piperidines and fluoroclebopride

Animals self-administer many of the drugs that humans abuse, including cocaine. This article describes studies using preclinical animal models to differentiate the influences of neurobiological predisposition from environmental modulation of cocaine addiction, including studies from the authors' laboratory using nonhuman primates.. Addiction is described in terms of vulnerability, maintenance, and abstinence. This review focuses on dopamine receptor function, in particular that of the D2-like receptors, as measured by the noninvasive imaging procedure positron emission tomography. Findings from human studies of addiction and animal models are reviewed.. There appears to be an inverse relationship between D2 receptor availability and vulnerability to the reinforcing effects of cocaine. Environmental variables can increase or decrease D2 receptor binding in an orderly fashion, and the resulting changes in D2 function influence the vulnerability to abuse cocaine. In maintenance, chronic cocaine exposure produces decreases in D2 receptor binding, which may be a mechanism that contributes to continued drug use. Finally, during abstinence there are individual differences in rates of recovery of D2 receptor availability.. The goal of the preclinical research described in this review is to achieve a better understanding of individual differences in susceptibility and vulnerability to the reinforcing effects of cocaine. It is clear that the development of novel animal models will extend our understanding of the neurobiological basis of drug addiction to include a greater appreciation of the role of environmental factors in affecting predisposition, mediating continued drug use, and triggering relapse.

Topics: Animals; Autoradiography; Basal Ganglia; Behavior, Addictive; Behavior, Animal; Benzamides; Brain; Cocaine-Related Disorders; Corpus Striatum; Disease Models, Animal; Genetic Predisposition to Disease; Haplorhini; Humans; Piperidines; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Social Dominance; Social Environment

Cocaine use during pregnancy is associated with alterations in the dopamine (DA) system in the fetal brain. However, little is known about the effects of prenatal cocaine exposure on the postnatal dopaminergic system.. The objective of the study was to examine DA receptor function in adult monkeys that were prenatally exposed to cocaine.. Male and female rhesus monkeys (approximately 13 years old) that had been prenatally exposed to cocaine (n = 10) and controls (n = 10) were used in all studies. First, DA D2-like receptor availability was assessed using positron emission tomography and the D2-like receptor radiotracer [(18)F]fluoroclebopride (FCP). Next, D(3) receptor function was assessed by measuring quinpirole-induced yawning (0.03-0.3 mg/kg). Finally, D1-like receptor function was examined by measuring eye blinking elicited by the high-efficacy D1-like receptor agonist SKF81297 (0.3-3.0 mg/kg).. There were no differences between groups or sexes in D2-like receptor availability in the caudate nucleus, putamen or amygdala. However, quinpirole elicited significantly more yawns in prenatally cocaine-exposed monkeys compared with control monkeys. A significant correlation between gestational dose of cocaine and peak effects of quinpirole was observed. In all monkeys, administration of SKF81297 elicited dose-dependent increases in eye blinks that did not differ between groups.. These findings suggest that prenatal cocaine exposure can have long-term effects on DA D(3) receptor function in adults.

Topics: Animals; Benzamides; Benzazepines; Blinking; Cocaine; Dopamine Agonists; Female; Fluorine Radioisotopes; Macaca mulatta; Male; Piperidines; Pregnancy; Pregnancy, Animal; Prenatal Exposure Delayed Effects; Quinpirole; Radioligand Assay; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; Yawning

