bp-897 and Substance-Related-Disorders

As a continuation of our work with SB-277011A, we have examined the effects of another highly elective dopamine (DA) D3 receptor antagonist, N-(4-[4-{2,3-dichlorophenyl}-1-piperazinyl]butyl)-2-fluorenylcarboxamide (NGB 2904), in animal models of addiction. Our results indicate that by systemic administration, NGB 2904 inhibits intravenous cocaine self-administration maintained under a progressive-ratio (PR) reinforcement schedule, cocaine- or cocaine cue-induced reinstatement of cocaine-seeking behavior, and cocaine- or other addictive drug-enhanced brain stimulation reward (BSR). The action of NGB 2904 on PR cocaine self-administration was long-lasting (1-2 days) after a single injection, supporting its potential use in treatment of cocaine addiction. The effects of NGB 2904 in the BSR paradigm were dose-dependent for both NGB 2904 and cocaine; that is, only lower doses of NGB 2904 were effective, and their putative antiaddiction effect could be overcome by increasing the doses of cocaine or other addictive drugs. A dopamine-dependent mechanism is proposed to explain the effects of NGB 2904 on cocaine's actions in these animal models of drug addiction. The data reviewed in this paper suggest that NGB 2904 or other D3-selective antagonists may have potential in controlling motivation for drug-taking behavior or relapse to drug-seeking behavior, but may have a limited role in antagonizing the acute rewarding effects produced by cocaine or other addictive drugs. In addition, NGB 2904 may also act as a useful tool to study the role of D3 receptors in drug addiction.

Topics: Animals; Behavior, Addictive; Disease Models, Animal; Dopamine Antagonists; Fluorenes; Piperazines; Rats; Receptors, Dopamine D3; Substance-Related Disorders

Topics: Animals; Biological Availability; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Humans; Receptors, Dopamine D2; Receptors, Dopamine D3; Structure-Activity Relationship; Substance-Related Disorders

Topics: Acetylcarnitine; Animals; Cholinesterase Inhibitors; Congresses as Topic; Dehydroepiandrosterone; Humans; Nitriles; Piperazines; Quinazolines; Rats; Societies, Scientific; Substance-Related Disorders; Tetrahydroisoquinolines

The importance of dopamine D3 receptors in reward related processes, especially in cocaine addiction, has been investigated extensively. However, in the reported studies a combination of different experimental conditions and different ligands have been used which renders the interpretation and comparison of the diverse results extremely difficult. Here, we report one comparative study investigating a wide range of dopamine D3 receptor ligands in one model of cocaine abuse: the place conditioning paradigm in rats. Of the antagonists tested, the moderately D3 selective nafadotride and the more selective SB-277011 did not produce any place conditioning effect while U-99194A caused place-preference. The most D3 selective agonist PD-128907, the less selective 7-OH-DPAT and the moderately selective partial agonist BP-897 all caused significant place aversion. None of the compounds influenced the cocaine-induced place preference. Results suggest the D3-preferring agonists could affect the reward mechanisms of the brain, however, modulation of D3 receptor function does not appear to be a significant mechanism for modifying the place conditioning effect of cocaine.

Topics: Animals; Avoidance Learning; Benzazepines; Benzopyrans; Cocaine; Conditioning, Classical; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Haloperidol; Indans; Male; Naphthalenes; Nitriles; Oxazines; Piperazines; Pyrrolidines; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; Reinforcement, Psychology; Reward; Spatial Behavior; Substance-Related Disorders; Tetrahydroisoquinolines; Tetrahydronaphthalenes

Growing attention has been directed towards the potential involvement of the dopamine D3 receptor (D3R) in modulating effects of psychomotor stimulants. BP 897 (N-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]-2-naphthylcarboxamide; aka BP 4.897 and DO897) is amongst the most selective partial agonists for the D3R receptor thus far reported. BP 897 was tested for its ability to support self-administration in rhesus monkeys (0.3-30 microg/kg) and for its ability to produce cocaine- and D-amphetamine-like discriminative stimulus effects in mice (0.01-17 mg/kg i.p.). BP 897 was not self-administered above vehicle and saline levels in any of the four monkeys tested, and produced less than 30% generalization from either the cocaine or D-amphetamine stimulus. When BP 897 was administered before administrations of cocaine or D-amphetamine, percent drug-lever selections were reduced. These results suggest that BP 897 has a profile of activity suitable for consideration as a potential treatment for cocaine dependency disorders.

Topics: Animals; Cocaine; Conditioning, Operant; Dextroamphetamine; Discrimination, Psychological; Dopamine Agonists; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Generalization, Psychological; Macaca mulatta; Male; Piperazines; Receptors, Dopamine D2; Receptors, Dopamine D3; Self Administration; Substance-Related Disorders