models of alcohol use disorders. Assessing unconditioned behaviors, such as drug-elicited yawning in models that permit long-term alcohol ingestion, may be a valuable complement to more invasive and costly procedures. The present studies investigated previous unexpected findings of ethanol-induced yawning in nonhuman primates. Subjects were adult male rhesus monkeys (n = 8), all of which had experience self-administering intravenous cocaine for several years. Four monkeys also had experience consuming 2.0 g/kg ethanol over 1 h per day, 5 days per week, for 6.8–12.0 months. All monkeys received saline or ethanol (0.25–1.0 g/kg) infused intravenously (i.v.) over 10 min, and the number of yawns elicited during the infusion was counted. A second experiment in the ethanol-experienced monkeys examined whether ethanol-induced yawning could be blocked by PG01037 (1.0, 3.0 mg/kg, i.v.), a selective antagonist at dopamine D3 receptors (D3R). Ethanol significantly and dose-dependently increased yawns in the ethanol-experienced animals, but not the ethanol-naive animals. In the ethanol-experienced monkeys, this effect of ethanol was blocked by the D3R antagonist. The pharmacology of yawning is complex and a good deal of model development remains to be performed to characterize the potential involvement of other neurotransmitter systems. Nonetheless, drug-elicited yawning may be a useful unconditioned behavioral assay to assess the effects of long-term alcohol consumption in established nonhuman primate models.

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.

BACKGROUND: Primary care settings provide opportunities to identify electronic-cigarette (e-cigarette) use and to implement strategies for changing tobacco use behavior. However, a better understanding of the extent and associated characteristics of e-cigarette use among primary care patients are needed to inform such efforts. OBJECTIVE: To describe patient demographic and substance use characteristics by e-cigarette use status among a large sample of primary care patients. To examine the prevalence and correlates of e-cigarette use among tobacco users in the sample. DESIGN: Cross-sectional analysis from a multisite validation study of a substance use screening instrument. PARTICIPANTS: Adult primary care patients aged 18 and older (n = 2000) recruited across 5 primary care clinics in the Eastern USA from 2014 to 2015. MAIN MEASURES: Patients reported past 3-month e-cigarette use, sociodemographics, tobacco use, and other substance use. Current nicotine dependence and DSM-5 criteria for past-year substance use disorders were also assessed. KEY RESULTS: Among the total sample, 7.7% (n = 154) adults reported past 3-month e-cigarette use. Adults who reported e-cigarette use (vs. no use) were more likely to be younger, white, or have frequent tobacco use, nicotine dependence, or past-year illicit drug use/disorders. Among past 3-month tobacco users, 16.3% reported e-cigarette use. Adjusted logistic regression indicated that odds of e-cigarette use were greater among tobacco users who had some college education or more (vs. < high school) or were daily/almost daily tobacco users (vs. not); odds were lower among Blacks/African-Americans (vs. whites). E-cigarette use among tobacco users was associated with increased odds of current nicotine dependence or tobacco use disorder as well as more severe dependence/disorder. CONCLUSIONS: Enhanced surveillance of e-cigarette use among adult tobacco users in primary care, particularly among those who use tobacco frequently, may have implications for helping patients with tobacco cessation using established approaches including behavioral support, pharmacotherapy, or referral to specialized care.

Background The emergency department (ED) is well-suited as an opportunity to increase treatment access for prescription opioid use disorder (POUD). We examined sex differences in ED utilization among individuals with POUD to understand potential sex-specific treatment barriers and needs. Methods Data from the 2005-2014 National Surveys on Drug use and Health were analyzed to examine the prevalence and correlates of past-year ED utilization among male and female adults aged 18 or older with POUD (n = 4412). Results Overall, 58.2% of adults with POUD reported past-year ED utilization. Adjusted logistic regression revealed that females (vs. males) with POUD were more likely to report past-year ED utilization. Among females with POUD, older age, lower income, obtaining opioids from a physician, major depressive episode, and greater POUD severity were associated with increased odds of ED utilization. Among males with POUD, public insurance and obtaining opioids from a physician were associated with ED utilization. A larger proportion of males with POUD reporting ED use had multiple substance use disorders than those with no ED use. Treatment history (lifetime or past-year) for alcohol, drugs, or opioid use was associated with increased odds of ED use among males and females with POUD. Conclusions/Importance: Males and females with POUD presenting to the ED may have distinct predisposing, enabling, and need-related correlates. Sex-specific screening and intervention strategies may be useful to maximize the utility of the ED to address POUD.

