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Previous studies in humans and in animals have shown dramatic effects of cocaine on measures of brain function that persist into abstinence. The purpose of this study was to examine the neurobiological consequences of abstinence from cocaine, using a model that removes the potential confound of cocaine cues. Adult male rhesus monkeys self-administered cocaine (0.3 mg/kg/injection; N = 8) during daily sessions or served as food-reinforcement controls (N = 4). Two times per week, monkeys were placed in a neutral environment and presented with a cartoon video for ~30 min, sometimes pre- and sometimes post-operant session, but no reinforcement was presented during the video. After ~100 sessions and when the cocaine groups had self-administered 900 mg/kg cocaine, the final experimental condition was a terminal 2-[14C]-deoxyglucose procedure, which occurred in the neutral (cartoon video) environment; for half of the monkeys in each group, this occurred after 1 day of abstinence and for the others after 30 days of abstinence. Rates of local cerebral glucose metabolism were measured in 57 brain regions. Global rates of cerebral metabolism were significantly lower in animals 1 day and 30 days post-cocaine self-administration when compared to those of food-reinforced controls. Effects were larger in 30- vs. 1-day cocaine abstinence, especially in prefrontal, parietal and cingulate cortex, as well as dorsal striatum and thalamus. Because these measures were obtained from monkeys while in a neutral environment, the deficits in glucose utilization can be attributed to the consequences of cocaine exposure and not to effects of conditioned stimuli associated with cocaine.

Microtubules (MTs) are structural units in the cytoskeleton. In brain cells they are responsible for axonal transport, information processing, and signaling mechanisms. Proper function of these processes is critical for healthy brain functions. Alcohol and substance use disorders (AUD/SUDs) affects the function and organization of MTs in the brain, making them a potential neuroimaging marker to study the resulting impairment of overall neurobehavioral and cognitive processes. Our lab reported the first brain-penetrant MT-tracking Positron Emission Tomography (PET) ligand [11C]MPC-6827 and demonstrated its in vivo utility in rodents and non-human primates. To further explore the in vivo imaging potential of [11C]MPC-6827, we need to investigate its mechanism of action. Here, we report preliminary in vitro binding results in SH-SY5Y neuroblastoma cells exposed to ethanol (EtOH) or cocaine in combination with multiple agents that alter MT stability. EtOH and cocaine treatments increased MT stability and decreased free tubulin monomers. Our initial cell-binding assay demonstrated that [11C]MPC-6827 may have high affinity to free/unbound tubulin units. Consistent with this mechanism of action, we observed lower [11C]MPC-6827 uptake in SH-SY5Y cells after EtOH and cocaine treatments (e.g., fewer free tubulin units). We are currently performing in vivo PET imaging and ex vivo biodistribution studies in rodent and nonhuman primate models of AUD and SUDs and Alzheimer's disease.

Degeneration of basal forebrain cholinergic circuitry represents an early event in the development of Alzheimer's disease (AD). These alterations in central cholinergic function are associated with disruptions in arousal, sleep/wake architecture, and cognition. Changes in sleep/wake architecture are also present in normal aging and may represent a significant risk factor for AD. M1 muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PAMs) have been reported to enhance cognition across preclinical species and may also provide beneficial effects for age- and/or neurodegenerative disease-related changes in arousal and sleep. In the present study, electroencephalography was conducted in young animals (mice, rats and nonhuman primates [NHPs]) and in aged mice to examine the effects of the selective M1 PAM VU0453595 in comparison with the acetylcholinesterase inhibitor donepezil, M1/M4 agonist xanomeline (in NHPs), and M1 PAM BQCA (in rats) on sleep/wake architecture and arousal. In young wildtype mice, rats, and NHPs, but not in M1 mAChR KO mice, VU0453595 produced dose-related increases in high frequency gamma power, a correlate of arousal and cognition enhancement, without altering duration of time across all sleep/wake stages. Effects of VU0453595 in NHPs were observed within a dose range that did not induce cholinergic-mediated adverse effects. In contrast, donepezil and xanomeline increased time awake in rodents and engendered dose-limiting adverse effects in NHPs. Finally, VU0453595 attenuated age-related decreases in REM sleep duration in aged wildtype mice. Development of M1 PAMs represents a viable strategy for attenuating age-related and dementia-related pathological disturbances of sleep and arousal.

It is critical to identify potential risk factors, such as a history of early life stress (ELS), that may confer specific vulnerabilities to increased drug intake. In this study, we examined whether male and female rhesus monkeys with a history of ELS (infant maltreatment; MALT) demonstrated significantly greater cocaine intake compared with controls. Monkeys were trained to self-administer cocaine during 4-h sessions at a peak dose (0.003–0.1 mg/kg/infusion; extended access, “EA peak”) and a dose of 0.1 mg/kg/infusion (EA 0.1) of cocaine. These data were compared with data obtained previously in monkeys trained during 1-h limited access (LA) sessions at the same peak dose of cocaine used here (Wakeford et al. Psychopharmacology, 236:2785-2796, 2019). Monkeys significantly increased total number of infusions earned in EA compared with LA, but total session response rates significantly decreased in EA compared with LA. There was no evidence of escalation in drug intake when we compared response rates to obtain the first 20 cocaine infusions between LA and EA peak conditions. Moreover, there was no evidence of escalation in drug intake during an additional 7 weeks of self-administration at 0.1 mg/kg/injection. The current study expands on previous reports demonstrating that rhesus macaques did not escalate cocaine intake under the experimental conditions employed and extended these findings by using a unique population of nonhuman primates with a history of infant MALT to test the hypothesis that ELS is a risk factor for escalation of cocaine intake in nonhuman primates. There was no clear evidence of escalation in cocaine intake as a consequence of ELS.

