piperidines and eticlopride

Anorexia nervosa (AN) is an eating disorder characterized by severe hypophagia and weight loss, and an intense fear of weight gain. Activity-based anorexia (ABA) refers to the weight loss, hypophagia and paradoxical hyperactivity that develops in rodents exposed to running wheels and restricted food access, and provides a model for aspects of AN. The atypical antipsychotic olanzapine was recently shown to reduce both AN symptoms and ABA. We examined which component of the complex pharmacological profile of olanzapine reduces ABA. Mice received 5-HT(2A/2C), 5-HT3, dopamine D1-like, D2, D3 or D2/3 antagonist treatment, and were assessed for food intake, body weight, wheel running and survival in ABA. D2/3 receptor antagonists eticlopride and amisulpride reduced weight loss and hypophagia, and increased survival during ABA. Furthermore, amisulpride produced larger reductions in weight loss and hypophagia than olanzapine. Treatment with either D3 receptor antagonist SB277011A or D2 receptor antagonist L-741,626 also increased survival. All the other treatments either had no effect or worsened ABA. Overall, selective antagonism of D2 and/or D3 receptors robustly reduces ABA. Studies investigating the mechanisms by which D2 and/or D3 receptors regulate ABA, and the efficacy for D2/3 and/or D3 antagonists to treat AN, are warranted.

Topics: Amisulpride; Animals; Anorexia Nervosa; Benzodiazepines; Disease Models, Animal; Dopamine D2 Receptor Antagonists; Eating; Female; Indoles; Mice; Mice, Inbred BALB C; Motor Activity; Nitriles; Olanzapine; Piperidines; Receptors, Dopamine D3; Salicylamides; Sulpiride; Tetrahydroisoquinolines; Weight Loss

An aspect of nicotine reinforcement that may contribute to tobacco addiction is the effect of nicotine to enhance the motivational properties of reward-associated cues, or conditioned stimuli (CSs). Several studies have now shown that nicotine enhances responding for a stimulus that has been paired with a natural reinforcer. This effect of nicotine to enhance responding for a conditioned reinforcer is likely due to nicotine-induced enhancements in mesolimbic dopaminergic activity, but this has not been directly assessed. In this study, we assessed roles for dopamine (DA) D1 or D2 receptors, and two serotonin (5-HT) receptor subtypes known to modulate DA activity, the 5-HT2C or 5-HT2A subtypes, on nicotine-enhanced responding for a conditioned reinforcer. Water-restricted rats were exposed to Pavlovian conditioning sessions, where a CS was paired with water delivery. Then, in a second phase, animals were required to perform a novel, lever-pressing response for presentations of the CS as a conditioned reinforcer. Nicotine (0.4 mg/kg) enhanced responding for the conditioned reinforcer. To examine potential roles for dopamine (DA) and serotonin (5-HT) receptors in this effect, separate groups of animals were used to assess the impact of administering the D1 receptor antagonist SCH 23390, D2 receptor antagonist eticlopride, 5-HT2C receptor agonist Ro 60-0175, or 5-HT2A receptor antagonist M100907 on nicotine-enhanced responding for conditioned reinforcement. SCH 23390, eticlopride, and Ro 60-0175 all reduced responding for conditioned reinforcement, and the ability of nicotine to enhance this effect. M100907 did not alter this behavior. Together, these studies indicate that DA D1 and D2 receptors, but not 5-HT2A receptors, contribute to the effect of nicotine to enhance responding for a conditioned reinforcer. This effect can also be modulated by 5-HT2C receptor activation.

Topics: Animals; Benzazepines; Conditioning, Classical; Dopamine Antagonists; Ethylamines; Fluorobenzenes; Indoles; Male; Nicotine; Piperidines; Rats, Long-Evans; Reinforcement, Psychology; Salicylamides; Serotonin 5-HT2 Receptor Antagonists

It is well known that amphetamine induces disrupted prepulse inhibition (PPI) in humans and rodents. We have previously reported that intracerebroventricular (i.c.v.) administration of p-hydroxyamphetamine (p-OHA) induces multiple behavioral responses, such as increased locomotor activity and head-twitch response in rodents. To reveal the characteristics of p-OHA on sensorimotor function in rodents, herein we tested the effects of p-OHA on PPI in mice. i.c.v. administration of p-OHA dose-dependently induced PPI disruptions for all prepulse intervals tested. This effect of p-OHA on PPI was attenuated by pretreatment with haloperidol or clozapine. p-OHA-induced PPI disruptions were also attenuated by pretreatment with L-741,626 (a selective D(2) receptor antagonist), L-745,870 (a selective D(4) receptor antagonist) or 6-hydroxydopamine (a neurotoxin which targets DA-containing neurons), but not by SCH 23390 (a selective D(1) receptor antagonist), eticlopride (a D(2)/D(3) receptor antagonist) or GBR 12909 (a DA-reuptake inhibitor). These results indicate that selective blockade of either the D(2) or D(4) receptor subtype may prevent disruption of PPI induced by p-OHA via presynaptic DA release.

