Nociceptin Receptors Upregulated in Cocaine Use Disorder: A Positron Emission Tomography Imaging Study Using [11C]NOP-1A.

OBJECTIVE: Nociceptin/orphanin FQ (N/OFQ) is an antistress neuropeptide transmitter in the brain that counteracts corticotropin-releasing factor (CRF)-mediated stress and anxiety symptoms during drug and alcohol withdrawal. It also inhibits the release of a wide array of neurotransmitters, including dopamine and glutamate, which allows for it to block the rewarding properties of cocaine. Chronic cocaine administration in rodents has been shown to decrease N/OFQ and increase nociceptive opioid peptide (NOP) receptors in the nucleus accumbens. No previous studies have reported on the in vivo status of NOP in chronic cocaine-abusing humans. METHODS: [11C]NOP-1A and positron emission tomography (PET) were used to measure in vivo NOP binding in 24 individuals with cocaine use disorder and 26 healthy control subjects matched for age, sex, and smoking status. Participants with cocaine use disorder with no comorbid psychiatric or medical disorders were scanned after 2 weeks of outpatient-monitored abstinence. [11C]NOP-1A distribution volume (VT) was measured with kinetic analysis using the arterial input function in brain regions that mediate reward and stress behaviors. Participants with cocaine use disorder were followed up for 12 weeks after PET scanning to document relapse and relate it to VT. RESULTS: A significant increase in [11C]NOP-1A VT was observed in the cocaine use disorder group compared with the healthy control group. This increase, which was generalized across all regions of interest (approximately 10%), was most prominent in the midbrain, ventral striatum, and cerebellum. However, increased VT in these regions did not predict relapse. CONCLUSIONS: Increased NOP in cocaine use disorder suggests an adaptive response to decreased N/OFQ, or increased CRF transmission, or both. Future studies should examine the interactions between CRF and NOP to elucidate their role in negative reinforcement and relapse. NOP agonist medications to enhance N/OFQ should be explored as a therapeutic to treat cocaine use disorder.

Decreased Nociceptin Receptors Are Related to Resilience and Recovery in College Women Who Have Experienced Sexual Violence: Therapeutic Implications for Posttraumatic Stress Disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a stress disorder that develops in only some individuals following a traumatic event. Data suggest that a substantial fraction of women recover after sexual violence. Thus, the investigation of stress and antistress neuropeptides in this sample has the potential to inform the neurochemistry of resilience following trauma. Nociceptin is an antistress neuropeptide in the brain that promotes resilience in animal models of PTSD. METHODS: [11C]NOP-1A positron emission tomography was used to measure the in vivo binding to nociceptin receptors in 18 college women who had experienced sexual violence irrespective of whether they met DSM-5 diagnostic criteria for PTSD. [11C]NOP-1A data from 18 healthy control subjects were also included to provide a contrast with the sexual violence group. [11C]NOP-1A total distribution volume (VT) in the regions of interest were measured with kinetic analysis using the arterial input function. The relationships between regional VT and Clinician-Administered PTSD Scale for DSM-5 total symptom and subscale severity were examined using correlational analyses. RESULTS: No differences in [11C]NOP-1A VT were noted between the sexual violence and control groups. VT in the midbrain and cerebellum were positively correlated with PTSD total symptom severity in the past month before positron emission tomography. Intrusion/re-experiencing and avoidance subscale symptoms drove this relationship. Stratification of subjects by a DSM-5 PTSD diagnosis and contrasting their VT with that in control subjects showed no group differences. CONCLUSIONS: Decreased midbrain and cerebellum nociceptin receptors are associated with less severe PTSD symptoms. Medications that target nociceptin should be explored to prevent and treat PTSD.

Imaging phosphodiesterase-10a availability in cocaine use disorder with [11 C]IMA107 and PET.

