bp-897 and nafadotride

The noncompetitive NMDA receptor antagonist MK801 (dizocilpine) produces behavioral stimulation mediated, in part, through indirect activation of the dopamine (DA) system. Previous reports indicate that D2/3 agonists inhibit MK801-induced stereotypies; however, it is unclear if these agonists also attenuate MK801-induced locomotion. As such, the ability of the D2/3 agonists, quinelorane and quinpirole, and the partial D3 agonist, BP897, to attenuate the locomotor activating effects of MK801 was examined in mice. MK801 (0.1-1.0 mg/kg) produced a biphasic effect on total distance traveled with the intermediate dose of 0.3 mg/kg producing the greatest stimulation. The increase in MK801-induced total distance traveled was attenuated by the coadministration of quinelorane and quinpirole at doses that alone had no effect on activity. Similarly, the partial D3 agonist, BP897, blocked the effects of MK801. The D3-preferring antagonist, nafadotride, reversed the attenuation of quinelorane and partially reversed the attenuation of quinpirole. The D2-preferring antagonist, eticlopride, reversed the attenuating effects of quinelorane, but was not effective against quinpirole. Nafadotride and eticlopride were ineffective against the attenuating effects of BP897 on MK801-induced locomotion. Because BP897 is a partial agonist it was tested against quinelorane/MK801 and quinpirole/MK801 combinations. BP897 reversed the attenuating effects of quinelorane, but not those of quinpirole on MK801's effects. These results demonstrate that the DA system, through D2/3 receptor activation, modulates the locomotor activating effects produced by noncompetitive NMDA receptor blockade.

Topics: Animals; Dizocilpine Maleate; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Male; Mice; Motor Activity; Naphthalenes; Piperazines; Pyrrolidines; Quinolines; Quinpirole; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, N-Methyl-D-Aspartate; Salicylamides; Stereotyped Behavior

Mu opioid receptor agonists such as morphine stimulate the release of dopamine (DA) in various brain regions. These increases in DA are thought to be involved in some of the behavioral effects of mu agonists. The present study was designed to examine the modulatory actions of two D2/3 antagonists (nafadotride and eticlopride), the D2/3 partial agonist BP897, the D1/2 antagonist flupenthixol, and the D1 antagonist SCH23390 on the discriminative stimulus effects of the mu partial agonist nalbuphine and the higher-efficacy mu agonists heroin, methadone and morphine, in rats trained to discriminate heroin from water. Both nafadotride and eticlopride attenuated the effects of the mu agonists, whereas BP897 was effective against nalbuphine and partially effective against morphine. Flupenthixol attenuated the heroin-like discriminative stimulus effects of heroin and morphine, although not as completely as nafadotride or eticlopride. SCH23390 was least effective and produced little attenuation. These results demonstrate that the discriminative stimulus effects of mu agonists in rats are more readily attenuated by drugs that block D2-like, rather than D1-like, receptors.

Topics: Animals; Benzazepines; Brain; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Flupenthixol; Heroin; Methadone; Morphine; Motivation; Nalbuphine; Naphthalenes; Piperazines; Pyrrolidines; Rats; Rats, Long-Evans; Receptors, Dopamine D1; Receptors, Dopamine D3; Receptors, Opioid, mu; Salicylamides

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

In monkeys rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), expression of the dopamine D3 receptor was decreased. However, levodopa-induced dyskinesia (LID), similar to the debilitating and pharmacoresistant involuntary movements elicited after long-term treatment with levodopa in patients with Parkinson disease (PD), was associated with overexpression of this receptor. Administration of a D3 receptor-selective partial agonist strongly attenuated levodopa-induced dyskinesia, but left unaffected the therapeutic effect of levodopa. In contrast, attenuation of dyskinesia by D3 receptor antagonists was accompanied by the reappearance of PD-like symptoms. These results indicated that the D3 receptor participated in both dyskinesia and the therapeutic action of levodopa, and that partial agonists may normalize D3 receptor function and correct side effects of levodopa therapy in patients with PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Acrylamides; Animals; Antiparkinson Agents; Dopamine Agents; Dopamine Antagonists; Dyskinesia, Drug-Induced; Female; Haplorhini; Humans; Isoquinolines; Levodopa; Molecular Structure; Motor Activity; MPTP Poisoning; Naphthalenes; Neostriatum; Piperazines; Pyrrolidines; Rats; Receptors, Dopamine D2; Receptors, Dopamine D3