Background Chronic non-cancer pain (CNCP) among patients with substance use disorder (SUD) poses a risk for worse treatment outcomes. Understanding the association of CNCP with SUD is important for informing the need and potential benefits of pain assessment/management among those with SUDs. Methods We analyzed electronic health record data from 2013 to 2018 among adults aged ≥18 years (N = 951,533; mean age: 48.4 years; 57.4 % female) in a large academic healthcare system. Adjusted logistic regression models were conducted to estimate the association of CNCP conditions with opioid overdose, emergency department utilization, and inpatient hospitalization stratified by different SUD diagnoses and by gender. Results Among the total sample, the prevalence of CNCP was 46.6 % and any SUD was 11.2 %. The majority of patients with a SUD had CNCP (opioid: 74.7 %; sedative: 72.3 %; cannabis: 64.3 %; alcohol: 58.7 %; tobacco: 59.5 %). The prevalence of CNCP was greater in females vs. males for most SUD diagnoses. The presence of CNCP was associated with more mental health disorders and chronic medical conditions among each SUD group. CNCP was associated with significantly decreased odds of overdose among those with opioid use disorder but increased odds of overdose and healthcare utilization among other SUDs. CNCP was positively associated with overdose in females, but not males, with alcohol or non-opioid drug use disorders. Conclusions The direction and magnitude of the association between CNCP and negative health indicators differed as a function of SUD type and gender, respectively. Greater awareness of potential unmet pain treatment need may have implications for improving SUD outcomes.

Cannabis-related impairments to cognitive function may represent novel therapeutic targets for cannabis-use disorder, although the nature, persistence, and reversibility of such deficits remain unclear. Adult male rhesus monkeys (N = 6) responded in the morning on tasks designed to assess different cognitive domains using the Cambridge Neuropsychological Test Automated Battery (CANTAB) touchscreens followed by responding maintained under a fixed-ratio (FR) 10 schedule of food presentation in different operant chambers. First, the acute effects of Δ9-tetrahydrocannabinol (THC; 0.01–0.56 mg/kg, i.v.) on cognitive performance, FR responding, and body temperature were determined. Next, THC (1.0–2.0 mg/kg, s.c.) was administered daily after FR 10 sessions for 12 weeks, during which the residual effects of THC (i.e., 22 hours after administration) on cognition were examined and the acute effects of THC were redetermined. In a subgroup of monkeys, dopamine D2/D3 receptor availability was assessed after 4 weeks of chronic THC exposure and compared with drug-naive controls using positron emission tomography and [11C]-raclopride (N = 4/group). Acute THC pretreatments dose-dependently decreased FR responding and body temperature, and impairment to cognitive performance was task specific. During chronic treatment, THC produced persistent residual impairment only to working memory; tolerance differentially developed to acute cognitive impairments. There was recovery from residual cognitive impairments to working memory within 2 weeks of abstinence. Compared with controls, D2/D3 receptor availability was not altered during chronic THC treatment. In conclusion, THC-induced disruptions in cognition were task-specific, as was tolerance development, and not related to changes in D2/D3 receptor availability. Intervention strategies for cannabis-use disorder that enhance working memory performance may facilitate positive treatment outcomes.

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.

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.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.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.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.

Reinforcing effects of Δ9-tetrahydrocannabinol (THC), the primary active ingredient in marijuana, as assessed with self-administration (SA), has only been established in New World primates (squirrel monkeys). The objective of this study was to investigate some experimental factors that may enhance intravenous SA of THC and the cannabinoid receptor (CBR) agonist CP 55 940 in Old World monkeys (rhesus and cynomolgus), a species that has been used extensively in biomedical research. In one experiment, male rhesus monkeys (N=9) were trained to respond under a fixed-ratio 10 schedule of food presentation. The effects of CP 55 940 (1.0–10 μg/kg, i.v.) and THC (3.0–300 μg/kg, i.v.) on food-maintained responding and body temperature were determined in these subjects prior to giving them access to self-administer each drug. Both drugs dose-dependently decreased food-maintained responding. CP 55 940 (0.001–3.0 μg/kg) functioned as a reinforcer in three monkeys, whereas THC (0.01–10 μg/kg) did not have reinforcing effects in any subject. CP 55 940 was least potent to decrease food-maintained responding in the monkeys in which CP 55 940 functioned as a reinforcer. Next, THC was administered daily to monkeys until tolerance developed to rate-decreasing effects. When THC SA was reexamined, it functioned as a reinforcer in three monkeys. In a group of cocaine-experienced male cynomolgus monkeys (N=4), THC SA was examined under a second-order schedule of reinforcement; THC functioned as reinforcer in two monkeys. These data suggest that SA of CBR agonists may be relatively independent of their rate-decreasing effects in Old World monkeys. Understanding individual differences in vulnerability to THC SA may lead to novel treatment strategies for marijuana abuse.

The dopamine (DA) D3 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) self-administration and found that monkeys with experience self-administering 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.