Stimulant abuse is a persistent public health problem with no Food and Drug Administration–approved pharmacotherapy. Although monoamine-releasing drugs such as d-amphetamine can decrease cocaine self-administration in human and animal laboratory studies, their potential for abuse limits clinical utility. “Abuse-deterrent” formulations of monoamine releasers, such as prodrugs, hold greater clinical promise if their abuse potential is, as theorized, lower than that of cocaine. In these studies, we determined the reinforcing strength of phendimetrazine (PDM), a prodrug for the amphetamine-like monoamine releaser phenmetrazine; both drugs have been shown to decrease cocaine self-administration in laboratory animals. To date, no study has directly compared PDM (Schedule III) with cocaine (Schedule II) under progressive-ratio (PR) schedules of reinforcement, which are better suited than fixed-ratio schedules to directly compare reinforcing strength of drugs. Dose-response curves for cocaine (saline, 0.001–0.3 mg/kg per injection) and PDM (0.1–1.0 mg/kg per injection) were generated in six cocaine-experienced male rhesus monkeys during 4-hour sessions with a 20-minute limited hold (LH). Under these conditions, the maximum number of injections was not significantly different between cocaine and PDM. The reinforcing strength of doses situated on the peaks of the cocaine and PDM dose-effect curves were redetermined with a 60-minute LH. The mean number of injections increased for both drugs, but not for saline. Cocaine presentations resulted in significantly higher peak injections than PDM with a 60-minute LH, which is consistent with the lower scheduling of PDM. These results support PDM as Schedule III and highlight the importance of schedule parameters when comparing reinforcing strength of drugs using a PR schedule of reinforcement. SIGNIFICANCE STATEMENT: One strategy for reducing cocaine use is to identify a treatment that substitutes for cocaine but has lower abuse potential. In a rhesus monkey model of drug abuse, this study compared the reinforcing strength of cocaine and phendimetrazine, a drug that has been shown to decrease cocaine use in some studies.

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.

At present, there are no US Food and Drug Administration-approved treatments for cocaine use disorders. One consideration for this lack of treatment efficacy stems from the appropriate use of animal models. The premise of this commentary is that social behavior needs to be incorporated in animal models of cocaine use disorder. The goal of this commentary is to describe some of the strengths and limitations of recent preclinical animal models of cocaine abuse which have incorporated social behavior. There are many ways to include social variables into preclinical research, and the study design will depend on the questions asked. Four general types of studies incorporating social factors are described: those involving aggression (that is, maternal neglect and social defeat), modeling, social reward, and social housing, including social isolation. The inclusion of social variables into preclinical research will help identify biobehavioral markers that may lead to an individualized treatment approach that more effectively decreases cocaine use. These studies will aid in the development of novel pharmacotherapies as well as non-pharmacological interventions (for example, punishment, alternative reinforcers, and environmental enrichment) that would be critical for informing policy decisions.

RATIONALE: Because chronic cocaine exposure produces profound effects on brain glutamate function, this system has been investigated as a target for novel medications for cocaine use disorder. Studies in animal models have provided encouraging results for drugs that target metabotropic glutamate receptors (mGluR), particularly Group II mGluRs which includes mGluR2 and mGluR3 receptors. OBJECTIVE: The present study examined the effects of the mGluR2/3 receptor-selective agonist, (−)-2-oxa-4-aminobicylco hexane-4,6-dicarboxylic acid (LY379268), in male rhesus monkeys self-administering cocaine under two procedures that assess the strength of cocaine as a reinforcer. METHODS AND RESULTS: In four monkeys, acute effects of LY379268 on food and cocaine self-administration were characterized using a multiple 10-response fixed-ratio food, progressive-ratio cocaine schedule of reinforcement. When monkeys self-administered 0.03 mg/kg per injection cocaine, a dose that resulted in maximal or near-maximal injections, LY379268 (0.001–0.56 mg/kg, i.v.) increased cocaine injections and disrupted food-maintained responding. Another group of monkeys (n=3) responded under a food-cocaine choice procedure in which a dose-effect curve for self-administered cocaine (0.0, 0.003–0.1 mg/kg per injection) was generated daily. Acute LY379268 (0.01–0.1 mg.kg, i.v.) produced a shift in allocation of responding towards cocaine without affecting the total reinforcers delivered. When treatment was extended to 5 consecutive days, tolerance developed to LY379268-induced increases in cocaine choice. CONCLUSIONS: These data from two complimentary nonhuman primate models of cocaine use disorder are consistently negative with respect to the potential of LY379268 as a pharmacotherapy for reducing ongoing cocaine use.

Early life stress (ELS), including childhood maltreatment, is a predictive factor for the emergence of cocaine use disorders (CUDs) in adolescence. Accordingly, we examined whether post-pubertal male and female rhesus macaques that experienced infant maltreatment (maltreated, n = 7) showed greater vulnerability to cocaine self-administration in comparison with controls (controls, n = 7). Infant emotional reactivity was measured to assess differences in behavioral distress between maltreated and control animals as a result of early life caregiving. Animals were then surgically implanted with indwelling intravenous catheters and trained to self-administer cocaine (0.001–0.3 mg/kg/infusion) under fixed-ratio schedules of reinforcement. Days to acquisition, and sensitivity to (measured by the EDMax dose of cocaine) and magnitude (measured by response rates) of the reinforcing effects of cocaine were examined in both groups. Maltreated animals demonstrated significantly higher rates of distress (e.g., screams) in comparison with control animals. When given access to cocaine, control males required significantly more days to progress through terminal performance criteria compared with females and acquired cocaine self-administration slower than the other three experimental groups. The dose that resulted in peak response rates did not differ between groups or sex. Under 5-week, limited-access conditions, males from both groups had significantly higher rates of responding compared with females. In control monkeys, these data support sex differences in cocaine self-administration, with females being more sensitive than males. These findings also suggest that ELS may confer enhanced sensitivity to the reinforcing effects of cocaine, especially in males.

Background Drugs that increase inhibitory neuronal activity in the brain have been proposed as potential medications for stimulant use disorders. Objective The present study assessed the ability of chronically administered levetiracetam (Keppra®), a clinically available anticonvulsant drug that increases GABA by binding to synaptic vesicle glycoprotein 2A, to modulate the reinforcing strength of cocaine in monkeys. Methods Three adult male rhesus monkeys (Macaca mulatta) self-administered cocaine intravenously each day under a progressive-ratio (PR) schedule of reinforcement. Two monkeys also responded to receive food pellets under a 50-response fixed-ratio schedule (FR 50) each morning. After determining a cocaine dose-response curve (0.001–0.3 mg/kg per injection, i.v.) in the evening, levetiracetam (5–75 mg/kg, p.o., b.i.d.) was administered for 12–16 days per dose. To model a treatment setting, cocaine self-administration sessions were conducted using the PR schedule every 4 days during levetiracetam treatment. After tapering the dose of levetiracetam over two weeks in the absence of cocaine sessions, cocaine dose-effect curves were re-determined. Results Lower doses of levetiracetam produced non-systematic fluctuations in numbers of cocaine injections received in each subject, whereas the highest tested dose significantly increased the reinforcing strength of cocaine; no effects on food-maintained responding were observed. After termination of levetiracetam treatment, dose-effect curves for cocaine self-administration were shifted to the left in two monkeys. Conclusion These data suggest that levetiracetam is not likely to be an efficacious pharmacotherapy for cocaine dependence. Rather, sensitivity to cocaine may be increased during and after levetiracetam treatment.