Phosphodiesterase-10a (PDE10a) is located exclusively in medium spiny neurons (MSN). Rodent studies show an increase in striatal MSN spine density following exposure to cocaine. These increases in MSN spine density are suggested to underlie neurobiological changes which contribute to cocaine self-administration. No postmortem or imaging studies have confirmed this finding in humans. Here, we hypothesized an increase in the MSN marker PDE10a in subjects with cocaine use disorder ("cocaine users") compared to controls. PDE10a availability was measured with [11 C]IMA107 and positron emission tomography in 15 cocaine users and 15 controls matched for age, gender, and nicotine status. Cocaine users with no comorbid psychiatric, medical, or drug abuse disorders were scanned following two weeks of outpatient-monitored abstinence. [11 C]IMA107 binding potential relative to nondisplaceable uptake (BPND ) in the regions of interest was derived with the simplified reference tissue method. No significant effect of diagnosis on BPND was demonstrated using linear mixed modeling with [11 C]IMA107 BPND as the dependent variable and regions of interest as a repeated measure. There were no significant relationships between BPND and clinical rating scales. To the extent that PDE10a is a valid proxy for MSN spine density, these results do not support its increase in recently abstinent cocaine users.

Amphetamine-Induced Striatal Dopamine Release Measured With an Agonist Radiotracer in Schizophrenia.

BACKGROUND: Receptor imaging studies have reported increased amphetamine-induced dopamine release in subjects with schizophrenia (SCH) relative to healthy control subjects (HCs). A limitation of these studies, performed with D2/3 antagonist radiotracers, is the failure to provide information about D2/3 receptors configured in a state of high affinity for the agonists (i.e., D2/3 receptors coupled to G proteins [D2/3 HIGH]). The endogenous agonist dopamine binds with preference to D2/3 HIGH receptors relative to D2/3 LOW receptors, making it critical to understand the status of D2/3 HIGH receptors in SCH. METHODS: D2/3 agonist positron emission tomography radiotracer [11C]N-propyl-norapomorphine ([11C]NPA) binding potential (BPND) was measured in 14 off-medication subjects with SCH and 14 matched HCs at baseline and after the administration of 0.5 mg kg-1 oral D-amphetamine. The amphetamine-induced change in BPND (ΔBPND) was calculated as the difference between BPND in the postamphetamine condition and BPND in the baseline condition and was expressed as a percentage of BPND at baseline. RESULTS: A trend-level increase was observed in comparing baseline [11C]NPA BPND (repeated-measures analysis of variance, F1,26 = 3.34, p = .08) between the SCH and HC groups. Amphetamine administration significantly decreased BPND in all striatal regions across all subjects in both groups. No differences were observed in [11C]NPA ΔBPND (repeated-measures analysis of variance, F1,26 = 1.9, p = .18) between HCs and subjects with SCH. Amphetamine significantly increased positive symptoms in subjects with SCH (19.5 ± 5.3 vs. 23.7 ± 4.1, paired t test, p < .0001); however, no correlations were noted with [11C]NPA BPND or ΔBPND. CONCLUSIONS: This study provides in vivo indication of a role for postsynaptic factors in amphetamine-induced psychosis in SCH.

An open-label positron emission tomography study to evaluate serotonin transporter occupancy following escalating dosing regimens of (R)-(-)-O-desmethylvenlafaxine and racemic O-desmethylvenlafaxine.

SEP-227162 [R(-)-O-desmethylvenlafaxine] is an enantiomer of the venlafaxine metabolite O-desmethylvenlafaxine (ODV, Pristiq™, Wyeth). This study compared the serotonin transporter (SERT) occupancy achieved by SEP-227162 and ODV, at daily doses of 25, 50, 100, and 150 mg using [11 C]DASB positron emission tomography (PET). Sixteen healthy male subjects participated in one of four dose groups (N = 4 per group) during which they were administered two doses of the study drug (SEP-227162 or ODV). For each study drug, total daily doses of 25, 50, 100, and150 mg were studied. Subjects underwent three PET scans with [11 C]DASB. A baseline, off-medication, scan was performed prior to dosing and a [11 C]DASB PET scan was performed after 72 hr at each dose level. [11 C]DASB binding potential (BPND ) was calculated using the simplified reference tissue method. SERT occupancy was calculated as the change in BPND (ΔBPND ) from baseline scan to the on-medication scan relative to the baseline BPND value. SEP-227162 and ODV significantly reduced regional distribution volumes and region BPND values in a dose-dependent manner. Across all doses ODV produced significantly greater SERT occupancy than SEP-227162 (ANOVA F = 21.8, df = 1,23, p < .001). The total daily dose required to provide 50% SERT occupancy was 24.8 mg for SEP-227162 and 14.4 mg for ODV. In vitro data suggests a ratio of 3.3:1 for binding at human SERT for SEP-227162 relative to ODV. Our study suggests a ratio of 1.7:1, highlighting the value of in vivo imaging in the drug development process.