Sex differences have been reported in a variety of affective and neurodegenerative disorders that involve dysfunctional dopamine (DA) neurotransmission. In addition, there is evidence for differences in sensitivity to the abuse-related effects of psychostimulants across the menstrual cycle which may result from effects of ovarian hormones on DA function. The goal of the present study was to extend previous work examining menstrual cycle-related changes in DA D2 receptor availability in humans to drug-naive female cynomolgus monkeys (n=7) using the selective D2-like receptor ligand [(18)F]fluoroclebopride (FCP) and a high-resolution microPET P4 scanner. Menstrual cycle phase was characterized by daily vaginal swabs and measurements of serum progesterone levels. PET studies were conducted once during the luteal phase and once during the follicular phase. Regions of interest in the caudate nucleus, putamen, and cerebellum were defined on coregistered MRIs. Distribution volumes were calculated for FCP in each structure and the distribution volume ratio (DVR) for both brain regions relative to the cerebellum was used as a measure of D2 receptor availability. FCP DVRs were significantly higher in the luteal phase compared to the follicular phase in both the caudate nucleus (11.7% difference, p=0.02) and putamen (11.6% difference, p=0.03). These findings extend earlier work in humans and suggest that changes in DA receptor availability may be involved in the variation in symptoms of various neuropsychiatric disorders across the menstrual cycle, including differences in sensitivity to the abuse-related effects of stimulants.

Topics: Animals; Benzamides; Caudate Nucleus; Cerebellum; Female; Follicular Phase; Luteal Phase; Macaca fascicularis; Magnetic Resonance Imaging; Menstrual Cycle; Piperidines; Positron-Emission Tomography; Progesterone; Putamen; Receptors, Dopamine D2

Social rank has been shown to influence dopamine (DA) D(2) receptor function and vulnerability to cocaine self-administration in cynomolgus monkeys. The present studies were designed to extend these findings to maintenance of cocaine reinforcement and to DA D(1) receptors.. Examine the effects of a high-efficacy D(1) agonist on an unconditioned behavior (eyeblinking) and a low-efficacy D(1) agonist on cocaine self-administration, as well as the effects of cocaine exposure on D(2) receptor function across social ranks, as determined by positron emission tomography (PET).. Effects of the high-efficacy D(1) agonist SKF 81297 and cocaine (0.3-3.0 mg/kg) on spontaneous blinking were characterized in eight monkeys during 15-min observation periods. Next, the ability of the low-efficacy D(1) agonist SKF 38393 (0.1-17 mg/kg) to decrease cocaine self-administration (0.003-0.1 mg/kg per injection, IV) was assessed in 11 monkeys responding under a fixed-ratio 50 schedule. Finally, D(2) receptor levels in the caudate and putamen were assessed in nineteen monkeys using PET.. SKF 81297, but not cocaine, significantly increased blinking in all monkeys, with slightly greater potency in dominant monkeys. SKF 38393 dose-dependently decreased cocaine-maintained response rates with similar behavioral potency and efficacy across social rank. After an extensive cocaine self-administration history, D(2) receptor levels did not differ across social ranks.. These results suggest that D(1) receptor function is not substantially influenced by social rank in monkeys from well-established social groups. While an earlier study showed that dominant monkeys had higher D(2) receptor levels and were less sensitive to the reinforcing effects of cocaine during initial exposure, the present findings indicate that long-term cocaine use changed D(2) receptor levels such that D(2) receptor function and cocaine reinforcement were not different between social ranks. These findings suggest that cocaine exposure attenuated the impact of social housing on DA receptor function.

Topics: Analysis of Variance; Animals; Behavior, Animal; Benzamides; Benzazepines; Blinking; Cocaine; Conditioning, Operant; Dopamine Agonists; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Hierarchy, Social; Macaca fascicularis; Male; Neostriatum; Piperidines; Receptors, Dopamine D1; Receptors, Dopamine D2; Self Administration; Tissue Distribution; Tomography, Emission-Computed

Topics: Animals; Benzamides; Brain; Brain Mapping; Electric Stimulation; Image Processing, Computer-Assisted; Macaca; Magnetic Resonance Imaging; Magnetics; Male; Phantoms, Imaging; Piperidines; Time Factors; Tomography, Emission-Computed