AIMS The aim of this retrospective analysis was to examine the pattern of cardiac 68Ga-fibroblast-activation protein-α inhibitor (FAPI) uptake in patients after acute myocardial infarction (AMI) using PET and to investigate its association with results of coronary angiography. We correlated FAPI uptake with biomarkers of myocardial damage including left ventricular function. METHODS AND RESULTS A cohort of 10 patients with no history of coronary artery disease underwent PET 18 ± 20.6 days after AMI (ST-segment elevation myocardial infarction [n = 5] and non-ST-segment elevation infarction [n = 5]), respectively. SUVmax, SUVmean, and SUVpeak of localized tracer uptake were calculated; tracer uptake volume was reported as fibroblast activation volume (FAV), with imaging data being correlated with clinical parameters. Focal FAPI uptake was observed in all patients. Average uptake at 10 minutes postinjection was 8.9 ± 4.4 (SUVmax), 7.6 ± 4.0 (SUVpeak), and 5.3 ± 2.8 (SUVmean), respectively. Affected myocardium showed a partial to complete match between tracer uptake and confirmed culprit lesion by coronary angiography in 44.4% and 55.6% of patients, respectively. A strong correlation between FAV and peak creatine kinase level (r = 0.90, P < 0.01) and inverse correlation of FAV with left ventricular function (r = -0.69, P < 0.05) was observed. CONCLUSIONS This analysis demonstrates in vivo visualization of fibroblast activation after AMI. The uptake area showed a very good agreement with the affected coronary territory. A strong correlation of the de novo established parameter FAV with left ventricular function and peak creatine kinase was observed. This imaging modality may provide important insights into mechanisms of structural remodeling after AMI at an early stage.

Dopamine (DA) signaling is central in hypothesized causal paths linking the influence of social and environmental variables with cognition, behavior and affective states, including vulnerability to drug dependence. Here, we study whether change in one’s social rank induces DA and norepinephrine (NE) changes using a novel pig model with a social-ranking-and-re-ranking protocol to investigate social context influences on catecholamine concentrations in cerebrospinal fluid (CSF) and blood. For two weeks, 16 recently weaned male piglets were socially housed in four groups, with video-recordings for social rank assessments (α, β, γ, and δ); CSF and blood were obtained from these stable social groups. Next, all four α were housed together, as were all four β, etc., again with video recording for blinded social ranking. CSF and blood samples were collected at three time points: prior to initial social housing, following social housing and following re-organization. Regression analyses disclosed a positive relationship between changes in social rank and post-rank change in CSF levels of DA; one unit increase of social rank predicted a 17.4 pg/ml increase in CSF dopamine concentrations (95% CI= 1.2, 33.7). Compared to piglets with downward shifts in ranks (i.e., high-to-low), piglets with upward shifts (i.e., low-to-high) had a statistically significant greater increase in CSF DA levels. No relationship was observed for CSF NE or blood concentrations of DA or NE at any phase of this experiment. This work, using a novel pig model, adds new evidence on alteration of the brain dopaminergic system induced by social rank change.

Background More than 50% of patients with major depressive episode (MDE) fail to respond to initial treatment with first line pharmacological therapy. Altered receptor and serotonin transporter function are considered to be associated with mental disorders. Our investigation aimed on the density of the HT1A receptor in mesiotemporal cortex (MTC) and raphe measured by F18-Mefway in patients with MDD. Methods Patients with untreated clinically suspected major depressive episode were recruited from June 2012 to May 2014. 49 patients were included into the study: 36 patients (73%) were identified as responders, whereas 13 (27%) were non-responders. Gender distribution was 26 men (56%) and 23 women (44%). For treatment, only a standard medication of a selective serotonin reuptake inhibitor (SSRI) with escitalopram in a range of 10-20 mg/day was permitted. Responders were defined by improvement of the MADRS>50%. Visually MTC had the highest uptake of F18-Mefway among all brain regions, an asymmetry could not be observed in any patient. An elliptical region was drawn over the amygdala and hippocampus area and a small circular region was drawn over the raphe nuclei. All data were calculated related to (unspecific) cerebellar uptake. Results The quotient of the right MTC was 5.00 [4.33; 5.50] in all patients, in responders 5.00 [4.00; 5.75] and in non-responders 5.00 [4.50; 5.50] (P=0.56). The quotient of the left MTC presented with a median level of 4.50 [4.50; 5.50] in all persons. The responders had 4.50 [4.50; 5.75] which was not statistically significant to the data of the non-responders with 5.00 [4.50; 5.50] at P=0.64. The raphe had a median quotient of 2.50 [2.00; 3.00] in all and the cohort of responders, whereas non-responders had 2.50 [2.00; 2.50] (P=0.61). Also the absolute values of SUV in the three brain regions were not statistically different between the cohorts. Additionally, we did not find any sex-related differences in our patient group. Conclusions Serotonin 1A receptor density can be assessed efficiently by F18-Mefway and PET-CT in patients with MDE. The method can be estimated as a possible tool for clinical and academic investigation, marked tracer uptake can constantly be observed at MTC and the raphe. Anyhow, under conditions of real life in patient care, it is not possible to distinguish patients with a good prognosis who will respond to standard SSRI therapy from non-responders who would benefit from a different therapeutic approach starting earlier.

