bp-897 and eticlopride

Cocaine-paired stimuli can suppress food-reinforced operant behavior in rats, providing an animal model of conditioned drug effects. To study the neuropharmacological basis of this phenomenon, we examined the effects of various dopamine receptor antagonists on the acquisition and expression of cocaine-induced conditioned suppression in rats. Superimposed on an ongoing baseline of food-reinforced operant responding, a stimulus was paired with response-independent cocaine (3.0 mg/kg, i.v.) during each of 8 training sessions. To study acquisition, independent groups of rats were given saline, the dopamine D(1)-like receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390) (0.001-0.03 mg/kg, i.p.), or the dopamine D(2)-like receptor antagonist eticlopride (0.001-0.03 mg/kg, i.p.) prior to each training session. To study expression, independent groups of rats were trained first, then given saline, SCH 23390, eticlopride, or N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide (BP 897) (a dopamine D(3) partial receptor agonist; 0.1-1.0 mg/kg, i.p.) before test sessions in which the stimulus was presented without cocaine. Pre-treatment with either SCH 23390 or eticlopride during acquisition reduced the direct suppressant effects of cocaine, but conditioning was blocked only in rats that were treated with SCH 23390 during acquisition training. Expression of conditioning was attenuated only by eticlopride. Thus, dopamine at least partially mediates both the acquisition and expression of cocaine-induced conditioned suppression, with activation of dopamine D(1)- and D(2)-like receptors underlying these respective processes.

Topics: Animals; Behavior, Animal; Benzazepines; Cocaine; Conditioning, Operant; Conditioning, Psychological; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Injections, Intravenous; Learning; Male; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; Salicylamides

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