Topics: Animals; Benzazepines; Clozapine; Dopamine; Dose-Response Relationship, Drug; Drug Interactions; Haloperidol; Indoles; Injections, Intraventricular; Male; Mice; Mice, Inbred Strains; Oxidopamine; p-Hydroxyamphetamine; Piperazines; Piperidines; Pyridines; Pyrroles; Reflex, Startle; Salicylamides; Sensory Gating; Sympathomimetics; Synaptic Transmission

Cannabinoid CB1 antagonists/inverse agonists suppress food-motivated behaviors and are being evaluated as potential appetite suppressants. It has been suggested that the effects of CB1 antagonism on food motivation could be related to actions on mesolimbic dopamine (DA). If this were true, then the effects of interference with cannabinoid CB1 transmission should closely resemble the effects of interference with DA transmission.. To directly compare the effects of DA antagonists with those of CB1 antagonists/inverse agonists, the present studies employed a concurrent lever-pressing/chow-intake procedure. With this task, interference with DA transmission shifts choice behavior such that lever pressing for a preferred food is decreased but chow intake is increased.. Rats treated with IP injections of the DA D1 antagonist SCH39166 (ecopipam; 0.05-0.2 mg/kg) or the D2 antagonist eticlopride (0.025-0.1 mg/kg) showed substantial decreases in lever pressing and concomitant increases in chow consumption. In contrast, IP administration of the CB1 neutral antagonist AM4113 (4.0-16.0 mg/kg) or the CB1 antagonist/inverse agonist AM251 (2.0-8.0 mg/kg) decreased operant responding for pellets, but there was no corresponding increase in chow intake.. These effects of CB1 antagonists/inverse agonists were similar to those produced by the appetite suppressant fenfluramine and by prefeeding. In contrast, low doses of DA antagonists leave primary food motivation intact, but shift behaviors toward food reinforcers that can be obtained with lower response costs. These results suggest that the effects of interference with CB1 transmission are readily distinguishable from those of reduced DA transmission.

Topics: Animals; Benzazepines; Choice Behavior; Conditioning, Operant; Dopamine Antagonists; Feeding Behavior; Food Preferences; Injections, Intraperitoneal; Male; Motivation; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Reinforcement Schedule; Salicylamides

Dopamine influences the release of neurohypophysial peptides in vivo. However, the extent to which this effect is caused by a direct dopaminergic action within the neurohypophysis remains unclear. With use of the patch-clamp technique on thin slices of rat posterior pituitary glands, we now provide evidence that dopaminergic agonists inhibit potassium current (IK) in neurohypophysial nerve terminals. Superfusion with the dopamine receptor agonist, (+/-)-2-(N-phenylethyl-N-propyl)-amino-5-hydroxytetralin (PPHT), causes a reversible inhibition of whole-terminal IK under voltage clamp. This effect is concentration-dependent, with a maximal inhibition of 40 +/- 5% and an EC50 of 1.8 +/- 1.0 microM. It can be blocked with either a nonselective D2-like antagonist (100 microM eticlopride) or with the highly selective D4 antagonist, RBI-257 (10 microM). U101958 (a derivative of RBI-257) exhibits agonist activity similar to PPHT. Neither SKF 38393 (a D1/D5 agonist) nor quinpirole (a D2/D3 agonist) had any effect on whole-terminal IK in this preparation. Kinetic analysis demonstrated that the amplitude of both the rapidly and slowly inactivating phases of neurohypophysial IK are reduced by D4 receptor activation. These two separate current components have previously been shown to represent current through two distinct potassium channels, an A-current channel and a high-conductance Ca++-activated K+ channel. Thus, both channel types can be modulated by D4 receptors. This effect is likely to enhance the release of neurohypophysial peptides in vivo.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Aminopyridines; Animals; Dopamine Agonists; Dopamine Antagonists; Electric Conductivity; Female; Kinetics; Male; Membrane Potentials; Nerve Endings; Patch-Clamp Techniques; Phenethylamines; Piperidines; Pituitary Gland, Posterior; Potassium; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Dopamine D4; Salicylamides