1260 Objectives: Most clinical trials on castration resistant prostate cancer (CRPC) rely on baseline staging by conventional imaging rather than novel positron-emission-tomography (PET). We investigated the impact of PSMA-PET on PCWG3 clinical subtype classification, frequently used to define clinical trial target populations. Methods: Databases at three participating PET centers were retrospectively screened for patients with prostate cancer, for whom PSMA-PET was performed between 2014 and 2019, and who had: (a) documented CRPC, (b) PSA values ≥1 ng/mL and (c) conventional imaging (CI) i.e. bone scan and CT (78%) or whole-body MRI (22% of patients) within 6 months of the PSMA-PET without changes of therapy between the staging modalities. Clinical PCWG3 subtype, i.e. nonmetastatic (nmCRPC), locally recurrent, nodal spread, bone disease and visceral disease, as well as PROMISE stage were determined for PET versus CI by three independent blinded readers. Inter-reader agreement was assessed by Fleiss’ Kappa. Results: 67 patients were included with a median PSA level of 53.2 ng/mL (IQR 5.8-334.6 ng/mL). Median time between PSMA-PET and CI was 1 month (IQR 0-2). 37/67 patients (55%) underwent ADT plus at least one line of a second line treatment for CRPC (docetaxel, cabazitaxel, abiraterone, enzalutamide or Radium-223). Overall CI was positive in 87% (58/67) of patients whereas PSMA-PET in 92% (62/67). PCWG3 clinical subtypes identified by PSMA-PET vs. CI were: 7% (5/67) vs. 13% (9/67) for nmCRPC, 4% (3/67) vs. 0% (0/67) for locally recurrent CRPC, 10% (7/67) vs. 6% (4/67) for nodal spread, 60% (40/67) vs. 58% (39/67) for bone disease and 18% (12/67) vs. 22% (15/67) for visceral disease, respectively. Overall, PSMA-PET and CI were concordant in 70% (47/67) of patients. PSMA-PET led to up-staging in 15% (10/67) and down-staging in 15% (10/67) of patients; down-staging occurred most often for visceral disease (7/67, 10%) (Table 1). PSA at the time of PET, D’Amico risk group and number of different systemic therapies were not significantly associated with a PSMA-PET up-staging compared to CI. There was a statistically significant association between higher D’Amico risk group and a PSMA-PET down-staging compared to CI (p=0.003). PET vs. CI interobserver agreement was 0.81 vs. 0.51, 0.74 vs. 0.47, 0.95 vs. 0.72, or 0.58 vs. 0.65 for locally recurrent, nodal spread, bone disease, or visceral disease, respectively. Conclusions: In our multicenter, retrospective study, PSMA-PET demonstrates high level of concordance with CI for per-patient PCWG3 clinical subtype. PSMA-PET delivers higher reproducibility and more accurate assessment of nmCRPC as well as visceral disease and should be implemented in future enrollment/screening procedures. $$table_{5171EA87-920E-4F20-902F-8532986F59A4}$$

[Image: see text] Herein, we report the discovery of a novel potent, selective, CNS penetrant, and orally bioavailable mGlu(4) PAM, VU0652957 (VU2957, Valiglurax). VU2957 possessed attractive in vitro and in vivo pharmacological and DMPK properties across species. To advance toward the clinic, a spray-dried dispersion (SDD) formulation of VU2957 was developed to support IND-enabling toxicology studies. Based on its overall profile, VU2957 was evaluated as a preclinical development candidate for the treatment of Parkinson’s disease.

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 United States is currently facing an opioid crisis. Novel tools to better comprehend dynamic molecular changes in the brain associated with the opioid abuse are limited. Recent studies have suggested the usefulness of plasma exosomes in better understanding CNS disorders. However, no study has ever characterized exosomes (small extracellular vesicles of endocytic origin) secreted by brain cells to understand the potential neurodegenerative effects of long-term oxycodone self-administration (SA). Methods MRI of Cynomolgus monkeys (Macaca fascicularis) was performed to assess alterations in gray matter volumes with oxycodone SA. We isolated total exosomes (TE) from the plasma of these monkeys; from TE, we pulled-out neuron-derived exosomes (NDE), astrocytes-derived exosomes (ADE), and microglia-derived exosomes (MDE) using surface biomarkers L1CAM (L1 cell adhesion molecule), GLAST (Glutamate aspartate transporter) and TMEM119 (transmembrane protein119), respectively. Findings We observed a significantly lower gray matter volume of specific lobes of the brain (frontal and parietal lobes, and right putamen) in monkeys with ∼3 years of oxycodone SA compared to controls. Higher expression of neurodegenerative biomarkers (NFL and α-synuclein) correlates well with the change in brain lobe volumes in control and oxycodone SA monkeys. We also identified a strong effect of oxycodone SA on the loading of specific miRNAs and proteins associated with neuro-cognitive disorders. Finally, exosomes subpopulation from oxycodone SA group activated NF-κB activity in THP1- cells. Interpretation These results provide evidence for the utility of brain cells-derived exosomes from plasma in better understanding and predicting the pro-inflammatory and neurodegenerative consequence of oxycodone SA. Funding NIH

Individual differences in response to social stress and environmental enrichment may contribute to variability in response to behavioral and pharmacological treatments for drug addiction. In monkeys, social status influences the reinforcing effects of cocaine and the effects of some drugs on cocaine self-administration. In this study, we used male cynomolgus macaques (n=15) living in established social groups to examine the effects of social confrontation on the reinforcing effects of cocaine using a food-drug choice procedure. On the test day, a dominant or subordinate monkey was removed from his homecage and placed into another social pen; 30 min later he was studied in a cocaine-food choice paradigm. For the group, following social confrontation, sensitivity to cocaine reinforcement was significantly greater in subordinate monkeys compared with dominant animals. Examining individual-subject data revealed that for the majority of monkeys (9/15), serving as an intruder in another social group affected cocaine self-administration and these effects were dependent on the social rank of the monkey. For subordinate monkeys, sensitivity to the reinforcing effects of cocaine increased while sensitivity decreased in dominant monkeys. To investigate potential mechanisms mediating these effects, brain glucose metabolism was studied in a subset of monkeys (n=8) using [18F]fluorodeoxyglucose ([18F]FDG) with positron emission tomography. Dominant and subordinate monkeys displayed distinctly different patterns of brain glucose metabolism in their homecage, including areas associated with vigilance and stress/anxiety, respectively, and during social confrontation. These data demonstrate that, depending on an individual’s social status, the same social experience can have divergent effects on brain function and cocaine self-administration. These phenotypic differences in response to social conditions support a personalized treatment approach to cocaine addiction.

Background A major goal of treatments for cocaine addiction is to reduce relapse-associated cravings, which are typically induced by environmental stimuli associated with cocaine use and related to changes in dopamine neurotransmission. Methods The present study used an animal model of cocaine seeking to determine functional consequences of cue exposure using fluorodeoxyglucose positron emission tomography and to relate findings to juvenile levels of dopamine transporter and D 2 -like receptor availabilities determined before any drug exposure. Adult male rhesus monkeys ( N = 11) self-administered cocaine (0.2 mg/kg per injection) under a second-order schedule of reinforcement, in which responding was maintained by conditioned reinforcers. Positron emission tomography scans assessing glucose utilization, a marker of functional activation, were conducted during cocaine-cue responding and food-reinforced responding in a context where cocaine was never available. Results Compared with the noncocaine condition, we found significant functional activation in the medial prefrontal cortex, anterior cingulate, precuneus region of the parietal cortex, and striatum—findings similar to those reported in humans who abuse cocaine. Furthermore, these functional activations in the prefrontal, cingulate, and parietal cortex measured during cocaine-cue responding were significantly correlated with juvenile measures of dopamine transporter availability, whereas no significant relationship with prior D 2 -like receptor availability was observed in any brain region. Conclusions The similarity between the present findings and findings in humans who use cocaine supports the use of this model for examination of factors that affect the development and intensity of cue-induced drug seeking and provides evidence for potential biomarkers for the evaluation of potential treatments (behavioral and pharmacologic) for cocaine abuse.