Nociceptin Receptors in Alcohol Use Disorders: A Positron Emission Tomography Study Using [11C]NOP-1A.

BACKGROUND: The neuropeptide transmitter nociceptin, which binds to the nociceptin/orphanin FQ peptide (NOP) receptor, is a core component of the brain's antistress system. Nociceptin exerts its antistress effect by counteracting the functions of corticotropin-releasing factor, the primary stress-mediating neuropeptide in the brain. Basic investigations support a role for medications that target nociceptin receptors in the treatment of alcohol use disorders. Thus, it is of high interest to measure the in vivo status of NOP receptors in individuals with alcohol use disorders. METHODS: Here, we used [11C]NOP-1A and positron emission tomography to measure the in vivo binding to NOP receptors in 15 alcohol-dependent humans as identified by DSM-IV and 15 healthy control subjects matched for age, sex, and smoking status. Alcohol-dependent individuals with no comorbid psychiatric, medical, or drug abuse disorders were scanned following 2 weeks of outpatient monitored abstinence (confirmed with three times per week urine alcohol metabolite testing). [11C]NOP-1A distribution volume in regions of interest (including the amygdala, hippocampus, and midbrain, striatal, and prefrontal cortical subdivisions) was measured with kinetic analysis using the arterial input function. RESULTS: Regional [11C]NOP-1A distribution volume in alcohol dependence was not significantly different compared with healthy control subjects. No relationship between [11C]NOP-1A distribution volume and other clinical measures (including duration and severity of alcohol abuse, craving, and anxiety or depressive symptoms) were significant after correction for the multiple hypotheses tested. CONCLUSIONS: The results of this study do not support alterations in the binding to NOP receptors in alcohol dependence. However, this finding does not necessarily rule out alterations in nociceptin transmission in alcohol dependence.

In vivo measurement of GABA transmission in healthy subjects and schizophrenia patients.

OBJECTIVE: Postmortem studies in schizophrenia reveal alterations in gene products that regulate the release and extracellular persistence of GABA. However, results of in vivo studies of schizophrenia measuring total tissue GABA with magnetic resonance spectroscopy (MRS) have been inconsistent. Neither the postmortem nor the MRS studies directly address the physiological properties of GABA neurotransmission. The present study addresses this question through an innovative positron emission tomography (PET) paradigm. METHOD: The binding of [(11)C]flumazenil, a benzodiazepine-specific PET radiotracer, was measured before and after administration of tiagabine (0.2 mg/kg of body weight), a GABA membrane transporter (GAT1) blocker, in 17 off-medication patients with schizophrenia and 22 healthy comparison subjects. Increased extracellular GABA, through GAT1 blockade, enhances the affinity of GABAA receptors for benzodiazepine ligands, detected as an increase in [(11)C]flumazenil tissue distribution volume (VT). RESULTS: [(11)C]Flumazenil VT was significantly increased across all cortical brain regions in the healthy comparison group but not in the schizophrenia group. This lack of effect was most prominent in the antipsychotic-naive schizophrenia group. In this subgroup, [(11)C]flumazenil ΔVT in the medial temporal lobe was correlated with positive symptoms, and baseline [(11)C]flumazenil VT in the medial temporal lobe was negatively correlated with visual learning. In the healthy comparison group but not the schizophrenia group, [(11)C]flumazenil ΔVT was positively associated with gamma-band oscillation power. CONCLUSIONS: This study demonstrates, for the first time, an in vivo impairment in GABA transmission in schizophrenia, most prominent in antipsychotic-naive individuals. The impairment in GABA transmission appears to be linked to clinical symptoms, disturbances in cortical oscillations, and cognition.

