sb-277011 and nafadotride

Studies investigating the role of the dopamine D3 receptor in the regulation of motor activity of rodents have used several ligands; however, there have been few comparative studies using agonist-antagonist interactions. In the present study, we compared the effects of dopamine D3 antagonists with different levels of selectivity over D2 receptors (nafadotride, U 99194A and SB 277011) on motor activity as well as on agonist-induced hypoactivity, in mice and rats. Horizontal and vertical movements were measured in photocell activity cages. 7-Hydroxy-2-(di-n-propylamino)tetralin (7-OH-DPAT) and PD 128907 were used as dopaminergic agonists. Both dose-dependently inhibited motor activity in mice and vertical activity in rats, while decreasing horizontal activity of rats at doses of 0.01 and 0.1 mg/kg s.c., with no effect (7-OH-DPAT) or stimulation (PD 128907) at the 1 mg/kg dose. In mice habituated to the activity cage, nafadotride (0.1-3 mg/kg i.p.) caused a dose-dependent decrease in motor activity but did not affect the hypomotility evoked by either 7-OH-DPAT (0.1 mg/kg) or PD 128907 (0.1 mg/kg). In habituated rats it had no significant effect on motor activity and was not able to antagonize the hypoactivity caused by PD 128907 (0.1 mg/kg s.c.). U 99194A (5, 10 and 20 mg/kg s.c.) dose-dependently and significantly increased motor activity in mice and inhibited the effects of both agonists. In rats, nafadotride produced considerable motor stimulation and significantly inhibited the PD 128907-induced decrease in horizontal, but not in vertical, activity. SB 277011 (15-45 mg/kg p.o.) significantly increased motor activity in mice and partially blocked the action of 7-OH-DPAT on vertical, but not on horizontal, activity while against PD 128907, its significant inhibitory effect was restricted to a single dose (20 mg/kg). In habituated rats, SB 277011 (13.5, 20 and 30 mg/kg p.o.) exerted no significant effects on motor activity and did not antagonize the hypoactivity caused by PD 128907. Considerable species differences and movement-type differences (horizontal versus vertical) were observed between the effects of the tested dopamine D2/D3 ligands on motor activity in rodents. The antagonists also differed markedly in the robustness of their action. The poorly D3 selective antagonist, nafadotride, had little effect on motor behaviour. The moderately selective U 99194A exerted marked stimulatory effects on motility, and potently inhibited the actions of agonists.

Topics: Animals; Benzopyrans; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Antagonism; Indans; Injections, Subcutaneous; Male; Mice; Motor Activity; Naphthalenes; Nitriles; Oxazines; Pyrrolidines; Rats; Rats, Wistar; Receptors, Dopamine D2; Receptors, Dopamine D3; Species Specificity; Tetrahydroisoquinolines; Tetrahydronaphthalenes

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