Dysregulation of microtubules is commonly associated with several psychiatric and neurological disorders, including addiction and Alzheimer’s disease. Imaging of microtubules in vivo using positron emission tomography (PET) could provide valuable information on their role in the development of disease pathogenesis and aid in improving therapeutic regimens. We developed [11C]MPC-6827, the first brain-penetrating PET radiotracer to image microtubules in vivo in the mouse brain. The aim of the present study was to assess the reproducibility of [11C]MPC-6827 PET imaging in non-human primate brains. Two dynamic 0–120 min PET/CT imaging scans were performed in each of four healthy male cynomolgus monkeys approximately one week apart. Time activity curves (TACs) and standard uptake values (SUVs) were determined for whole brains and specific regions of the brains and compared between the “test” and “retest” data. [11C]MPC-6827 showed excellent brain uptake with good pharmacokinetics in non-human primate brains, with significant correlation between the test and retest scan data (r = 0.77, p = 0.023). These initial evaluations demonstrate the high translational potential of [11C]MPC-6827 to image microtubules in the brain in vivo in monkey models of neurological and psychiatric diseases.

It has been shown that exposure to cocaine can result in neuroinflammatory responses. Microglia, the resident CNS immune cells, undergo a transition to an activated state when challenged. In rodents, and possibly humans, cocaine exposure activates microglia. The goal of this study was to assess the extent and magnitude of microglial activation in rhesus monkeys with an extensive history of cocaine self-administration. Male rhesus monkeys (N=4/group) were trained to respond on a fixed-interval 3-min schedule of food or 0.3 mg/kg/injection cocaine presentation (30 reinforcers/session) for 300 sessions. At the end of the final session, monkeys were administered 2-[(14)C]deoxyglucose intravenously and 45 min later euthanized. Brain sections were used for autoradiographic assessments of glucose utilization and for microglia activation with [(3)H]PK11195, a marker for the microglial18kda translocator protein. There were no group differences in gray matter [(3)H]PK11195 binding, while binding was significantly greater in cocaine self-administration animals as compared to food controls in 8 of the 11 white matter tracts measured at the striatal level. Binding did not differ from control at other levels. There were also significant increases in white matter local cerebral glucose utilization at the striatal level, which were positively correlated with [(3)H]PK11195 binding. The present findings demonstrate an elevation in [(3)H]PK11195 binding in forebrain white matter tracts of nonhuman primates with a prolonged history of cocaine self-administration. These elevations were also associated with greater cerebral metabolic rates. These data suggest that white matter deficits may contribute to behavioral, motivational, and cognitive impairments observed in cocaine abusers.

Labyrinthitis is inflammation of the membranous and bony labyrinth of the inner ear. Typical portals of entry include hematogenous spread from the cochlear vasculature, passage of otitis media pathogens through the round window, and most commonly, meningogenic spread from the subarachnoid space. The sequela of chronic inner ear inflammation is labyrinthitis ossificans, in which inner ear structures are replaced by fibrous and osseous tissues. Labyrinthitis in humans has been reported concurrently with infection due to various viruses (for example, varicella–zoster, measles, mumps) and bacteria (for example, Treponema pallidum, Streptococcus pneumoniae) and may be associated with vertebrobasilar ischemia and meningitis. Profound sensorineural hearing loss is a common, serious complication of this disease. Here, we report a case of labyrinthitis ossificans in a cynomolgus macaque (Macaca fascicularis) with a potential infectious etiology. Historically, this animal had an indwelling femoral intravenous catheter for more than 4 y. He presented with a right-sided head tilt and incoordination of 2 mo duration. The macaque was treated with NSAID and antibiotics, which corrected the incoordination but not the head tilt. MRI revealed right-sided labyrinthitis, and euthanasia was elected due to clinical signs that were refractory to treatment. Gross pathology was unremarkable, but histopathology revealed chronic labyrinthitis ossificans with local fibroplasia and vestibuloauditory neuritis. We describe here the clinical features, imaging, and histologic lesions of labyrinthitis in a macaque.

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.

Physiological and behavioral differences between dominant and subordinate monkeys have been useful in preclinical models investigating numerous disease states. In captivity, it has been inferred that subordinate monkeys live in a context of chronic social stress and may be at risk for a variety of dysfunctions; however, the factors that influence eventual rank are not entirely known. The goal of the present study was to first evaluate several phenotypic characteristics as potential trait markers for eventual social rank and then to determine the consequences of social hierarchy on these measures (i.e., state markers). Baseline estradiol, progesterone, cortisol and testosterone concentrations were obtained from 16 pair-housed female cynomolgus monkeys before and after introduction into new social groups (n = 4/group). Furthermore, effects of the initial week of social rank establishment on outcome measures of cognitive performance and homecage activity were examined. Baseline body weight and mean serum estradiol concentrations were the only statistically significant predictors of eventual rank, with future subordinate monkeys weighing less and having higher estradiol concentrations. During initial hierarchy establishment, future subordinate monkeys had increased morning and afternoon cortisol concentrations, increased locomotor activity and impaired cognitive performance on a working memory task. After 3 months of social housing, subordinate monkeys had blunted circulating estradiol and progesterone concentrations. These findings demonstrate differential effects on gonadal hormones and cortisol as a function of social context in normally cycling female monkeys. Furthermore, disruptions in cognitive performance were associated with subordinate status, suggesting strong face validity of this model to the study of factors related to the etiology and treatment of human diseases associated with chronic stress. Am. J. Primatol. 78:402-417, 2016. © 2015 Wiley Periodicals, Inc.