Cocaine abuse in humans is not associated with increased microglial activation: an 18-kDa translocator protein positron emission tomography imaging study with [11C]PBR28.

Basic science investigations have consistently shown that repeated exposure to psychostimulant drugs, such as cocaine, activate the immune response and lead to inflammatory changes in the brain. No previous in vivo studies have confirmed this observation in chronic cocaine-abusing humans. To test this hypothesis, we used positron emission tomography imaging to measure the binding of [(11)C]PBR28 to the 18 kDa translocator protein (TSPO), a marker for microglial activation in a group of 15 recently abstinent cocaine abusers and 17 matched healthy controls. [(11)C]PBR28 volumes of distribution expressed relative to total plasma ligand concentration (VT) were measured in subjects with kinetic analysis using the arterial input function. Subjects were also genotyped for the TSPO alanine147 threonine (Ala147Thr, rs6971) polymorphism that has been shown to influence the in vivo binding of PBR28 to TSPO. Consistent with previous reports, the TSPO Ala147Thr genotype predicted the in vivo binding of [(11)C]PBR28. No significant differences in [(11)C]PBR28 VT were observed in the cortical and subcortical regions in cocaine abusers compared with healthy controls. The results of this in vivo study do not support increased TSPO expression and, by extension, microglial activation in chronic cocaine-abusing humans. Further research with more direct markers of microglial activation is necessary to conclusively rule out neuroinflammation in cocaine dependence.

Decreased prefrontal cortical dopamine transmission in alcoholism.

OBJECTIVE: Basic studies have demonstrated that optimal levels of prefrontal cortical dopamine are critical to various executive functions such as working memory, attention, inhibitory control, and risk/reward decisions, all of which are impaired in addictive disorders such as alcoholism. Based on this and imaging studies of alcoholism that have demonstrated less dopamine in the striatum, the authors hypothesized decreased dopamine transmission in the prefrontal cortex in persons with alcohol dependence. METHOD: To test this hypothesis, amphetamine and [11C]FLB 457 positron emission tomography were used to measure cortical dopamine transmission in 21 recently abstinent persons with alcohol dependence and 21 matched healthy comparison subjects. [11C]FLB 457 binding potential, specific compared to nondisplaceable uptake (BPND), was measured in subjects with kinetic analysis using the arterial input function both before and after 0.5 mg kg-1 of d-amphetamine. RESULTS: Amphetamine-induced displacement of [11C]FLB 457 binding potential (ΔBPND) was significantly smaller in the cortical regions in the alcohol-dependent group compared with the healthy comparison group. Cortical regions that demonstrated lower dopamine transmission in the alcohol-dependent group included the dorsolateral prefrontal cortex, medial prefrontal cortex, orbital frontal cortex, temporal cortex, and medial temporal lobe. CONCLUSIONS: The results of this study, for the first time, unambiguously demonstrate decreased dopamine transmission in the cortex in alcoholism. Further research is necessary to understand the clinical relevance of decreased cortical dopamine as to whether it is related to impaired executive function, relapse, and outcome in alcoholism.

Aminomethyl tetrahydronaphthalene biphenyl carboxamide MCH-R1 antagonists--Increasing selectivity over hERG.

Aminomethyl tetrahydronaphthalene biphenyl carboxamide MCH-R1 antagonists with greater selectivity over hERG were identified. SAR studies addressing two distinct alternatives for structural modifications leading to improve hERG selectivity are described.

Novel pyrazolopiperazinone- and pyrrolopiperazinone-based MCH-R1 antagonists.

The synthesis and biological testing of novel classes of potent melanin-concentrating hormone (MCH-R1) antagonists based on pyrazolopiperazinone and pyrrolopiperazinone scaffolds are described.

Design and synthesis of substituted quinolines as novel and selective melanin concentrating hormone antagonists as anti-obesity agents.

A novel series of substituted quinoline analogs were designed and synthesized as potent and selective melanin concentrating hormone (MCH) antagonists. These analogs show potent (nM) activity (12a-k) with a moderate selectivity. Conversely, the conformationally constrained thienopyrimidinone analogs (18a-g) showed improved activity in MCH-1R and selectivity over 5HT2C.