raclopride and Opioid-Related-Disorders

Topics: Analgesics, Opioid; Brain; Carbon Radioisotopes; Dopamine; Healthy Volunteers; Humans; Male; Morphine; Opioid-Related Disorders; Positron-Emission Tomography; Raclopride

The recent and precipitous increase in opioid analgesic abuse and overdose has inspired investigation of the dopamine D3 receptor (D3R) as a target for therapeutic intervention. Metabolic instability or predicted toxicity has precluded successful translation of previously reported D3R-selective antagonists to clinical use for cocaine abuse. Herein, we report a series of novel and D3R crystal structure-guided 4-phenylpiperazines with exceptionally high D3R affinities and/or selectivities with varying efficacies. Lead compound 19 was selected based on its in vitro profile: D3R Ki = 6.84 nM, 1700-fold D3R versus D2R binding selectivity, and its metabolic stability in mouse microsomes. Compound 19 inhibited oxycodone-induced hyperlocomotion in mice and reduced oxycodone-induced locomotor sensitization. In addition, pretreatment with 19 also dose-dependently inhibited the acquisition of oxycodone-induced conditioned place preference (CPP) in rats. These findings support the D3R as a target for opioid dependence treatment and compound 19 as a new lead molecule for development.

Topics: Animals; Behavior, Animal; Conditioning, Psychological; Dopamine Antagonists; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Locomotion; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Opioid-Related Disorders; Oxycodone; Rats; Rats, Long-Evans; Receptors, Dopamine D3; Salicylamides; Structure-Activity Relationship

The rewarding properties of some abused drugs are thought to reside in their ability to increase striatal dopamine levels. Similar increases have been shown in response to expectation of a positive drug effect. The actions of opioid drugs on striatal dopamine release are less well characterized. We examined whether heroin and the expectation of heroin reward increases striatal dopamine levels in human opioid addiction. Ten opioid-dependent participants maintained on either methadone or buprenorphine underwent [(11) C]raclopride positron emission tomography imaging. Opioid-dependent participants were scanned three times, receiving reward from 50-mg intravenous heroin (diamorphine; pharmaceutical heroin) during the first scan to generate expectation of the same reward at the second scan, during which they only received 0.1-mg intravenous heroin. There was no heroin injection during the third scan. Intravenous 50-mg heroin during the first scan induced pronounced effects leading to high levels of expectation at the second scan. There was no detectable increase in striatal dopamine levels to either heroin reward or expectation of reward. We believe this is the first human study to examine whether expectation of heroin reward increases striatal dopamine levels in opioid addiction. The absence of detectable increased dopamine levels to both the expectation and delivery of a heroin-related reward may have been due to the impact of substitute medication. It does however contrast with the changes seen in abstinent stimulant users, suggesting that striatal dopamine release alone may not play such a pivotal role in opioid-maintained individuals.

Topics: Adult; Aged; Analgesics, Opioid; Anticipation, Psychological; Buprenorphine; Corpus Striatum; Dopamine; Dopamine Antagonists; Humans; Male; Methadone; Middle Aged; Opioid-Related Disorders; Positron-Emission Tomography; Raclopride; Reward; Young Adult

Animal data suggest that the strong euphoriant effects of cocaine are related to the drug's enhancement of available dopamine at the synaptic cleft. The authors' goal was to determine whether this mechanism is the same in humans because the development of putative pharmacological agents for treatment of cocaine dependence depends on this knowledge.. Positron emission tomography with [11C]raclopride was used to examine the effects of the intravenous administration of 48 mg of cocaine (a typical "street" dose) on the occupancy of dopamine 2 receptors in the putamen of 11 self-identified intravenous drug abusers.. All 11 subjects reported subjective stimulation and euphoria in response to cocaine administration. Radioligand occupancy at dopamine receptors was decreased significantly after cocaine administration, suggesting that higher dopamine concentrations were competing at the receptor site.. These results support the concept of dopamine system involvement in human cocaine abuse.

Topics: Adult; Binding, Competitive; Carbon Radioisotopes; Cerebellum; Cocaine; Dopamine Antagonists; Dose-Response Relationship, Drug; Euphoria; Humans; Injections, Intravenous; Male; Opioid-Related Disorders; Putamen; Raclopride; Radioligand Assay; Receptors, Dopamine; Salicylamides; Substance Abuse, Intravenous; Tomography, Emission-Computed

Topics: Animals; Behavior; Brain; Brain Chemistry; Cocaine; Dopamine; Dopamine Antagonists; Dopamine Uptake Inhibitors; Humans; Methylphenidate; Opioid-Related Disorders; Raclopride; Receptors, Dopamine; Research Design; Reward; Salicylamides; Substance-Related Disorders