The purpose of the present study was to determine whether positron emission tomography (PET) studies in monkeys with the dopamine (DA) D2 receptor ligand [18F]fluoroclebopride (FCP) would be significantly influenced by anesthetic induction with isoflurane (approximately 5.0%) compared to induction with 10 mg/kg ketamine. Five experimentally-naive adult male cynomolgus monkeys (Macaca fascicularis) were trained to sit calmly in a primate restraint chair. Before the first PET scan, each monkey was anesthetized, by mask, with isoflurane. After complete sedation, the monkey was intubated and anesthesia was maintained throughout the PET study by isoflurane (approximately 1.5%). At least 1 month later, a second PET study was conducted in which anesthesia was induced with ketamine and maintained by isoflurane (approximately 1.5%). Irrespective of induction anesthetic, there was a high uptake of [18F]FCP and a linear rate of washout from the basal ganglia for all monkeys. There were also no differences in time to peak uptake (approximately 25 min), in clearance half-life (t1/2 = 140-164 min) or in D2 binding (distribution volume ratios of 2.48 vs. 2.50). These results indicate that induction anesthetic did not differentially affect D2 binding of [18F]FCP in monkeys. Furthermore, the low variability between studies indicates that [18F]FCP is an excellent ligand for longitudinal studies of D2 receptors in nonhuman primates.

Topics: Anesthetics; Animals; Benzamides; Drug Interactions; Fluorine Radioisotopes; Isoflurane; Ketamine; Macaca fascicularis; Male; Piperidines; Radiopharmaceuticals; Receptors, Dopamine D2; Tomography, Emission-Computed

Topics: Animals; Basal Ganglia; Benzamides; Corpus Striatum; Female; Hierarchy, Social; Macaca fascicularis; Piperidines; Receptors, Dopamine D2; Tomography, Emission-Computed

The purpose of the present set of studies was to characterize, in vitro and in vivo, two benzamide analogues, 2,3-dimethoxy-N-[1-(4-fluorobenzyl)piperidin4yl]benzamide (MBP) and 4'-fluoroclebopride (FCP), for studying dopamine D2 receptors with Positron Emission Tomography (PET). In vitro binding studies were conducted to determine the affinities of MBP and FCP to the three subtypes of dopamine D2 receptors: D2(long), D3, and D4 receptors. MBP was found to have a high affinity (Ki = 1-8 nM) for all three subtypes of the D2 receptor, whereas FCP had nanomolar affinity (Ki approximately 5.5 nM) for D2(long) and D3 receptors, and a lower affinity for D4 receptors (Ki = 144 nM). In vitro binding studies also revealed that MBP had a relatively high affinity for rho1 receptors (Ki = 11 nM) compared to FCP (Ki = 340 nM). PET imaging studies were conducted in rhesus monkeys with the fluorine-18 labeled analogues of each compound. Both [18F]MBP and [18F]FCP displayed reversible binding kinetics during the 3 h time course of PET. [18F]FCP was found to have a higher basal ganglia:cerebellum ratio and lower variability in the rate of washout from D2 receptors in vivo relative to [18F]MBP. Neither radiotracer was found to produce radiolabeled metabolites capable of crossing the blood-brain barrier. The high rho1 binding affinity and low basal ganglia:cerebellum ratio of [18F]MBP indicate that this ligand may not be suitable for quantitative studies of D2 receptors. The results from the in vitro and in vivo studies indicate that [18F]FCP is a promising ligand for studying D2 receptors with PET.

Topics: Animals; Benzamides; Binding Sites; Guinea Pigs; Macaca mulatta; Male; Piperidines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Time Factors; Tomography, Emission-Computed

[18F]4-Fluorobenzyl iodide ([18F]FBI) was prepared, and a series of model alkylation studies were conducted to determine its chemical reactivity toward nitrogen and sulfur nucleophiles of varying nucleophilicities. [18F]FBI was found to react rapidly with secondary amines and anilines to give the corresponding N-[18F]4-fluorobenzyl analogue in high yield. Amides and thiol groups required the use of a base catalyst. The utility of [18F]FBI was documented by investigation of dopamine D1 and D2 receptor-based radiotracers.

Topics: Alkylation; Animals; Benzamides; Benzazepines; Fluorine Radioisotopes; Fluorobenzenes; Isotope Labeling; Kinetics; Models, Chemical; Nitrogen; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Dopamine D2; Sulfur; Tomography, Emission-Computed