nafadotride and quinelorane

Dopamine D3 receptors are present in the nucleus accumbens and in lobules 9 and 10 of the cerebellum. Their function is not fully understood. In the present study, the involvement of D3 receptors in locomotor activity and sleep in the two structures was investigated. The method used was the measure of locomotor activity in an open field and the measure of sleep and sleep/waking stages by electroencephalographic recordings in the rat. Dopamine receptor agonists (7-OH-DPAT, quinelorane and SKF38393) and antagonists (amisulpride, nafadotride and haloperidol) were microinjected into the two structures. Concerning locomotor activity, the results show that D3 receptor stimulation, as well as concomitant stimulation of D1 and D3 receptors, have opposite effects in the cerebellum and in the core of nucleus accumbens, with an inhibition of locomotion in the cerebellum and a stimulation of locomotion in the nucleus accumbens. D1 and D3 stimulation have mutual potentiating locomotor effects. The results also show that in the cerebellum, the effects are selective to lobules 9 and 10, and are not observed with microinjections into lobule 8. Concerning sleep, the effects of agonists and antagonists show a similar tendency in the cerebellum and nucleus accumbens, with a somnogenic effect of D2 blockage, an awakening effect of at least one of the D2/D3 agonists, and a dose-dependent awakening effect of the D2/D3 antagonists. In conclusion, this study suggests that dopamine D3 receptors in the cerebellum and nucleus accumbens are involved in several aspects of the regulation of locomotor activity and sleep.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Amisulpride; Amphetamine; Animals; Cerebellum; Dopamine Agonists; Dopamine Antagonists; Dopamine Uptake Inhibitors; Female; Haloperidol; Microinjections; Motor Activity; Naphthalenes; Nucleus Accumbens; Pyrrolidines; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Dopamine D3; Sleep; Sulpiride; Tetrahydronaphthalenes

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

Dopaminergic mechanisms are thought to be critically involved in reward-related processes and seeking behaviour.. To examine the involvement of dopamine in seeking behaviour supported by a natural reinforcer, food, and assess the role of D(2) and D(3) receptor subtypes in food-seeking, using an operant reinstatement procedure.. Wistar rats were subjected to a within-session extinction procedure. Experimental sessions consisted of a 15-min rewarded period during which each right lever press delivered one food pellet and initiated a 10-s time out period (FR1:TO(10s)), followed by a 45-min extinction period during which responding was no longer rewarded. The reinstating effects of dopaminergic drugs, food priming, or the combination of both treatments, were investigated during spaced test sessions. In dose range studies, dopamine receptor ligands were administered 20 or 30 min into the test sessions. In interaction studies, antagonists were injected immediately before testing. Food priming consisted of two pellets non-contingently delivered 45 min into the test sessions.. Well trained rats emitted many responses during the rewarded period but almost none during extinction. During the last 15 min of the test sessions, non-rewarded responding was reinstated by the D(2)/D(3) agonist, apomorphine (0.125-0.25 mg/kg, SC), and the D(3) preferring agonist, 7-OH-DPAT (2-4 mg/kg, SC), but not by quinelorane (0.004-2 mg/kg, SC), another D(3) preferring agonist. In interaction studies, the D(2) preferring antagonist, raclopride (0.06-0.125 mg/kg, IP), and the D(3) preferring antagonist, l-nafadotride (1 mg/kg, IP), counteracted the reinstating effect of apomorphine and 7-OH-DPAT. Pellets non-contingently delivered during extinction, reinstated modest, but significant, responding. Such food-primed food-seeking was altered by neither nafadotride (0.015-1 mg/kg, IP) nor the D(2)/D(3) antagonists, amisulpride (0.25-1 mg/kg, IP) or sulpiride (2-4 mg/kg, IP). Food- and apomorphine-induced response reinstatement were additive, and food-primed food-seeking behaviour was potentiated by 7-OH-DPAT (0.125-1 mg/kg, SC) and quinelorane (7.5-15 micro g/kg, SC). Such a potentiation was reversed by two D(2) antagonists, haloperidol (0.05 mg/kg, IP) and raclopride (0.125 mg/kg, IP), but not by nafadotride (1 mg/kg, IP) and another D(3) preferring antagonist, S 33084 (0.25-2 mg/kg, SC).. These results indicate that reinstatement of non-reinforced responding by non-contingent food delivery and by dopamine agonists probably depend on different mechanisms. The properties of D(2)/D(3) receptor agonists, to reinstate food seeking at larger doses, and to potentiate food-primed response reinstatement at lower doses, are preferentially mediated by D(2) rather than by D(3) receptors.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Amisulpride; Analysis of Variance; Animals; Apomorphine; Benzazepines; Benzopyrans; Conditioning, Operant; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Synergism; Feeding Behavior; Haloperidol; Male; Naphthalenes; Pyrroles; Pyrrolidines; Quinolines; Raclopride; Rats; Rats, Wistar; Receptors, Dopamine D2; Receptors, Dopamine D3; Reinforcement, Psychology; Sulpiride; Tetrahydronaphthalenes