There are several case reports of nonmedicinal quetiapine abuse, yet there are very limited preclinical studies investigating quetiapine self-administration. The goal of this study was to investigate the reinforcing effects of quetiapine alone and in combination with intravenous cocaine in monkeys. In experiment 1, cocaine-experienced female monkeys (N = 4) responded under a fixed-ratio (FR) 30 schedule of food reinforcement (1.0-g banana-flavored pellets), and when responding was stable, quetiapine (0.003–0.1 mg/kg per injection) or saline was substituted for a minimum of five sessions; there was a return to food-maintained responding between doses. Next, monkeys were treated with quetiapine (25 mg, by mouth, twice a day) for approximately 30 days, and then the quetiapine self-administration dose-response curve was redetermined. In experiment 2, male monkeys (N = 6) self-administered cocaine under a concurrent FR schedule with food reinforcement (three food pellets) as the alternative to cocaine (0.003–0.3 mg/kg per injection) presentation. Once choice responding was stable, the effects of adding quetiapine (0.03 or 0.1 mg/kg per injection) to the cocaine solution were examined. In experiment 1, quetiapine did not function as a reinforcer, and chronic quetiapine treatment did not alter these effects. In experiment 2, cocaine choice increased in a dose-dependent fashion. The addition of quetiapine to cocaine resulted in increases in low-dose cocaine choice and number of cocaine injections in four monkeys, while not affecting high-dose cocaine preference. Thus, although quetiapine alone does not have abuse potential, there was evidence of enhancement of the reinforcing potency of cocaine. These results suggest that the use of quetiapine in cocaine-addicted patients should be monitored.

Preclinical research has demonstrated that cognitive function may be influenced by estradiol (E2) and progesterone (P4) concentrations, although few cognition studies involve normally cycling females. The present study examined cognitive performance in normally cycling female cynomolgus macaques (n = 14), a species with similarities to humans in brain organization and a nearly identical menstrual cycle to women. Initial assessments compared cognitive measures to circulating concentrations of E2 and P4 (n = 12). Once a relationship was characterized between hormones and cognitive performance, the menstrual cycle was divided into four distinct phases: early follicular (EF), late follicular (LF), early luteal (EL) and late luteal (LL), verified by the onset of menses and serum concentrations of E2 and P4. Concentrations of E2 were highest during the LF phase and P4 concentrations peaked during the EL phase. All monkeys were trained on two cognitive tasks: reversal learning, involving simple discrimination (SD) and reversal (SDR), which measured associative learning and behavioral flexibility, respectively (n = 3-4 per phase) and a delayed match-to-sample (DMS) task which assessed working memory (n = 11). P4 concentrations were positively correlated with number of trials and errors during acquisition of SD performance, but not during acquisition of the SDR task or maintenance of the reversal-learning task. Across the menstrual cycle, significantly fewer errors were made in the SDR task during the LF phase, when E2 concentrations were high and P4 concentrations low. Working memory, assessed with the DMS task, was not consistently altered based on previously characterized menstrual cycle phases. These findings demonstrate a relationship between P4, E2 and cognitive performance in normally cycling cynomolgus monkeys that is task dependent. Knowledge of these interactions may lead to a better understanding of sex-specific cognitive performance.

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.

Exposure to stimuli and environments associated with drug use is considered one of the most important contributors to relapse among substance abusers. Neuroimaging studies have identified neural circuits underlying these responses in cocaine-dependent subjects. But these studies are often difficult to interpret because of the heterogeneity of the participants, substances abused, and differences in drug histories and social variables. Therefore, the goal of this study was to assess the functional effects of exposure to cocaine-associated stimuli in a non-human primate model of cocaine self-administration, providing precise control over these variables, with the 2-[(14) C]deoxyglucose method. Rhesus monkeys self-administered 0.3 mg/kg/injection cocaine (n = 4) under a fixed-interval 3-minute (FI 3-min) schedule of reinforcement (30 injections/session) for 100 sessions. Control animals (n = 4) underwent identical schedules of food reinforcement. Sessions were then discontinued for 30 days, after which time, monkeys were exposed to cocaine- or food-paired cues, and the 2-[(14) C]deoxyglucose experiment was conducted. The presentation of the cocaine-paired cues resulted in significant increases in functional activity within highly restricted circuits that included portions of the pre-commissural striatum, medial prefrontal cortex, rostral temporal cortex and limbic thalamus when compared with control animals presented with the food-paired cues. The presentation of cocaine-associated cues increased brain functional activity in contrast to the decreases observed after cocaine consumption. Furthermore, the topography of brain circuits engaged by the expectation of cocaine is similar to the distribution of effects during the earliest phases of cocaine self-administration, prior to the onset of neuroadaptations that accompany chronic cocaine exposure.

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.

Drugs acting at D3 dopamine receptors have been suggested as medications for cocaine dependence. These experiments examined the effects of intravenously and orally administered buspirone, a D2-like receptor antagonist with high affinity for D3 and D4 receptors, on the relative reinforcing strength of cocaine in group-housed male cynomolgus monkeys. Use of socially housed monkeys permitted the assessment of whether social status, known to influence D2-like receptor availability, modulates the behavioral effects of buspirone. Buspirone was administered acutely to monkeys self-administering cocaine under a food–drug choice procedure in which a cocaine self-administration dose–effect curve was determined daily. When administered by either route, buspirone significantly decreased cocaine choice in dominant-ranked monkeys. In subordinate monkeys, however, i.v. buspirone was ineffective on average, and oral buspirone increased choice of lower cocaine doses. The effects of buspirone only differed according to route of administration in subordinate monkeys. Moreover, it is noteworthy that the effects of buspirone were similar to those of the D3 receptor-selective antagonist PG01037 and qualitatively different than those of less selective drugs that act at D2-like or serotonin (5-HT)1A receptors, suggesting a D3 and possibly D4 receptor mechanism of action for buspirone. Taken together, the data support the utility of drugs targeting D3/D4 receptors as potential treatments for cocaine addiction, particularly in combination with enriching environmental manipulations.