Background Concurrent alcohol use among cocaine abusers is common but the behavioral variables that promote co-abuse are not well understood. The present study examined the effects of intragastric (i.g.) ethanol (EtOH) administration in monkeys responding under a schedule of cocaine reinforcement in which extensive drug seeking was maintained by conditioned stimuli. Methods Four adult male cynomolgus monkeys ( Macaca fascicularis ) were trained to respond under a second-order fixed-interval (FI) 600 s (fixed-ratio (FR) 30:S) schedule of cocaine (0.003–0.56 mg/kg/injection) presentation. Sessions ended after 5 injections or 90 min had elapsed. Different EtOH doses (0.5–2.0 g/kg, i.g.) were administered 30 min before the session, typically on Tuesdays and Fridays. Blood ethanol concentrations (BECs) were also assessed. Pattern of FI responding was assessed by determining quarter-life (QL) values. Results Cocaine self-administration was characterized as an inverted U-shaped function of dose; QL values increased monotonically with dose. EtOH pretreatments dose-dependently decreased self-administration at several cocaine doses in 3 of 4 monkeys. In one animal, EtOH increased low-dose cocaine-maintained responding. For all monkeys, QL values were increased by EtOH when low- and high-cocaine doses were self-administered, suggesting additive effects of EtOH and cocaine. Furthermore, BECs were not altered following cocaine self-administration. Conclusions The reductions in cocaine self-administration and the increases in QL values following EtOH, suggest that EtOH was enhancing cocaine-related conditioned reinforcement. A better understanding of the behavioral mechanisms that mediate the co-abuse of alcohol and cocaine will lead to improved treatments for both drugs.

The dopamine D3 receptor (D3R) has been shown to mediate many of the behavioral effects of psychostimulants associated with high abuse potential. This study extended the assessment of the highly selective D3R antagonist PG01037 on cocaine and methamphetamine (MA) self-administration to include a food-drug choice procedure. Eight male rhesus monkeys (n=4/group) served as subjects in which complete cocaine and MA dose-response curves were determined daily in each session. When choice was stable, monkeys received acute and five-day treatment of PG01037 (1.0-5.6 mg/kg, i.v.). Acute administration of PG01037 was effective in reallocating choice from cocaine to food and decreasing cocaine intake, however, tolerance developed by day 5 of treatment. Up to doses that disrupted responding, MA choice and intake were not affected by PG01037 treatment. PG01037 decreased total reinforcers earned per session and the behavioral potency was significantly greater on MA-food choice compared to cocaine-food choice. Furthermore, the acute efficacy of PG01037 was correlated with the sensitivity of the D3/D2R agonist quinpirole to elicit yawning. These data suggest (1) that efficacy of D3R compounds in decreasing drug choice is greater in subjects with lower D3R, perhaps suggesting that it is percent occupancy that is the critical variable in determining efficacy and (2) differences in D3R activity in chronic cocaine vs. MA users. Although tolerance developed to the effects of PG01037 treatment on cocaine choice, tolerance did not develop to the disruptive effects on food-maintained responding. These findings suggest that combination treatments that decrease cocaine-induced elevations in DA may enhance the efficacy of D3R antagonists on cocaine self-administration.

The dopamine D3 receptor (D3R) has been shown to mediate many of the behavioral effects of psychostimulants associated with high abuse potential. This study extended the assessment of the highly selective D3R antagonist PG01037 on cocaine and methamphetamine (MA) self-administration to include a food-drug choice procedure. Eight male rhesus monkeys (n=4/group) served as subjects in which complete cocaine and MA dose-response curves were determined daily in each session. When choice was stable, monkeys received acute and five-day treatment of PG01037 (1.0-5.6 mg/kg, i.v.). Acute administration of PG01037 was effective in reallocating choice from cocaine to food and decreasing cocaine intake, however, tolerance developed by day 5 of treatment. Up to doses that disrupted responding, MA choice and intake were not affected by PG01037 treatment. PG01037 decreased total reinforcers earned per session and the behavioral potency was significantly greater on MA-food choice compared to cocaine-food choice. Furthermore, the acute efficacy of PG01037 was correlated with the sensitivity of the D3/D2R agonist quinpirole to elicit yawning. These data suggest (1) that efficacy of D3R compounds in decreasing drug choice is greater in subjects with lower D3R, perhaps suggesting that it is percent occupancy that is the critical variable in determining efficacy and (2) differences in D3R activity in chronic cocaine vs. MA users. Although tolerance developed to the effects of PG01037 treatment on cocaine choice, tolerance did not develop to the disruptive effects on food-maintained responding. These findings suggest that combination treatments that decrease cocaine-induced elevations in DA may enhance the efficacy of D3R antagonists on cocaine self-administration.

Within the dopaminergic system, the D3R has been shown to mediate many of the behavioral effects of psychostimulants associated with high abuse potential. The present studies examined the effects of D3-selective partial agonists and D3/D2R antagonists in three models of cocaine and MA abuse in rhesus monkeys. The highly selective D3 partial agonist PG619 and the D3/D2R antagonists buspirone and eticlopride were administered chronically to monkeys self-administering cocaine and MA (n=3/group) under a food-drug choice procedure in which complete cocaine and MA dose-response curves were determined each session. Neither PG 619 (0.1-3.0 mg/kg, i.v.), buspirone (0.01-0.3 mg/kg, i.m.) nor eticlopride (0.001-0.01 mg/kg, i.v.) significantly decreased cocaine or MA choice and intake while buspirone significantly increased the choice of low drug doses. The ability of buspirone to block reinstatement was also examined. Using the choice procedure in which saline was substituted for the self-administered drug, buspiron...