l-745870 and eticlopride

In animal models of retinitis pigmentosa the dopaminergic system in the retina appears to be dysfunctional, which may contribute to the debilitated sight experienced by retinitis pigmentosa patients. Since dopamine D2-like receptors are known to modulate the activity of dopaminergic neurons, I examined the effects of dopamine D2-like receptor antagonists on the light responses of retinal ganglion cells (RGCs) in the P23H rat model of retinitis pigmentosa. Extracellular electrical recordings were made from RGCs in isolated transgenic P23H rat retinas and wild-type Sprague-Dawley rat retinas. Intensity-response curves to flashes of light were evaluated prior to and during bath application of a dopamine D2-like receptor antagonist. The dopamine D2/D3 receptor antagonists sulpiride and eticlopride and the D4 receptor antagonist L-745,870 increased light sensitivity of P23H rat RGCs but decreased light sensitivity in Sprague-Dawley rat RGCs. In addition, L-745,870, but not sulpiride or eticlopride, reduced the maximum peak responses of Sprague-Dawley rat RGCs. I describe for the first time ON-center RGCs in P23H rats that exhibit an abnormally long-latency (>200 ms) response to the onset of a small spot of light. Both sulpiride and eticlopride, but not L-745,870, reduced this ON response and brought out a short-latency OFF response, suggesting that these cells are in actuality OFF-center cells. Overall, the results show that the altered dopaminergic system in degenerate retinas contributes to the deteriorated light responses of RGCs.

Topics: Action Potentials; Animals; Disease Models, Animal; Dopamine D2 Receptor Antagonists; Light; Pyridines; Pyrroles; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Retinal Ganglion Cells; Retinitis Pigmentosa; Salicylamides; Sulpiride

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

Psychopharmacological studies have implicated the mesolimbic dopamine (DA) system in the mediation of cost/benefit evaluations about delay or effort-related costs associated with larger rewards. However, the role of DA in risk-based decision making remains relatively unexplored. The present study investigated the effects of systemic manipulations of DA transmission on risky choice using a probabilistic discounting task. Over discrete trials, rats chose between two levers; a press on the 'small/certain' lever always delivered one reward pellet, whereas a press on the other, 'large/risky' lever delivered four pellets, but the probability of receiving reward decreased across the four trial blocks (100, 50, 25, 12.5%). In separate groups of well-trained rats we assessed the effects of the DA releaser amphetamine, as well as receptor selective agonists and antagonists. Amphetamine consistently increased preference for the large/risky lever; an effect that was blocked or attenuated by co-administration of either D(1) (SCH23390) or D(2) (eticlopride) receptor antagonists. Blockade of either of these receptors alone induced risk aversion. Conversely, stimulation of D(1) (SKF81297) or D(2) (bromocriptine) receptors also increased risky choice. In contrast, activation of D(3) receptors with PD128,907 reduced choice of the large/risky lever. Likewise, D(3) antagonism with nafadotride potentiated the amphetamine-induced increase in risky choice. Blockade or stimulation of D(4) receptors did not reliably alter behavior. These findings indicate that DA has a critical role in mediating risk-based decision making, with increased activation of D(1) and D(2) receptors biasing choice toward larger, probabilistic rewards, whereas D(3) receptors appear to exert opposing effects on this form of decision making.

Topics: Animals; Behavior, Animal; Benzamides; Benzazepines; Benzopyrans; Bromocriptine; Conditioning, Operant; Decision Making; Dextroamphetamine; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Naphthalenes; Oxazines; Piperazines; Pyridines; Pyrroles; Pyrrolidines; Rats; Rats, Long-Evans; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Dopamine D4; Reinforcement Schedule; Risk; Salicylamides