Morphine produces robust increases in locomotor activity in mice. Recent data indicate that dopamine (DA) D2/3 agonists attenuate the discriminative stimulus and antinociceptive effects of mu opioid agonists such as morphine. The present study was designed to determine the extent to which D2/3 receptor activation and blockade can modulate morphine-induced locomotion using a novel cumulative dosing procedure in Swiss-Webster mice. The results indicate that morphine-induced locomotion is nonsignificantly attenuated by the D2/3 agonists quinelorane and quinpirole, whereas the D2/3 antagonists eticlopride and nafadotride, as well as the partial D2/3 agonist BP897, significantly reduced morphine-induced locomotion. To determine the specificity of this modulation, these agonists and antagonists were examined in combination with caffeine, a drug that also indirectly alters DAergic activity. Unlike the effects on morphine, caffeine-induced locomotion was unaltered by eticlopride, nafadotride and BP897, but was attenuated by quinelorane and quinpirole. These results indicate that modulation of D2/3 receptors can, in turn, alter the locomotor-activating effects of morphine.

Topics: Animals; Caffeine; Central Nervous System Stimulants; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Male; Mice; Morphine; Motor Activity; Naphthalenes; Narcotic Antagonists; Narcotics; Pyrrolidines; Quinolines; Quinpirole; Receptors, Dopamine D2; Receptors, Dopamine D3; Salicylamides; Water

The three dopamine agonists with highest reported D3 receptor selectivity in vitro, pramipexole, quinelorane and PD128,907, decreased self-administration of a high dose of cocaine in rats as a result of a leftward shift in the cocaine dose-effect function. In contrast the D3 preferring antagonist nafadotride increased cocaine self-administration. Moreover the relative potencies of these and other D2-like dopamine agonists (lisuride, 7-OH-DPAT, quinpirole, apomorphine, bromocriptine) to modulate cocaine self-administration were highly correlated with their relative potencies for increasing mitogenesis in vitro in cell lines expressing D3 but not D2 receptors. These results support the hypothesis that the D3 receptor may be an important target for pharmacotherapies for cocaine abuse and dependence.

Topics: Animals; Benzopyrans; Benzothiazoles; Cocaine; Dopamine Agonists; Dopamine Antagonists; In Vitro Techniques; Male; Naphthalenes; Opioid-Related Disorders; Oxazines; Pramipexole; Pyrrolidines; Quinolines; Rats; Receptors, Dopamine D2; Receptors, Dopamine D3; Self Administration; Thiazoles

The mechanism by which two D3 receptor-preferring agonists, 7-hydroxydipropylaminotetralin (7-OH-DPAT) and quinelorane, modulate cocaine reinforcement was examined by monitoring nucleus accumbens dopamine levels with in vivo microdialysis while rats intravenously self-administered the following four different drug solutions consecutively: (1) cocaine; (2) a combination of cocaine plus a low dose of either agonist; (3) either agonist alone; and finally, (4) a physiological saline solution. Both 7-OH-DPAT (4 micrograms/infusion) and quinelorane (0.25 microgram/infusion) decreased cocaine (0.25 mg/infusion) intake in a manner indicating an enhancement of cocaine reinforcement and simultaneously decreased the cocaine-induced elevations in nucleus accumbens dopamine levels by > 50%. Subsequent self-administration of either 7-OH-DPAT (4 micrograms/infusion) or quinelorane (0.25 microgram/infusion) alone resulted in significant, but stable, increases in drug intake, with a concurrent decrease in nucleus accumbens dopamine levels to approximately 50% below nondrug baseline levels. These findings indicate that postsynaptic D3 receptor stimulation in the nucleus accumbens enhances the reinforcing properties of cocaine. In a second experiment, local application of 7-OH-DPAT via reverse dialysis (30 and 100 nM perfusate concentrations) dose-dependently decreased nucleus accumbens dopamine efflux to 76 +/- 3.9 and 61 +/- 6.3% of baseline, respectively, whereas there was no effect of this agonist on dopamine efflux in the ipsilateral striatum of these same animals. Coperfusion with the D3 receptor-preferring antagonist nafadotride dose-dependently blocked the effect of 7-OH-DPAT on nucleus accumbens dopamine efflux. These results suggest that, at low concentrations, 7-OH-DPAT selectively activates D3 receptors in vivo.

Topics: Animals; Cocaine; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Male; Microdialysis; Naphthalenes; Neostriatum; Nucleus Accumbens; Pyrrolidines; Quinolines; Rats; Rats, Wistar; Receptors, Dopamine D2; Receptors, Dopamine D3; Self Administration; Tetrahydronaphthalenes