Clinical literature suggests a link between substance abuse and sleep disturbances. Quetiapine, an atypical antipsychotic, has shown efficacy in treating sleep disturbances, with clinical studies showing promise for quetiapine as a treatment for cocaine abuse. The goal of this study was to examine the effects of quetiapine on cocaine self-administration and behavioral indices of sleep in monkeys. Seven adult male rhesus monkeys, fitted with Actical® activity monitors, were trained to respond under a choice paradigm of food (1.0-g pellets) and cocaine (0.003–0.3 mg/kg per injection) presentation. First, monkeys received acute pretreatment (45 min) with quetiapine (25–75 mg, p.o.) prior to choice sessions; three cocaine doses were studied in combination with quetiapine. Next, the effect of chronic (14–16 days) quetiapine treatment (25–250 mg, p.o., BID) was examined in combination with the lowest preferred cocaine dose (≥80 % cocaine choice). Behavioral indices of sleep, based on activity measures obtained during lights-out, were recorded throughout the study. Acute quetiapine decreased cocaine choice in four of the seven monkeys. Chronic quetiapine treatment resulted in initial decreases in cocaine choice, but tolerance developed to these effects. Acute doses of quetiapine did not improve sleep efficiency the following night nor did chronic quetiapine. The first night after discontinuing quetiapine treatment resulted in significant decreases in sleep efficiency and increases in nighttime activity. These findings do not offer support for the use of quetiapine as a monotherapy for treatment of cocaine abuse nor as an adjunct therapy to treat sleep disturbances associated with stimulant 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.

Neuroimaging studies of cocaine users have demonstrated white matter abnormalities associated with behavioral measures of impulsivity and decision-making deficits. The underlying bases for this dysregulation in white matter structure and function have yet to be determined. The aim of the present studies was to investigate the influence of prolonged cocaine self-administration on the levels of myelin-associated proteins and mRNAs in nonhuman primate white matter.Rhesus monkeys (N=4) self-administered cocaine (0.3mg/kg/inj, 30 reinforcers per session) for 300 sessions. Control animals (N=4) responded for food. Following the final session monkeys were euthanized and white matter tissue at three brain levels was processed for immunoblotting analysis of proteolipid protein (PLP) and myelin basic protein (MBP), as well as for in situ hybridization histochemical analysis of PLP and MBP mRNAs.Both MBP and PLP immunoreactivities in white matter at the level of the precommissural striatum were significantly lower in tissue from monkeys self-administering cocaine as compared to controls. No significant differences were seen for either protein at the levels of the prefrontal cortex or postcommissural striatum. In addition, no differences were observed in expression of mRNA for either protein.These preliminary findings, in a nonhuman model of prolonged cocaine self-administration, provide further evidence that compromised myelin may underlie the deficits in white matter integrity described in studies of human cocaine users.

Rationale Chronic treatment with dopamine (DA) receptor agonists and antagonists can differentially affect measures of DA D2/D3 receptor number and function, but the effects of chronictreatmentwithapartialD2/D3receptoragonistarenot clear. Objective We used a within-subjects design in male cynomolgus monkeys to determine the effects of repeated (17-day) treatment with the D2/D3 receptor partial agonist aripiprazole (ARI; 0.03 mg/kg and 0.1 mg/kg i.m.) on foodreinforced behavior (n=5) and on D2/D3 receptor availability as measured with positron emission tomography (PET; n=9). Methods Five monkeys responded under a fixed-ratio 50 schedule of food reinforcement and D2/D3 receptor availability was measured before and 4 days after ARI treatment using PET and the D2/D3 receptor-selective radioligand [ 18 F]fluoroclebopride (FCP). Four additional monkeys were studied using [ 11 C]raclopride and treated sequentially with each dose of ARI for 17 days. Results ARI decreased food-maintained responding with minimal evidence of tolerance. Repeated ARI administration increased FCP and raclopride distribution volume ratios (DVRs)inthecaudatenucleusandputameninmostmonkeys, but decreases were observed in monkeys with the highest baseline DVRs. Conclusions The results indicate that repeated treatment with a low-efficacy DA receptor partial agonist produces effects on brain D2/D3 receptor availability that are qualitatively different from those of both high-efficacy receptor agonists and antagonists, and suggest that the observed individual differences in response to ARI treatment may reflect its partial agonist activity.

Many children diagnosed with attention deficit hyperactivity disorder are treated with methylphenidate (MPH), despite limited information on later vulnerability to drug abuse. A previous study in adolescent monkeys treated with MPH for 1 year did not reveal differences in acquisition to cocaine reinforcement compared to controls (Gill et al., 2012). The present study extended this characterization to include MPH self-administration. Adolescent male rhesus monkeys previously treated with a sustained-release formulation of MPH (beginning at ∼ 30 months old) and control monkeys (n=8/group) were used. All had prior experience of self-administering cocaine under a fixed-ratio (FR) 30 schedule of reinforcement. Responding was maintained by food (1.0-g banana-flavored pellets) and MPH (saline, 0.001 – 0.1 mg/kg per injection) was substituted for food for at least 5 consecutive sessions. MPH functioned as a reinforcer in all monkeys; there were no differences between groups in MPH self-administration. These findings extend earlier research with cocaine reinforcement showing that MPH treatment in adolescent monkeys does not increase future reinforcing effects of stimulant drugs.

Epidemiological data indicate that rates of methamphetamine misuse surpass those of D-amphetamine, but self-administration research in animals and humans has not typically demonstrated differences in their reinforcing effects. The present study used a within-session, exponentially increasing progressive-ratio schedule and extended-access conditions to assess the relative reinforcing strength of D-amphetamine and methamphetamine in rhesus monkeys (n=5) trained to self-administer cocaine. A range of doses of methamphetamine (0.003-0.1 mg/kg/injection), D-amphetamine (0.003-0.1 mg/kg/injection), and cocaine (0.003-0.3 mg/kg/injection) was tested to capture the ascending and descending limbs of the dose-effect functions. Each drug functioned as a reinforcer, but the peak number of self-administered D-amphetamine injections was significantly lower compared with methamphetamine and cocaine; the peak number of self-administered injections of cocaine and methamphetamine did not differ. Although differences in availability and other social factors likely impact relative rates of abuse, the present data suggest that the greater reinforcing strength of methamphetamine contributes to its increased use compared with D-amphetamine.