The function of striatopallidal neurons is regulated by N-methyl-D-aspartate (NMDA) and dopamine D2 receptors. Previous studies show that immediate early gene induction by D2 receptor blockade is suppressed by NMDA receptor antagonists. Because the pharmacology of NMDA receptors depends on the incorporation of different NR2 subunits and NR2 subunits show regional and cellular differences in their expression in striatum, our study examined whether different NMDA receptor antagonists would have differential effects on eticlopride-induced immediate early gene expression in striatum. Male Sprague-Dawley rats were pretreated with vehicle, CGS 19755, MK-801 or ifenprodil. Rats then received injections of eticlopride and were killed 40 min later. In situ hybridization histochemistry was used to determine the expression of c-fos and zif268 in the striatum. Eticlopride increased immediate early gene expression in striatum, with the increase generally being greater in lateral than in medial striatum. Pretreatment with each of the NMDA receptor antagonists dose-dependently decreased the expression of the immediate early genes. This suppression of eticlopride-induced gene expression was significant only in the medial-central aspect of striatum. Although there was a trend toward suppression of the gene induction in lateral striatum, it did not reach statistical significance and was not typically dose dependent. The data suggest that different types of NMDA receptor antagonists do not exert differential effects on D2 dopamine receptor-mediated function in the striatum. In addition, the data indicate that eticlopride-induced gene expression in the striatum is not uniformly dependent on NMDA receptor activation.

Topics: Animals; Corpus Striatum; Dizocilpine Maleate; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Gene Expression; Genes, Immediate-Early; Male; Pipecolic Acids; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Salicylamides

We tested whether D2 ligands inhibit basal and forskolin-stimulated [3H]ACh release from dissociated striata, as opposed to striatal slices. Quinpirole inhibited both basal (40% maximal inhibition; IC50 approximately 50 nM) and 10 microM forskolin-stimulated release (80% inhibition; IC50 approximately 25 nM quinpirole) and both actions were blocked by a D2 antagonist. Vesamicol prevented the quinpirole and forskolin actions. The ability of D2 agonists to inhibit basal and cyclase-stimulated acetylcholine release emanating from vesamicol-sensitive vesicles appears to be tonically suppressed by inhibitory elements within striatal circuitry.

Topics: Acetylcholine; Adenylyl Cyclases; Animals; Colforsin; Dopamine Agonists; Dopamine Antagonists; In Vitro Techniques; Interneurons; Male; Neostriatum; Neuromuscular Depolarizing Agents; Parasympathetic Nervous System; Piperidines; Quinpirole; Rats; Receptors, Dopamine D2; Salicylamides

Previous studies of radiolabeled vesamicol receptor (VR) ligands suggest that the latter may be used in conjunction with dopamine D2 antagonists to measure changes in striatal cholinergic function. In this study, the effects of aging on vesicular acetylcholine storage/release were investigated with the high-affinity VR ligand (+)-meta-[125I)iodobenzyltrozamicol [(+)-[125I]MIBT].. Male Fischer 344 rats (aged 3 and 24 mo) were injected either with a vehicle or a D2 antagonist [haloperidol or S-(-)-eticlopride]. At prescribed intervals thereafter, all animals were intravenously injected with 10 microCi of (+)-[125I]MIBT. Three hours after radiotracer injection, the animals were killed and their brains dissected. The concentration of radiotracer in the striatum, cortex and cerebellum were then determined.. In control animals, comparable levels of (+)-[125I]MIBT were observed in corresponding brain regions of young adult and aged Fischer 344 rats. Moreover, in haloperidol- and S-(-)-eticlopride-treated young adult rats, striatal levels of (+)-[125I]MIBT were elevated by 35% and 66%, respectively, relative to controls. In contrast, haloperidol treatment failed to alter the striatal levels of (+)-[125I]MIBT in aged rats while S-(-)-eticlopride displayed a twofold reduction in potency in aged rats.. Aging is associated with a reduction in striatal cholinergic plasticity or striatal cholinergic reserve and that the D2-stimulated increase in VR ligand binding is a functionally relevant parameter.

Topics: Aging; Animals; Brain; Dopamine Antagonists; Haloperidol; Iodine Radioisotopes; Iodobenzenes; Male; Piperidines; Radionuclide Imaging; Rats; Rats, Inbred F344; Rats, Wistar; Receptors, Cholinergic; Salicylamides; Time Factors