We evaluated the potential of 18F-fluoromethyldimethyl-2-hydroxyethyl-ammonium (FCH) PET/CT in the detection of recurrent disease or distant metastases and correlated its diagnostic accuracy with prostate-specific antigen (PSA) levels in prostate cancer patients with biochemical evidence of recurrence. Furthermore, the influences of androgen deprivation therapy (ADT) and its duration on 18F-FCH PET were assessed in this study. Methods: This prospective study included 250 prostate cancer patients with PSA relapse who underwent 18F-FCH PET/CT. At the time of 18F-FCH PET/CT imaging, the mean PSA level was 46.9 ± 314.7 ng/mL and 55.2% (138/250) of patients were receiving ADT. Overall, ADT was performed on 67.2% (168/250) of patients after initial treatment. Imaging was performed on an integrated PET/CT system. Acquisition started 1 min after intravenous injection of 18F-FCH (4.07 MBq/kg of body weight) with dynamic PET images in the pelvic region during 8 min (1 min/frame) followed by a static semi–whole-body acquisition. The final diagnosis of positive PET lesions was based on histopathology or a consensus of clinical findings, additional imaging, or follow-up imaging modalities. Results:18F-FCH PET/CT was able to correctly detect malignant lesions in 74% (185/250) of patients but was negative in 26% (65/250). In 28% of patients, only 1 lesion was detected (69/250); from these, 65.2% (45 patients) had a local recurrence, 18.8% (13 patients) a single lymph node, and 15.9% (11 patients) a solitary bone metastasis. The sensitivity of the 18F-FCH PET was significantly higher (P = 0.001) in patients with ongoing ADT (85%; confidence interval, 80%–91%) than in patients without ADT (59.5%; confidence interval, 50%–69%). 18F-FCH PET sensitivity was 77.5%, 80.7%, 85.2%, and 92.8% for the trigger PSA levels of more than 0.5, 1.0, 2.0, and 4.0 ng/mL, respectively. Scan sensitivity was 33% in patients with a trigger PSA level of less than 0.3 ng/mL and 77% in patients with a trigger PSA level of greater than 0.3 ng/mL, respectively (P = 0.001). Using a binary logistic regression analysis model, we showed trigger PSA and ADT to be the only significant predictors of positive PET findings. Conclusion:18F-FCH PET/CT proved its potential as a noninvasive 1-stop diagnostic modality enabling us to correctly detect occult disease in 74% of patients and to differentiate localized from systemic disease. In patients with biochemical recurrence, it also guides to an optimal treatment approach after initial treatment. Trigger PSA and ADT are the 2 significant predictors of 18F-FCH–positive PET lesions. ADT seems not to impair 18F-FCH uptake in hormone-refractory prostate cancer patients.

Cocaine use is associated with impaired cognitive function, which may negatively impact treatment outcomes. One pharmacological strategy to improve cognition involves nicotinic acetylcholine receptor (nAChR) stimulation. However, the effects of chronic cocaine exposure on nAChR distribution and function have not been characterized. Thus, one goal of this study was to examine nAChR availability in rhesus monkeys with an extensive cocaine self-administration history (n = 4; ~6 years, mean intake, 1463 mg/kg) compared to age-matched cocaine-naive control monkeys (n = 5). Using [¹¹C]-nicotine and positron emission tomography (PET) imaging, cocaine-experienced monkeys showed significantly higher receptor availability in the hippocampus compared to cocaine-naive monkeys. A second goal was to examine the effects of nAChR agonists on multiple domains of cognitive performance in these same monkeys. For these studies, working memory was assessed using a delayed match-to-sample (DMS) task, associative learning and behavioral flexibility using stimulus discrimination and reversal learning tasks. When administered acutely, the nonselective high-efficacy agonist nicotine, the low-efficacy α4β2* subtype-selective agonist varenicline and the high-efficacy α7 subtype-selective agonist, PNU-282987 significantly improved DMS performance in both cocaine-naive and cocaine-experienced monkeys. Individual doses of nicotine and varenicline that engendered maximum cognitive enhancing effects on working memory did not affect discrimination or reversal learning, while PNU-282987 disrupted reversal learning in the cocaine-naive monkeys. These findings indicate that a cocaine self-administration history influenced nAChR distribution and the effects of nAChR agonists on cognitive performance, including a reduced sensitivity to the disrupting effects on reversal learning. The cognitive enhancing effects of nAChR agonists may be beneficial in combination with behavioral treatments for cocaine addiction. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Despite the critical need, no previous research has substantiated safe opioid analgesics without abuse liability in primates. Recent advances in medicinal chemistry have led to the development of ligands with mixed mu opioid peptide (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor agonist activity to achieve this objective. BU08028 is a novel orvinol analog that displays a similar binding profile to buprenorphine with improved affinity and efficacy at NOP receptors. The aim of this preclinical study was to establish the functional profile of BU08028 in monkeys using clinically used MOP receptor agonists for side-by-side comparisons in various well-honed behavioral and physiological assays. Systemic BU08028 (0.001-0.01 mg/kg) produced potent long-lasting (i.e., >24 h) antinociceptive and antiallodynic effects, which were blocked by MOP or NOP receptor antagonists. More importantly, the reinforcing strength of BU08028 was significantly lower than that of cocaine, remifentanil, or buprenorphine in monkeys responding under a progressive-ratio schedule of drug self-administration. Unlike MOP receptor agonists, BU08028 at antinociceptive doses and ∼10- to 30-fold higher doses did not cause respiratory depression or cardiovascular adverse events as measured by telemetry devices. After repeated administration, the monkeys developed acute physical dependence on morphine, as manifested by precipitated withdrawal signs, such as increased respiratory rate, heart rate, and blood pressure. In contrast, monkeys did not show physical dependence on BU08028. These in vivo findings in primates not only document the efficacy and tolerability profile of bifunctional MOP/NOP receptor agonists, but also provide a means of translating such ligands into therapies as safe and potentially abuse-free opioid analgesics.

Position in the social hierarchy can influence brain dopamine function and cocaine reinforcement in nonhuman primates during early cocaine exposure. With prolonged exposure, however, initial differences in rates of cocaine self-administration between dominant and subordinate monkeys dissipate. The present studies used a choice procedure to assess the relative reinforcing strength of cocaine in group-housed male cynomolgus monkeys with extensive cocaine self-administration histories. Responding was maintained under a concurrent fixed-ratio 50 schedule of food and cocaine (0.003-0.1 mg/kg per injection) presentation. Responding on the cocaine-associated lever increased as a function of cocaine dose in all monkeys. Although response distribution was similar across social rank when saline or relatively low or high cocaine doses were the alternative to food, planned t tests indicated that cocaine choice was significantly greater in subordinate monkeys when choice was between an intermediate dose (0.01 mg/kg) and food. When a between-session progressive-ratio procedure was used to increase response requirements for the preferred reinforcer (either cocaine or food), choice of that reinforcer decreased in all monkeys. The average response requirement that produced a shift in response allocation from the cocaine-associated lever to the food-associated lever was higher in subordinates across cocaine doses, an effect that trended toward significance (p = 0.053). These data indicate that despite an extensive history of cocaine self-administration, most subordinate monkeys were more sensitive to the relative reinforcing strength of cocaine than dominant monkeys.